Amoxicillin/Clavulanate potassium

Description

Amoxicillin and clavulanate potassium tablets are an oral antibacterial combination that includes the semisynthetic antibiotic amoxicillin and the β-lactamase inhibitor clavulanate potassium, which is 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.

In addition, infections caused by ampicillin-susceptible organisms are also amenable to treatment with amoxicillin and clavulanate potassium tablets due to their amoxicillin content.

No teratogenic or nonteratogenic effects have been reported.

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 of 250 mg/125 mg every 8 hours. For more severe infections, particularly those affecting the respiratory tract, the recommended dosage is one tablet of 875 mg/125 mg every 12 hours, or one tablet of 500 mg/125 mg every 8 hours.

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

Patients undergoing hemodialysis should receive either 500 mg/125 mg or 250 mg/125 mg every 24 hours, with an additional dose administered during and at the end of dialysis, based on the severity of the infection. For patients with hepatic impairment, dosing should be approached with caution, and hepatic function should be monitored at regular intervals.

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 prescribed until the pediatric patient reaches a weight of 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 administered at the start of a meal. To minimize gastrointestinal intolerance, taking the tablets 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, the administration of ampicillin-class antibiotics, including amoxicillin and clavulanate potassium, is contraindicated in 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 severe reactions in patients with a history of penicillin hypersensitivity who were treated with cephalosporins. Prior to initiating therapy with amoxicillin and clavulanate potassium, a thorough inquiry regarding 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, as treatment with antibacterial agents disrupts the normal flora of the colon, leading to C. difficile overgrowth. C. difficile produces toxins A and B, which are implicated in the development of CDAD. Hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality, as these infections may be refractory to antimicrobial therapy and could necessitate colectomy. CDAD should be considered in all patients presenting with diarrhea following antibiotic use, and careful medical history is warranted, as CDAD can occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Management should include appropriate fluid and electrolyte replacement, protein supplementation, antibiotic treatment for C. difficile, and surgical evaluation as clinically indicated.

Amoxicillin and clavulanate potassium should be used with caution in patients exhibiting evidence of hepatic dysfunction. While hepatic toxicity associated with this medication is generally reversible, rare cases of death have been reported (less than one death per estimated four million prescriptions worldwide), typically in patients with serious underlying conditions or those taking concomitant medications.

Although amoxicillin and clavulanate potassium are characterized by low toxicity typical of the penicillin group of antibiotics, periodic assessment of organ system functions—including renal, hepatic, and hematopoietic function—is advisable during prolonged therapy. It is important to note that a significant percentage of patients with mononucleosis who receive ampicillin develop an erythematous skin rash; therefore, ampicillin-class antibiotics should not be administered to these patients.

Healthcare professionals should remain vigilant for the possibility of superinfections with mycotic or bacterial pathogens during therapy. If superinfections occur, typically involving Pseudomonas or Candida, the drug should be discontinued, and appropriate therapy should be initiated.

Prescribing amoxicillin and clavulanate potassium tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to benefit the patient and may increase the risk of developing drug-resistant bacteria.

Periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is recommended during prolonged therapy to ensure patient safety.

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, with onset potentially occurring during or after antibiotic treatment.

Hypersensitivity reactions have been reported, including skin rashes, pruritus, urticaria, angioedema, and serum sickness-like reactions characterized by urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever. Rare but serious hypersensitivity reactions such as erythema multiforme, acute generalized exanthematous pustulosis, hypersensitivity vasculitis, exfoliative dermatitis (including toxic epidermal necrolysis), and anaphylactic reactions have also been documented.

Liver-related adverse reactions may manifest as a moderate rise in AST (SGOT) and/or ALT (SGPT), hepatic dysfunction (including hepatitis and cholestatic jaundice), and increases in serum transaminases, serum bilirubin, and/or alkaline phosphatase. Severe hepatic dysfunction, which is usually reversible, has been reported, along with rare instances of death associated with hepatic dysfunction.

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

Hemic and lymphatic system-related adverse reactions 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.

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

Miscellaneous adverse reactions include tooth discoloration (brown, yellow, or gray staining), which has been rarely reported, primarily in pediatric patients.

Drug Interactions

Probenecid has been shown to decrease the renal tubular secretion of amoxicillin. When amoxicillin and clavulanate potassium are administered concurrently with probenecid, there may be an increase in blood levels of amoxicillin, leading to prolonged exposure. Therefore, coadministration of probenecid with amoxicillin and clavulanate potassium is not recommended.

