Amoxicillin/Clavulanate potassium

Description

Amoxicillin and clavulanate potassium tablets USP are an oral antibacterial combination comprising the semisynthetic antibiotic amoxicillin and the β-lactamase inhibitor clavulanate potassium, the potassium salt of clavulanic acid. Amoxicillin, an analog of ampicillin, is derived from the basic penicillin nucleus, 6-aminopenicillanic acid. Its chemical structure is represented as (2S, 5R, 6R)-6-((R)-(-)-2-Amino-2-(p-hydroxyphenyl)acetamido-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo3.2.0heptane-2-carboxylic acid trihydrate, with a molecular weight of 419.46 and a structural formula of C₁₆H₁₉N₃O₅S•3H₂O.

Clavulanic acid, produced by the fermentation of Streptomyces clavuligerus, is a β-lactam that is structurally related to penicillins. It effectively inactivates a wide variety of β-lactamases by blocking their active sites, particularly those that are plasmid-mediated and responsible for drug resistance to penicillins and cephalosporins. The chemical structure of clavulanate potassium is potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo3.2.0-heptane-2-carboxylate, with a molecular weight of 237.25 and a structural formula of C₈H₈KNO₅.

Each tablet contains either 500 mg or 875 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid as the potassium salt. Additionally, each tablet provides 0.63 mEq of potassium.

Uses and Indications

Amoxicillin and clavulanate potassium tablets are indicated for the treatment of infections caused by susceptible strains of designated organisms in the following conditions:

Lower Respiratory Tract Infections This drug is indicated for infections caused by β-lactamase-producing strains of Haemophilus influenzae and Moraxella catarrhalis.

Otitis Media This drug is indicated for otitis media caused by β-lactamase-producing strains of Haemophilus influenzae and Moraxella catarrhalis.

Sinusitis This drug is indicated for sinusitis caused by β-lactamase-producing strains of Haemophilus influenzae and Moraxella catarrhalis.

Skin and Skin Structure Infections This drug is indicated for skin and skin structure infections caused by β-lactamase-producing strains of Staphylococcus aureus, Escherichia coli, and Klebsiella spp.

Urinary Tract Infections This drug is indicated for urinary tract infections caused by β-lactamase-producing strains of Escherichia coli, Klebsiella spp., and Enterobacter spp.

Infections caused by ampicillin-susceptible organisms are also amenable to treatment with amoxicillin and clavulanate potassium tablets due to their amoxicillin content. Therefore, mixed infections caused by ampicillin-susceptible organisms and β-lactamase-producing organisms susceptible to amoxicillin and clavulanate potassium do not require the addition of another antibiotic. The majority of Streptococcus pneumoniae strains with intermediate susceptibility to ampicillin or penicillin are fully susceptible to amoxicillin and amoxicillin and clavulanate potassium.

No teratogenic or nonteratogenic effects have been mentioned.

Dosage and Administration

The usual dosage for adults is one amoxicillin and clavulanate potassium tablet USP, 500 mg/125 mg administered every 12 hours, or one tablet USP, 250 mg/125 mg every 8 hours. For more severe infections, including those of the respiratory tract, the recommended dosage is one amoxicillin and clavulanate potassium tablet USP, 875 mg/125 mg every 12 hours, or one tablet USP, 500 mg/125 mg every 8 hours.

In patients with impaired renal function, dosing adjustments are necessary. For those with a glomerular filtration rate (GFR) less than 30 mL/min, amoxicillin and clavulanate potassium tablets USP, 875 mg/125 mg should not be administered. Patients with a GFR between 10 to 30 mL/min may receive either amoxicillin and clavulanate potassium tablets USP, 500 mg/125 mg or 250 mg/125 mg every 12 hours, depending on the severity of the infection. For patients with a GFR less than 10 mL/min, the recommended dosage is either 500 mg/125 mg or 250 mg/125 mg every 24 hours, again based on the severity of the infection. Hemodialysis patients should receive amoxicillin and clavulanate potassium tablets USP, 500 mg/125 mg or 250 mg/125 mg every 24 hours, with an additional dose during and at the end of dialysis, depending on the severity of the infection.

For pediatric patients weighing 40 kg or more, dosing should follow the adult recommendations. Amoxicillin and clavulanate potassium tablets USP, 250 mg/125 mg should not be administered until the pediatric patient weighs at least 40 kg.

Amoxicillin and clavulanate potassium tablets USP may be taken without regard to meals; however, to enhance the absorption of clavulanate potassium, it is recommended that the tablets be taken at the start of a meal. To minimize gastrointestinal intolerance, administration at the beginning of a meal is advised.

