Amoxicillin/Clavulanate potassium

Description

Amoxicillin and Clavulanate Potassium Tablet USP is an oral antibacterial combination that includes 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, with a molecular formula of C₁₆H₁₉N₃O₅S·3H₂O and a molecular weight of 419.46 g/mol. Its chemical structure is defined 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.

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 plasmid-mediated β-lactamases that confer resistance to penicillins and cephalosporins. The molecular formula for clavulanate potassium is C₈H₈KNO₅, with a molecular weight of 237.25 g/mol, and its chemical structure is potassium (Z)-(2R, 5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo3.2.0-heptane-2-carboxylate.

Each film-coated tablet is available in two strengths: 500 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid as the potassium salt, or 875 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid as the potassium salt. Additionally, each tablet contains 0.63 mEq of potassium. Inactive ingredients include colloidal silicon dioxide, croscarmellose sodium (dried), crospovidone (dried), ethylcellulose, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose (dried), polysorbate 80, talc, titanium dioxide, and triethyl citrate.

Uses and Indications

Amoxicillin/clavulanate potassium is 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 Amoxicillin/clavulanate potassium is indicated for the treatment of 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 Amoxicillin/clavulanate potassium 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/clavulanate potassium due to its amoxicillin content. Therefore, mixed infections caused by ampicillin-susceptible organisms and β-lactamase-producing organisms susceptible to amoxicillin/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/clavulanate potassium.

No teratogenic or nonteratogenic effects have been mentioned.

Dosage and Administration

The usual adult dosage of Amoxicillin and Clavulanate Potassium is one tablet containing 500 mg of amoxicillin (as the trihydrate) and 125 mg of clavulanic acid (as clavulanate potassium) administered every 12 hours, or one tablet containing 250 mg of amoxicillin and 125 mg of clavulanate potassium taken every 8 hours. For more severe infections, particularly those affecting the respiratory tract, the recommended dosage is one tablet containing 875 mg of amoxicillin and 125 mg of clavulanate potassium every 12 hours, or one tablet containing 500 mg of amoxicillin and 125 mg of clavulanate potassium every 8 hours.

In patients with impaired renal function, specific dosing adjustments are necessary. For patients with a glomerular filtration rate (GFR) of less than 30 mL/minute, the 875 mg tablet is contraindicated. Patients with a GFR of 10 to 30 mL/minute may receive either 500 mg/125 mg or 250 mg/125 mg every 12 hours, depending on the severity of the infection. For those with a GFR of less than 10 mL/minute, the dosage should be adjusted to either 500 mg/125 mg or 250 mg/125 mg every 24 hours, again based on infection severity. 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.

For pediatric patients weighing 40 kg or more, dosing should follow the adult recommendations. The Amoxicillin and Clavulanate Potassium Tablet 250 mg/125 mg formulation is not recommended for pediatric patients until they reach a weight of at least 40 kg.

Amoxicillin and Clavulanate Potassium Tablets may be taken without regard to meals; however, to enhance the absorption of clavulanate potassium, it is advisable to administer the tablet at the start of a meal. To minimize gastrointestinal intolerance, taking the tablet at the beginning of a meal is recommended.

Contraindications

Amoxicillin/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/clavulanate potassium, as this may exacerbate liver-related complications.

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/clavulanate potassium, it is imperative to conduct a thorough inquiry regarding any previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. Should an allergic reaction occur, amoxicillin/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 essential. Additional supportive measures, including the administration of oxygen, intravenous steroids, and airway management (including intubation), should be provided as clinically indicated.

Pseudomembranous colitis has been associated with nearly all antibacterial agents, including amoxicillin/clavulanate potassium, and can range in severity from mild to life-threatening. Therefore, it is crucial to consider this diagnosis in patients who present with diarrhea following the administration of antibacterial agents.

Amoxicillin/clavulanate potassium should be used with caution in patients exhibiting evidence of hepatic dysfunction. While hepatic toxicity related to the use of amoxicillin/clavulanate potassium is typically reversible, there have been rare reports of fatalities (less than one death per estimated four million prescriptions worldwide). These cases have generally involved patients with serious underlying conditions or those receiving concomitant medications. Regular monitoring of liver function tests is recommended in patients at risk for hepatic impairment.