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

Amoxicillin and clavulanate potassium, like other broad-spectrum antibiotics, may reduce the efficacy of oral contraceptives. Patients using oral contraceptives should be advised to consider alternative or additional contraceptive measures during treatment.

Oral administration of amoxicillin and clavulanate potassium results in high urine concentrations of amoxicillin. This can lead to false-positive results when testing for glucose in urine using CLINITEST®, Benedict’s Solution, or Fehling’s Solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions, such as CLINISTIX®, be utilized to avoid this issue.

In pregnant women, administration of ampicillin has been associated with a transient decrease in plasma concentrations of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol. This effect may also be observed with amoxicillin and amoxicillin and clavulanate potassium. Monitoring of hormone levels may be warranted in pregnant patients receiving these medications.

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 through 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.

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 human milk. Caution should be exercised when administering this medication to lactating mothers due to the potential for exposure to breastfed infants. Healthcare professionals should consider the benefits of breastfeeding alongside the risks associated with the presence of the drug in breast milk when making treatment decisions.

Renal Impairment

Patients with renal impairment should use amoxicillin and clavulanate potassium with caution, particularly in the presence of hepatic dysfunction. Monitoring of renal function is recommended to ensure appropriate dosing adjustments and to mitigate potential risks associated with reduced kidney function.

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, deaths have been reported in patients receiving amoxicillin and clavulanate potassium, with less than one death reported per estimated four million prescriptions worldwide. These cases have generally occurred in individuals with serious underlying diseases or those taking concomitant medications that may contribute to hepatic impairment. Therefore, careful consideration of the patient's overall health status and concurrent therapies is advised when prescribing this medication to individuals with compromised liver function.

Overdosage

In cases of overdosage, patients have predominantly exhibited gastrointestinal symptoms, which include stomach and abdominal pain, vomiting, and diarrhea. Additionally, a small subset of patients has reported symptoms such as rash, hyperactivity, or drowsiness.

Upon suspicion of 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.

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

Renal impairment observed in these cases 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 the drug due to decreased renal clearance of both amoxicillin and clavulanate. Both compounds can be effectively removed from the circulation through hemodialysis.

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 assays, including in vitro tests such as the Ames test, a human lymphocyte cytogenetic assay, a yeast test, and a mouse lymphoma forward mutation assay, as well as in vivo assessments including 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 amoxicillin and clavulanate potassium. The severity of CDAD can range from mild diarrhea to fatal colitis, as treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile. This bacterium produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality, as these infections may be refractory to antimicrobial therapy and could necessitate colectomy. CDAD should be considered in all patients presenting with diarrhea following antibiotic use, and careful medical history is essential, as cases have been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued, and appropriate management should be instituted.

Hepatic dysfunction, including hepatitis and cholestatic jaundice, as well as increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been infrequently reported. These events have been more commonly observed in elderly patients, males, or those undergoing prolonged treatment. Histologic findings on liver biopsy have shown predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of hepatic dysfunction may occur during therapy or several weeks after discontinuation. While the dysfunction can be severe, it is usually reversible. Rarely, deaths have been reported, typically in patients with serious underlying diseases or those on concomitant medications.

Interstitial nephritis and hematuria have been reported rarely, along with crystalluria. Hematologic reactions, including anemia (hemolytic anemia), thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis, have also been noted during therapy with penicillins. These reactions are generally reversible upon discontinuation of therapy and are believed to be hypersensitivity phenomena.

Neuropsychiatric events such as agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported rarely. Additionally, tooth discoloration (brown, yellow, or gray staining) has been infrequently observed, 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 them unresponsive to amoxicillin and clavulanate potassium tablets or other antibacterial drugs in the future.

Patients should also be made aware that diarrhea is a frequent side effect associated with antibiotic use, which typically resolves upon discontinuation of the medication. Furthermore, they should be informed that it is possible to experience watery and bloody stools, with or without accompanying stomach cramps and fever, even as late as two months after completing the antibiotic course. In such cases, patients should be instructed to contact their physician promptly.

Storage and Handling

The product is supplied in a tight, light-resistant container that meets the specifications outlined in the United States Pharmacopeia (USP), and it includes a child-resistant closure as required.

Storage conditions must be maintained at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. It is recommended that patients keep the product in a closed container to ensure 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 H. J. Harkins Company, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)