Contraindications

Amoxicillin and clavulanate potassium is contraindicated in patients with a history of allergic reactions to any penicillin, due to the potential for severe hypersensitivity reactions. Additionally, it is contraindicated in individuals with a previous history of cholestatic jaundice or hepatic dysfunction associated with the use of amoxicillin and clavulanate potassium, as this may exacerbate liver-related complications.

Furthermore, ampicillin-class antibiotics should not be administered to patients with mononucleosis, as this may increase the risk of rash and other adverse effects.

Warnings and Precautions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients undergoing penicillin therapy. These reactions are particularly likely to occur in individuals with a history of penicillin hypersensitivity and/or sensitivity to multiple allergens. Notably, there have been instances of individuals with a history of penicillin hypersensitivity experiencing severe reactions when treated with cephalosporins. Prior to initiating therapy with amoxicillin and clavulanate potassium, a thorough inquiry regarding any previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens is essential. Should an allergic reaction occur, amoxicillin and clavulanate potassium must be discontinued immediately, and appropriate therapeutic measures should be instituted.

In cases of serious anaphylactic reactions, immediate emergency treatment with epinephrine is required. Additional interventions may include the administration of oxygen, intravenous steroids, and airway management, including intubation, as clinically indicated.

Clostridium difficile-associated diarrhea (CDAD) has been reported with the use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium. The severity of CDAD can range from mild diarrhea to fatal colitis. It is crucial to consider CDAD in all patients presenting with diarrhea following antibiotic use, as it has been documented to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic therapy not directed against C. difficile may need to be discontinued. Clinicians should ensure appropriate management, including fluid and electrolyte replacement, protein supplementation, antibiotic treatment for C. difficile, and surgical evaluation as necessary.

Amoxicillin and clavulanate potassium should be used with caution in patients exhibiting signs of hepatic dysfunction. While hepatic toxicity associated with this medication is generally reversible, there have been rare reports of fatalities (less than one death per estimated four million prescriptions worldwide).

Despite the low toxicity profile characteristic of the penicillin class of antibiotics, periodic assessment of organ system functions—including renal, hepatic, and hematopoietic function—is advisable during prolonged therapy with amoxicillin and clavulanate potassium.

Prescribing amoxicillin and clavulanate potassium tablets in the absence of a proven or strongly suspected bacterial infection, or without a prophylactic indication, is unlikely to benefit the patient and may increase the risk of developing drug-resistant bacteria.

Side Effects

Common adverse reactions observed in clinical trials include diarrhea or loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%), and vaginitis (1%).

Gastrointestinal adverse reactions may include diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic or pseudomembranous colitis. The onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment.

Hypersensitivity reactions can manifest as skin rashes, pruritus, urticaria, angioedema, and serum sickness-like reactions, which may include urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever. Rarely, erythema multiforme, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and exfoliative dermatitis (including toxic epidermal necrolysis) have been reported. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have also been documented.

Liver-related adverse reactions may include a moderate rise in AST (SGOT) and/or ALT (SGPT), hepatic dysfunction (including hepatitis and cholestatic jaundice), and increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase. Severe hepatic dysfunction, usually reversible, has been reported, along with rare instances of deaths associated with serious underlying diseases or concomitant medications.

Renal adverse reactions are rare and may include interstitial nephritis, hematuria, and crystalluria.

Hemic and lymphatic system reactions can include anemia (including hemolytic anemia), thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, agranulocytosis, slight thrombocytosis (less than 1%), and increased prothrombin time in patients receiving anticoagulant therapy concomitantly.

Central nervous system reactions are rare and may present as agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity.

Miscellaneous adverse reactions include tooth discoloration (brown, yellow, or gray staining), which is rare and primarily observed in pediatric patients.

Warnings include the potential for serious and occasionally fatal hypersensitivity (anaphylactic) reactions in patients undergoing penicillin therapy. Additionally, Clostridium difficile-associated diarrhea (CDAD) has been reported with the use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium, with severity ranging from mild diarrhea to fatal colitis.

Drug Interactions

Probenecid has been shown to decrease the renal tubular secretion of amoxicillin. When amoxicillin is coadministered with clavulanate potassium, this interaction may lead to increased and prolonged blood levels of amoxicillin. Therefore, the concurrent use of probenecid with amoxicillin and clavulanate potassium is not recommended.

In patients receiving amoxicillin alongside oral anticoagulants, there have been rare reports of abnormal prolongation of prothrombin time, indicated by an increased international normalized ratio (INR). It is advised that appropriate monitoring of INR levels be conducted when these medications are prescribed together. Adjustments to the dosage of oral anticoagulants may be necessary to maintain the desired anticoagulation effect.

The combination of allopurinol and ampicillin has been associated with a significantly higher incidence of rashes compared to patients receiving ampicillin alone. While it remains unclear whether this increased incidence is attributable to allopurinol or the hyperuricemia present in these patients, caution is warranted. There is currently no data available regarding the concurrent administration of allopurinol with amoxicillin and clavulanate potassium.