Side Effects

Patients may experience a range of adverse reactions while receiving treatment. Common adverse reactions, occurring in 1% to 9% of participants, include diarrhea or loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%), and vaginitis (1%).

Less common adverse reactions may include abdominal discomfort, flatulence, and headache. Gastrointestinal reactions are particularly notable and can encompass diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic or pseudomembranous colitis. It is important to note that symptoms of pseudomembranous colitis may arise 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, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis (including toxic epidermal necrolysis), and anaphylactic reactions, have also been documented.

Liver-related adverse reactions may include a moderate rise in AST (SGOT) and/or ALT (SGPT), hepatic dysfunction (evidenced by increases in serum transaminases, serum bilirubin, and/or alkaline phosphatase), and in rare cases, severe hepatic dysfunction, which is usually reversible but has been associated with occasional fatalities.

Renal adverse reactions are infrequent but may include interstitial nephritis, hematuria, and crystalluria. Hemic and lymphatic system effects can manifest as anemia (including hemolytic anemia), thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, agranulocytosis, and slight thrombocytosis (less than 1%). There have been rare reports of increased prothrombin time in patients receiving amoxicillin/clavulanate potassium alongside anticoagulant therapy.

Central nervous system effects, though rare, may include agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity. Additionally, there have been rare reports of tooth discoloration (brown, yellow, or gray staining), primarily in pediatric patients.

Drug Interactions

Probenecid is known to decrease the renal tubular secretion of amoxicillin. When amoxicillin/clavulanate potassium is used concurrently with probenecid, there may be an increase in blood levels of amoxicillin, leading to prolonged effects. Therefore, coadministration of probenecid with amoxicillin/clavulanate potassium is not recommended.

The concurrent use of allopurinol and 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 amoxicillin/clavulanate potassium and allopurinol.

Amoxicillin/clavulanate potassium, like other broad-spectrum antibiotics, may diminish the effectiveness of oral contraceptives. Patients using both medications should be advised to consider alternative or additional contraceptive methods.

Oral administration of amoxicillin/clavulanate potassium leads to elevated urine concentrations of amoxicillin. This can result in false-positive results for glucose when using Clinitest®, Benedict's Solution, or Fehling's Solution. To avoid this issue, it is recommended that glucose testing utilize enzymatic glucose oxidase reactions, such as Clinistix®.

In pregnant women, administration of ampicillin has been observed to cause a transient decrease in plasma concentrations of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol. This effect may also be applicable to amoxicillin and, consequently, amoxicillin/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 the adult recommendations for Amoxicillin and Clavulanate Potassium Tablets. However, the safety and effectiveness of this medication in pediatric patients weighing less than 40 kg have not been established. Therefore, caution is advised when considering treatment in this population.

Geriatric Use

An analysis of clinical studies involving Amoxicillin and Clavulanate Potassium Tablets included a cohort of 3,119 patients, of which 32% were aged 65 years and older, and 14% were aged 75 years and older. The findings from this analysis, along with additional clinical experience, did not reveal significant differences in drug responses between elderly patients and younger individuals. However, it is important to note that a greater sensitivity to the drug in some older patients cannot be excluded.

Given that Amoxicillin and Clavulanate Potassium Tablets are primarily excreted by the kidneys, there is an increased risk of toxic reactions in patients with impaired renal function. Elderly patients are more likely to experience decreased renal function; therefore, careful consideration should be given to dose selection in this population. It is advisable to monitor renal function in geriatric patients to mitigate potential risks associated with the use of this medication.

Pregnancy

Pregnant patients should be informed that amoxicillin/clavulanate potassium is classified as Pregnancy Category B. Reproductive studies conducted in pregnant rats and mice at oral dosages up to 1200 mg/kg/day have shown no evidence of harm to the fetus. However, there are no adequate and well-controlled studies in pregnant women to confirm the safety of this medication during pregnancy.

