Amoxicillin/Clavulanate potassium

Description

Amoxicillin and clavulanate potassium tablets, USP, are an oral antibacterial combination comprising amoxicillin and clavulanate potassium, the potassium salt of clavulanic acid. Amoxicillin, an analog of ampicillin, is derived from the 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 beta-lactam that is structurally related to penicillins and has the capability to inactivate certain beta-lactamases by obstructing their active sites. 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 tablet contains 500 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid, equivalent to 149 mg of clavulanate potassium. Additionally, each tablet provides 0.63 mEq of potassium. Inactive ingredients include colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, talc, titanium dioxide, triethyl citrate, ethylcellulose, cetyl alcohol, and sodium lauryl sulfate.

Uses and Indications

Amoxicillin and clavulanate potassium tablets are indicated for the treatment of the following infections in adults and pediatric patients: lower respiratory tract infections, acute bacterial otitis media, sinusitis, skin and skin structure infections, and urinary tract infections.

These tablets should be utilized exclusively for the treatment or prevention of infections that are proven or strongly suspected to be caused by bacteria. This approach is essential to reduce the development of drug-resistant bacteria and to maintain the effectiveness of this drug and other antibacterial agents.

There are no teratogenic or nonteratogenic effects associated with the use of amoxicillin and clavulanate potassium tablets.

Dosage and Administration

For adults and pediatric patients weighing greater 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, depending on the amoxicillin component.

In pediatric patients aged 12 weeks (3 months) and older, the dosage ranges from 25 to 45 mg/kg/day given every 12 hours, or 20 to 40 mg/kg/day given every 8 hours, not exceeding the adult dose.

For neonates and infants less than 12 weeks of age, the recommended dosage is 30 mg/kg/day, divided and administered every 12 hours, based on the amoxicillin component. 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 amoxicillin and clavulanate potassium tablets is contraindicated in patients with a history of serious hypersensitivity reactions, including anaphylaxis or Stevens-Johnson syndrome, to amoxicillin, clavulanate potassium, or other beta-lactams such as penicillins or cephalosporins. Additionally, patients with a history of cholestatic jaundice or hepatic dysfunction associated with the use of amoxicillin and clavulanate potassium tablets should not use this medication.

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.

Healthcare professionals should remain vigilant for Severe Cutaneous Adverse Reactions (SCAR) during treatment. Patients should be monitored closely for any signs of rash, and if the rash progresses, discontinuation of the medication is warranted.

Patients with pre-existing hepatic dysfunction are at an increased risk for cholestatic jaundice. It is essential to discontinue amoxicillin and clavulanate potassium if any signs or symptoms of hepatitis arise. Additionally, liver function tests should be monitored in patients with hepatic impairment to ensure safety during treatment.

Clostridioides difficile-associated diarrhea (CDAD) is a potential complication associated with antibiotic therapy. If a patient develops diarrhea, a thorough evaluation for CDAD should be conducted to rule out this serious condition.

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.

Finally, healthcare providers should be aware of the risk of overgrowth of non-susceptible organisms, including fungal or bacterial pathogens, during therapy. The possibility of superinfections should be considered, and appropriate measures should be taken if such occurrences arise.

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, although less frequent, warrant careful monitoring and prompt action. These include serious hypersensitivity reactions, which may be fatal; patients should discontinue the medication if such a reaction occurs. Severe cutaneous adverse reactions (SCAR) have also been reported, necessitating close monitoring and discontinuation if any rash progresses. Hepatic dysfunction and cholestatic jaundice are serious concerns, and patients should discontinue use if signs or symptoms of hepatitis arise, with liver function tests monitored in those with pre-existing hepatic impairment. Additionally, Clostridioides difficile-associated diarrhea (CDAD) should be evaluated in patients presenting with diarrhea during treatment.

It is important to note that patients with mononucleosis who receive amoxicillin and clavulanate potassium may develop skin rashes; therefore, the use of this medication in such patients should be avoided. The potential for superinfections with fungal or bacterial pathogens should also be considered during therapy.

Other significant adverse reactions include a history of serious hypersensitivity reactions, such as anaphylaxis or Stevens-Johnson syndrome, to amoxicillin and clavulanate potassium or other beta-lactams, as well as a history of cholestatic jaundice or hepatic dysfunction associated with this medication. Interstitial nephritis resulting in oliguric renal failure has been reported following overdosage, along with crystalluria, which in some cases has led to renal failure 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 therapeutic outcomes.

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 appropriate 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 measures 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 amoxicillin and clavulanate potassium tablets in this population is derived from studies conducted in adults, supplemented by data from a study involving pediatric patients aged 2 months to 12 years with acute otitis media.