Similar to other broad-spectrum antibiotics, amoxicillin and clavulanate potassium may diminish the effectiveness of oral contraceptives. Patients should be advised to consider alternative or additional contraceptive measures while on this antibiotic regimen.

Regarding laboratory test interactions, the oral administration of amoxicillin and clavulanate potassium can lead to high urine concentrations of amoxicillin. This may result in false-positive results for glucose when using tests such as CLINITEST®, Benedict’s Solution, or Fehling’s Solution. It is recommended that glucose testing utilize enzymatic glucose oxidase reactions, such as CLINISTIX®, to avoid this issue.

Additionally, following the administration of ampicillin to pregnant women, a transient decrease in plasma concentrations of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been observed. This effect may also be applicable to amoxicillin and amoxicillin with clavulanate potassium.

Packaging & NDC

The table below lists all NDC Code configurations of Amoxicillin and Clavulanate Potassium, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations. However, the safety and effectiveness of amoxicillin and clavulanate potassium tablets in pediatric patients weighing less than 40 kg have not been established. Caution is advised when considering the use of this medication in this population.

Geriatric Use

An analysis of clinical studies involving amoxicillin and clavulanate potassium included subjects aged 65 years and older to assess potential differences in response compared to younger patients. Among the 3,119 patients analyzed, 68% were younger than 65 years, while 32% were aged 65 years and older, including 14% who were 75 years and older. The findings from this analysis, along with additional clinical experience, did not reveal significant differences in responses between elderly patients and their younger counterparts. However, it is important to note that a greater sensitivity to the drug in some older individuals cannot be excluded.

Amoxicillin and clavulanate potassium is primarily excreted via the kidneys, which raises concerns regarding the risk of toxic reactions, particularly in patients with impaired renal function. Given that elderly patients are more likely to experience decreased renal function, careful consideration should be given to dose selection in this population. It is advisable to monitor renal function in geriatric patients to mitigate the risk of adverse effects and ensure appropriate dosing.

Pregnancy

Pregnancy category B indicates that reproduction studies conducted in pregnant rats and mice administered amoxicillin and clavulanate potassium at oral dosages up to 1,200 mg/kg/day—equivalent to 7,200 and 4,080 mg/m²/day, respectively—showed no evidence of harm to the fetus. These dosages represent 4.9 and 2.8 times the maximum human oral dose based on body surface area. However, there are no adequate and well-controlled studies in pregnant women to confirm the safety of this drug during pregnancy.

Due to the limitations of animal reproduction studies in predicting human response, amoxicillin and clavulanate potassium should be used during pregnancy only if clearly needed. Healthcare professionals are advised to weigh the potential benefits against any possible risks when considering this medication for pregnant patients.

Lactation

Ampicillin-class antibiotics, including amoxicillin and clavulanate potassium, are excreted in breast milk. Therefore, caution should be exercised when administering this medication to lactating mothers. The potential effects on breastfed infants have not been fully established, and healthcare professionals should consider the benefits of breastfeeding alongside the risks of exposure to the medication.

Renal Impairment

Patients with renal impairment should be monitored closely when receiving amoxicillin and clavulanate potassium. Caution is advised in this population, particularly in those with evidence of hepatic dysfunction. Dosing adjustments may be necessary based on the degree of renal impairment to ensure safety and efficacy. Regular assessment of renal function is recommended to guide appropriate dosing and minimize the risk of adverse effects.

Hepatic Impairment

Amoxicillin and clavulanate potassium should be used with caution in patients with evidence of hepatic dysfunction. While hepatic toxicity associated with the use of this medication is usually reversible, it is important to monitor liver function closely in these patients.

In rare instances, fatalities have been reported, with less than one death occurring per an estimated four million prescriptions worldwide. These cases have generally involved patients with serious underlying diseases or those taking concomitant medications that may contribute to hepatic impairment. Therefore, careful consideration and monitoring are advised when prescribing amoxicillin and clavulanate potassium to individuals with compromised liver function.

Overdosage

Following an overdosage of amoxicillin and clavulanate potassium, patients have primarily exhibited gastrointestinal symptoms, which include stomach and abdominal pain, vomiting, and diarrhea. In a minority of cases, additional symptoms such as rash, hyperactivity, or drowsiness have been reported.

Management of Overdosage In the event of an overdosage, it is imperative to discontinue the administration of amoxicillin and clavulanate potassium. Symptomatic treatment should be initiated, and supportive measures should be implemented as necessary. If the overdosage has occurred recently and there are no contraindications, healthcare professionals may consider inducing emesis or employing other methods to remove the drug from the stomach. A prospective study involving 51 pediatric patients at a poison center indicated that overdosages of less than 250 mg/kg of amoxicillin are generally not associated with significant clinical symptoms and do not necessitate gastric emptying.