Due to the limitations of animal reproduction studies in predicting human responses, amoxicillin/clavulanate potassium should be used during pregnancy only if clearly needed. Additionally, prophylactic treatment with this medication may be associated with an increased risk of necrotizing enterocolitis in neonates when administered to women with premature rupture of fetal membranes. Therefore, healthcare professionals should carefully weigh the potential benefits against the risks when considering this treatment for pregnant patients.

Lactation

Ampicillin-class antibiotics, including amoxicillin/clavulanate potassium, are excreted in human 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 potential risks associated with the use of this antibiotic in nursing women.

Renal Impairment

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

Hepatic Impairment

Amoxicillin/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 in these patients.

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

Overdosage

Following an overdosage of amoxicillin/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.

In the event of an overdosage, it is imperative to discontinue the administration of amoxicillin/clavulanate potassium immediately. 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.

Additionally, there have been reports of interstitial nephritis leading to oliguric renal failure in a small number of patients following overdosage. Crystalluria, which in some instances has resulted in renal failure, has also 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 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/clavulanate potassium at oral dosages up to 1200 mg/kg/day, which corresponds to 7200 and 4080 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, this drug should be utilized during pregnancy only when clearly necessary.

Amoxicillin/clavulanate potassium, at oral doses of up to 1200 mg/kg/day (5.7 times the maximum human dose, 1480 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 to assess the carcinogenic potential of amoxicillin/clavulanate potassium have not been conducted.

The mutagenic potential of amoxicillin/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

Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or sensitivity to multiple allergens.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including amoxicillin/clavulanate potassium, with severity ranging from mild to life-threatening. This diagnosis should be considered in patients presenting with diarrhea following the administration of antibacterial agents.

Hepatic dysfunction, characterized by increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been infrequently reported with amoxicillin/clavulanate potassium. It has been observed more commonly in elderly patients, males, or those undergoing prolonged treatment. The onset of hepatic dysfunction may occur during therapy or several weeks after discontinuation, and while it can be severe, it is usually reversible.

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

Neuropsychiatric effects such as agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported rarely. Tooth discoloration, including brown, yellow, or gray staining, has been infrequently observed, primarily in pediatric patients, with most cases showing improvement with dental cleaning or brushing.

Following overdosage, patients have primarily experienced gastrointestinal symptoms, including stomach and abdominal pain, vomiting, and diarrhea. Rash, hyperactivity, or drowsiness have also been noted in a small number of cases. Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after amoxicillin overdosage, with crystalluria leading to renal failure observed in both adult and pediatric patients.

Patient Counseling

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

When amoxicillin/clavulanate potassium is prescribed, it is important for patients to understand that while they may begin to feel better early in the treatment, the medication must be taken exactly as directed. Healthcare providers should emphasize the importance of adhering to the prescribed dosing schedule and completing the full course of therapy.

Patients should be made aware that skipping doses or failing to complete the entire treatment regimen may lead to decreased effectiveness of the immediate treatment. Additionally, such actions can increase the risk of bacteria developing resistance, potentially rendering amoxicillin/clavulanate potassium and other antibacterial drugs ineffective for future infections.

Storage and Handling

Tablets are supplied in tightly closed, moisture-proof containers to ensure their integrity and efficacy. They should be stored at a temperature range of 20 to 25°C (68 to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the quality of the product.

Additional Clinical Information

Quantitative methods are employed to determine the minimal inhibitory concentrations (MICs) of antimicrobial agents, specifically amoxicillin/clavulanate potassium. Clinicians should utilize standardized procedures based on dilution methods, either broth or agar, ensuring consistent inoculum concentrations and standardized concentrations of the drug. The recommended dilution pattern maintains a constant ratio of 2 parts amoxicillin to 1 part clavulanic acid across all test tubes, with MICs expressed in terms of amoxicillin concentration in the presence of clavulanic acid.

Standardized susceptibility testing requires the inclusion of laboratory control microorganisms to ensure the accuracy and reliability of the testing procedures. No additional information is available regarding abuse potential, administration routes, patient counseling, or postmarketing experiences.

FDA Insert (PDF)

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

View full prescribing information (PDF)