Amoxicillin/Clavulanate potassium

Description

Amoxicillin and clavulanate potassium tablets, USP; for oral suspension, USP; and chewable tablets, USP are oral antibacterial combinations that consist of amoxicillin and 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. 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 beta-lactam that is structurally related to penicillins and has the capability to inactivate certain beta-lactamases by blocking their active sites. The molecular formula for clavulanate potassium is C₈H₈KNO₅, with a molecular weight of 237.25, and its chemical structure is potassium (Z)(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo3.2.0-heptane-2-carboxylate.

Inactive ingredients in the tablets include colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, talc, titanium dioxide, triethyl citrate, ethylcellulose, cetyl alcohol, and sodium lauryl sulfate. Each tablet of amoxicillin and clavulanate potassium contains 0.63 mEq of potassium.

Uses and Indications

Amoxicillin and clavulanate potassium tablets, USP, for oral suspension, USP, and chewable tablets, USP are indicated for the treatment of the following infections: lower respiratory tract infections, acute bacterial otitis media, sinusitis, skin and skin structure infections, and urinary tract infections.

There are no teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

For adults and pediatric patients weighing more than 40 kg, the recommended dosage is either 500 mg or 875 mg administered every 12 hours, or 250 mg or 500 mg every 8 hours.

Pediatric patients aged 12 weeks (3 months) and older should receive a dosage of 25 to 45 mg/kg/day divided into two doses every 12 hours, or 20 to 40 mg/kg/day divided into three doses every 8 hours, with the total daily dose not exceeding the adult dosage.

For neonates and infants under 12 weeks of age, the recommended dosage is 30 mg/kg/day, divided into two doses every 12 hours. It is advised to use the 125 mg/5 mL oral suspension for this age group.

Healthcare professionals should ensure that the appropriate formulation and dosing schedule are selected based on the patient's age, weight, and clinical condition.

Contraindications

Use of this product is contraindicated in patients with a history of serious hypersensitivity reactions, such as anaphylaxis or Stevens-Johnson syndrome, to amoxicillin and clavulanate potassium or to other beta-lactams, including penicillins or cephalosporins. Additionally, it is contraindicated in individuals with a history of cholestatic jaundice or hepatic dysfunction associated with amoxicillin and clavulanate potassium.

Warnings and Precautions

Serious hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving amoxicillin and clavulanate potassium. In the event of such a reaction, it is imperative to discontinue the medication immediately.

Patients with pre-existing hepatic dysfunction are at an increased risk for developing cholestatic jaundice. Should any signs or symptoms of hepatitis arise, the use of amoxicillin and clavulanate potassium must be discontinued. Additionally, liver function tests should be closely monitored in patients with hepatic impairment to ensure safety during treatment.

Clostridium difficile-associated diarrhea (CDAD) is a potential complication associated with antibiotic therapy. Healthcare professionals should evaluate patients for CDAD if they present with diarrhea during or following treatment.

Amoxicillin and clavulanate potassium should be avoided in patients with mononucleosis, as these individuals are prone to developing skin rashes when treated with this medication.

Furthermore, clinicians should remain vigilant for the possibility of superinfections due to overgrowth of fungal or bacterial pathogens during therapy. Regular assessment of the patient's condition is recommended to identify any signs of such complications promptly.

Side Effects

Patients receiving amoxicillin and clavulanate potassium may experience a range of adverse reactions. 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%).

Serious adverse reactions have also been reported. These include serious hypersensitivity reactions, which can be fatal; therefore, amoxicillin and clavulanate potassium should be discontinued immediately if such a reaction occurs. Hepatic dysfunction and cholestatic jaundice have been noted, necessitating discontinuation of the medication if signs or symptoms of hepatitis arise, along with monitoring of liver function tests in patients with pre-existing hepatic impairment. Additionally, Clostridium difficile-associated diarrhea (CDAD) should be evaluated in patients who present with diarrhea during treatment. It is important to note that patients with mononucleosis who are treated with amoxicillin and clavulanate potassium may develop skin rashes, and the use of this medication should be avoided in these individuals. The potential for superinfections with fungal or bacterial pathogens should also be considered during therapy.

Other important considerations include a history of serious hypersensitivity reactions, such as anaphylaxis or Stevens-Johnson syndrome, to amoxicillin and clavulanate potassium or other beta-lactams, including penicillins and cephalosporins. A history of cholestatic jaundice or hepatic dysfunction associated with amoxicillin and clavulanate potassium is also relevant. Furthermore, interstitial nephritis resulting in oliguric renal failure has been reported following overdosage of amoxicillin and clavulanate potassium. Crystalluria, which in some cases has led to renal failure, has been documented after overdosage in both adult and pediatric patients.