Potential Complications There have been reports of interstitial nephritis leading to oliguric renal failure in a small number of patients following overdosage with amoxicillin. Additionally, crystalluria, which in some instances has resulted in renal failure, has been documented in both adult and pediatric patients. To mitigate the risk of crystalluria, it is essential to maintain adequate fluid intake and diuresis during the management of overdosage.

Renal Considerations Renal impairment observed in the context of overdosage appears to be reversible upon cessation of the drug. It is important to note that patients with impaired renal function may experience higher blood levels of amoxicillin and clavulanate due to decreased renal clearance. Both amoxicillin and clavulanate can be effectively removed from the circulation through hemodialysis, which may be considered in cases of significant overdosage.

Nonclinical Toxicology

Reproduction studies conducted in pregnant rats and mice administered amoxicillin and clavulanate potassium at oral dosages up to 1,200 mg/kg/day, which corresponds to 7,200 and 4,080 mg/m²/day respectively (4.9 and 2.8 times the maximum human oral dose based on body surface area), demonstrated no evidence of teratogenic effects on the fetus. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human outcomes, the use of this drug during pregnancy should be considered only when clearly necessary.

In terms of non-teratogenic effects, amoxicillin and clavulanate potassium administered at oral doses of up to 1,200 mg/kg/day (5.7 times the maximum human dose, 1,480 mg/m²/day, based on body surface area) did not adversely affect fertility or reproductive performance in rats treated with a 2:1 ratio formulation of amoxicillin to clavulanate.

Long-term studies in animals have not been conducted to assess the carcinogenic potential of amoxicillin and clavulanate potassium.

The mutagenic potential of amoxicillin and clavulanate potassium was evaluated through various in vitro assays, including the Ames test, a human lymphocyte cytogenetic assay, a yeast test, and a mouse lymphoma forward mutation assay, as well as in vivo assessments using mouse micronucleus tests and a dominant lethal test. All tests returned negative results, except for the in vitro mouse lymphoma assay, which indicated weak activity at very high, cytotoxic concentrations.

Postmarketing Experience

Postmarketing experience has identified several adverse events associated with the use of amoxicillin and clavulanate potassium. Clostridium difficile associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including this combination, and may vary in severity from mild diarrhea to fatal colitis. The alteration of normal colonic flora due to antibacterial treatment can lead to an overgrowth of C. difficile.

Hepatic dysfunction, which may be severe but is usually reversible, has been noted. Rare cases of death have been reported, with an estimated incidence of less than one death per 4 million prescriptions worldwide, typically in patients with serious underlying conditions or those taking concomitant medications. A moderate increase in AST (SGOT) and/or ALT (SGPT) levels has been observed in patients treated with ampicillin-class antibiotics; however, the clinical significance of these findings remains unclear. Infrequent reports of hepatic dysfunction, including hepatitis and cholestatic jaundice, as well as increases in serum transaminases, bilirubin, and alkaline phosphatase, have also been documented.

Rare occurrences of interstitial nephritis and hematuria have been reported, along with crystalluria. Hematological reactions such as anemia (including hemolytic anemia), thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been associated with penicillin therapy. These reactions are generally reversible upon discontinuation of the medication and are thought to be hypersensitivity phenomena.

Neuropsychiatric events, including agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity, have been reported infrequently. Additionally, tooth discoloration (brown, yellow, or gray staining) has been noted, primarily in pediatric patients, with most cases showing improvement or resolution following dental cleaning or brushing.

Patient Counseling

Patients should be counseled that antibacterial drugs, including amoxicillin and clavulanate potassium tablets, are indicated solely for the treatment of bacterial infections and are ineffective against viral infections, such as the common cold.

When prescribed amoxicillin and clavulanate potassium tablets for a bacterial infection, patients should be informed that it is common to feel improvement early in the treatment course; however, it is crucial to take the medication exactly as directed. Patients must be advised that skipping doses or failing to complete the full course of therapy may lead to decreased effectiveness of the treatment and increase the risk of bacteria developing resistance, rendering amoxicillin and clavulanate potassium tablets or other antibacterial drugs ineffective in the future.

Additionally, patients should be made aware that diarrhea is a frequent side effect associated with antibiotic use, typically resolving upon discontinuation of the medication. They should be instructed to monitor for the development of watery and bloody stools, which may occur even two months after completing the antibiotic course, and to contact their physician immediately if such symptoms arise, especially if accompanied by stomach cramps and fever.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and includes a child-resistant closure as required. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Patients are advised to keep the product in a closed container to maintain its integrity and effectiveness.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Amoxicillin and Clavulanate Potassium as submitted by Aidarex Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)