Drug Interactions

Co-administration of amoxicillin and clavulanate potassium with probenecid is not recommended due to potential interactions that may affect the pharmacokinetics of the drugs involved.

When used concurrently with oral anticoagulants, amoxicillin and clavulanate potassium may lead to an increased prolongation of prothrombin time. It is advisable to monitor prothrombin time closely in patients receiving this combination to ensure safe anticoagulation levels.

The concomitant use of amoxicillin and clavulanate potassium with allopurinol has been associated with an increased risk of rash. Clinicians should be vigilant for dermatological reactions in patients receiving both medications.

Additionally, amoxicillin and clavulanate potassium may reduce the efficacy of oral contraceptives. Patients should be counseled on the potential need for alternative or additional contraceptive methods during treatment with this antibiotic combination.

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

The safety and effectiveness of amoxicillin and clavulanate potassium for oral suspension and chewable tablets have been established in pediatric patients. Evidence supporting the use of these formulations in children is derived from studies involving amoxicillin and clavulanate potassium tablets in adults, supplemented by data from a study specifically examining the oral suspension in pediatric patients aged 2 months to 12 years with acute otitis media.

In pediatric patients, particularly those aged less than 12 weeks (or <3 months), dosing of amoxicillin and clavulanate potassium should be modified due to the incompletely developed renal function in neonates and young infants. This may result in delayed elimination of amoxicillin, while the elimination of clavulanate remains unaffected in this age group. Caution is advised when prescribing to this population to ensure appropriate dosing and monitoring.

Geriatric Use

In clinical studies involving amoxicillin and clavulanate potassium, 32% of the 3,119 patients analyzed were aged 65 years and older, with 14% being 75 years and older. Overall, no significant differences in safety or effectiveness were observed between elderly patients and their younger counterparts. However, it is important to note that greater sensitivity to the drug may be present in some older individuals, although this has not been definitively established through reported clinical experience.

Given that amoxicillin and clavulanate potassium is primarily excreted by the kidneys, there is an increased risk of adverse 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 to ensure appropriate dosing and minimize the risk of potential adverse effects.

Pregnancy

Pregnancy Category B indicates that reproduction studies conducted in pregnant rats and mice, which received amoxicillin and clavulanate potassium in a 2:1 ratio at oral doses up to 1200 mg/kg/day, showed no evidence of harm to the fetus. The doses administered to these animals were approximately 4 and 2 times the maximum recommended adult human oral dose of amoxicillin (875 mg every 12 hours) and approximately 9 and 4 times the maximum recommended adult human oral dose of clavulanate (125 mg every 8 hours), respectively.

Despite these findings, there are no adequate and well-controlled studies in pregnant women. Therefore, due to the limitations of animal reproduction studies in predicting human response, this medication should be used during pregnancy only if clearly needed. Healthcare professionals are advised to weigh the potential benefits against any possible risks when considering the use of amoxicillin and clavulanate potassium in pregnant patients.

Lactation

Amoxicillin has been shown to be excreted in human milk. The use of amoxicillin/clavulanate potassium by nursing mothers may lead to sensitization of breastfed infants. Therefore, caution should be exercised when administering amoxicillin/clavulanate potassium to a lactating mother.

Renal Impairment

Patients with renal impairment have no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to this population. Regular monitoring of renal function may be warranted in patients with reduced kidney function to ensure safety and efficacy.

Hepatic Impairment

Patients with hepatic impairment should be closely monitored for liver function tests. In the event that signs or symptoms of hepatitis occur, discontinuation of treatment is recommended. It is essential to assess liver function regularly to ensure patient safety and to make any necessary adjustments to the treatment regimen.

Overdosage

In the event of an overdosage, it is imperative to discontinue the medication immediately and provide symptomatic treatment along with supportive measures as necessary. A prospective study involving 51 pediatric patients at a poison-control center indicated that overdosages of amoxicillin below 250 mg/kg typically do not result in significant clinical symptoms.

Potential Symptoms and Complications Overdosage of amoxicillin/clavulanate potassium has been associated with interstitial nephritis, which can lead to oliguric renal failure. Additionally, crystalluria has been reported, occasionally resulting in renal failure in both adult and pediatric populations.

Management Recommendations To mitigate the risk of crystalluria following an overdosage of amoxicillin/clavulanate potassium, it is essential to maintain adequate fluid intake and promote diuresis. This approach helps to reduce the likelihood of crystallization in the renal system.

Renal impairment observed in cases of overdosage is generally reversible upon cessation of the drug. It is important to note that patients with pre-existing renal impairment may experience elevated blood levels of amoxicillin/clavulanate potassium due to decreased renal clearance. In such cases, hemodialysis may be employed to facilitate the removal of the drug from circulation.

Nonclinical Toxicology

Reproduction studies conducted in pregnant rats and mice administered amoxicillin and clavulanate potassium (2:1 ratio formulation) at oral doses up to 1200 mg/kg/day demonstrated no evidence of teratogenic effects. The doses of amoxicillin in these studies were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours) for rats and mice, respectively. For clavulanate, the corresponding multiples were approximately 9 and 4 times the maximum recommended adult human oral dose (125 mg every 8 hours). However, there are no adequate and well-controlled studies in pregnant women, and since animal reproduction studies may not always predict human response, this drug should be used during pregnancy only if clearly needed.

In terms of non-teratogenic effects, amoxicillin and clavulanate potassium at oral doses of up to 1200 mg/kg/day did not adversely affect fertility or reproductive performance in rats. The doses administered were approximately 4 times the maximum recommended adult human oral dose for amoxicillin and about 9 times higher for clavulanate, based on body surface area.

Long-term studies in animals have not been conducted to assess the carcinogenic potential of amoxicillin and clavulanate potassium (4:1 ratio formulation). The compound was found to be non-mutagenic in both the Ames bacterial mutation assay and the yeast gene conversion assay. Although it exhibited weak positivity in the mouse lymphoma assay, this trend towards increased mutation frequencies occurred at doses that were also associated with decreased cell survival. Furthermore, amoxicillin and clavulanate potassium was negative in the mouse micronucleus test and in the dominant lethal assay in mice. Potassium clavulanate alone was also tested in the Ames bacterial mutation assay and the mouse micronucleus test, yielding negative results in both assays.

Postmarketing Experience

Postmarketing experience has identified cases of severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Reports of hepatic dysfunction have included instances of cholestatic jaundice and hepatitis. Additionally, cases of renal impairment, specifically acute interstitial nephritis, have been documented. Instances of Clostridium difficile-associated diarrhea have also been reported, which can occur even after the antibiotic has been discontinued. Furthermore, allergic reactions, including anaphylaxis, have been noted in the postmarketing data.

Patient Counseling

Patients should be informed that amoxicillin and clavulanate potassium may be taken every 8 hours or every 12 hours, depending on the prescribed dosage. It is important for patients to take each dose with a meal or snack to minimize the risk of gastrointestinal upset.

Healthcare providers should counsel patients that antibacterial drugs, including amoxicillin and clavulanate potassium, are indicated solely for the treatment of bacterial infections and are ineffective against viral infections, such as the common cold. When prescribed for a bacterial infection, patients should be advised that it is common to feel better early in the course of therapy; however, the medication must be taken exactly as directed. Skipping doses or failing to complete the full course of therapy may reduce the effectiveness of the treatment and increase the risk of bacteria developing resistance, which could render amoxicillin and clavulanate potassium or other antibacterial drugs ineffective in the future.

Patients should be made aware that diarrhea is a common side effect associated with antibacterial use, typically resolving upon discontinuation of the medication. They should be informed that in some cases, watery and bloody stools may occur, potentially accompanied by stomach cramps and fever, even up to 2 months after completing the course of treatment. If diarrhea is severe or persists for more than 2 to 3 days, patients should be instructed to contact their physician.

For those receiving the suspension form of amoxicillin and clavulanate potassium, patients should be advised to keep the medication refrigerated and to shake it well before use. When administering the suspension to a child, a dosing spoon or medicine dropper should be utilized, and it is essential to rinse the spoon or dropper after each use. Patients should follow their healthcare provider's instructions regarding the appropriate dosage and duration of treatment for their child, and any unused medicine should be discarded.

Lastly, patients should be informed that amoxicillin and clavulanate potassium contains a penicillin-class drug, which may cause allergic reactions in some individuals.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in compliance with USP Controlled Room Temperature guidelines. It is essential to keep the product out of reach of children to ensure safety.

Additional Clinical Information

Patients should be informed that amoxicillin and clavulanate potassium chewable tablets and oral suspension contain aspartame, which includes phenylalanine. Specifically, each 200-mg chewable tablet contains 2 mg of phenylalanine, while each 400-mg chewable tablet contains 4 mg. Additionally, each 5 mL of the 200 mg/5 mL or 400 mg/5 mL oral suspension contains 7 mg of phenylalanine. It is important to note that other formulations of the medication do not contain phenylalanine.

No further information is available regarding laboratory tests, abuse potential, route, method, and frequency of administration, or postmarketing experience.

FDA Insert (PDF)

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

View full prescribing information (PDF)