In neonates and young infants, renal function is not fully developed, which may lead to delayed elimination of amoxicillin; however, the elimination of clavulanate remains unchanged in this age group. Therefore, dosing of amoxicillin and clavulanate potassium should be adjusted for pediatric patients aged less than 12 weeks (less than 3 months) to ensure safety and efficacy.

Geriatric Use

In clinical studies involving amoxicillin and clavulanate potassium, 32% of the 3,119 patients analyzed were aged 65 years or older, with 14% being 75 years or older. No significant differences in safety or effectiveness were observed between these elderly patients and their younger counterparts. However, while clinical experience has not identified notable differences in responses between elderly and younger patients, it is important to acknowledge that some older individuals may exhibit greater sensitivity to the drug.

Amoxicillin and clavulanate potassium is primarily excreted via the kidneys, which raises concerns regarding the potential for adverse reactions 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 to ensure appropriate dosing and minimize the risk of adverse effects.

Pregnancy

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 fetal harm. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human outcomes, amoxicillin and clavulanate potassium should be used during pregnancy only if clearly needed.

The effects of amoxicillin and clavulanate potassium on the fetus during labor or delivery are not well understood. It remains unknown whether the use of this medication in humans during these critical periods has immediate or delayed adverse effects on fetal outcomes, prolongs the duration of labor, or increases the likelihood of requiring obstetrical intervention. Therefore, healthcare professionals should carefully weigh the potential benefits against the risks when considering this medication for pregnant patients.

Lactation

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

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to this patient population.

Hepatic Impairment

Patients with hepatic impairment should be closely monitored for liver function tests. In the event that signs or symptoms of hepatitis occur, the treatment should be discontinued immediately. It is essential to assess liver function regularly to ensure the safety and efficacy of the therapy in this population.

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 less than 250 mg/kg of amoxicillin typically do not result in significant clinical symptoms.

However, it is important to note that interstitial nephritis leading to oliguric renal failure has been documented in patients following an overdosage of amoxicillin and clavulanate potassium. Additionally, crystalluria, which in some instances has progressed to renal failure, has been reported in both adult and pediatric patients after overdosage with amoxicillin and clavulanate potassium.

To mitigate the risk of crystalluria associated with amoxicillin and clavulanate potassium overdosage, 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 also noteworthy that patients with pre-existing renal impairment may experience elevated blood levels of the drug due to decreased renal clearance. In such cases, hemodialysis may be employed to facilitate the removal of amoxicillin and clavulanate potassium from circulation.

Nonclinical Toxicology

Amoxicillin and clavulanate potassium, administered in a 2:1 ratio at oral doses of up to 1,200 mg/kg/day, demonstrated no adverse effects on fertility and reproductive performance in rats. This dosage corresponds to approximately four times the maximum recommended adult human oral dose of amoxicillin (875 mg every 12 hours) and about nine times the maximum recommended adult human oral dose of clavulanate (125 mg every 8 hours), when adjusted for body surface area.

Long-term studies in animals to assess the carcinogenic potential of amoxicillin and clavulanate potassium have not been conducted. In mutagenicity assessments, the 4:1 formulation of amoxicillin and clavulanate potassium was found to be non-mutagenic in both the Ames bacterial mutation assay and the yeast gene conversion assay. However, it exhibited weakly positive results in the mouse lymphoma assay, where the observed trend toward increased mutation frequencies coincided with decreased cell survival at the tested doses. The compound was negative in the mouse micronucleus test and the dominant lethal assay in mice.

Potassium clavulanate, when tested independently, also yielded negative results in the Ames bacterial mutation assay and the mouse micronucleus test.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions reported voluntarily or through surveillance programs. Serious skin reactions have been noted, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Instances of hepatic dysfunction have been observed, encompassing cholestatic jaundice and hepatitis. Hematologic reactions reported include thrombocytopenia, leukopenia, and agranulocytosis. Additionally, renal impairment, specifically interstitial nephritis, has been documented. Anaphylaxis and other allergic reactions have also been reported. Furthermore, cases of Clostridium difficile-associated diarrhea have been identified.

Patient Counseling

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

Healthcare providers should counsel patients regarding the potential for allergic reactions, as amoxicillin and clavulanate potassium tablets contain a penicillin class drug. Patients should be made aware of the signs and symptoms of serious skin reactions. They should be instructed to discontinue the medication immediately and report any initial signs or symptoms of skin rash, mucosal lesions, or other indications of hypersensitivity.

Patients should also be advised that diarrhea is a common side effect associated with antibacterial medications, typically resolving upon discontinuation of the drug. However, it is crucial to inform patients that they may experience watery and bloody stools, with or without accompanying 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 contact their physician promptly.

It is essential to counsel patients that antibacterial drugs, including amoxicillin and clavulanate potassium tablets, are effective only against bacterial infections and do not treat viral infections, such as the common cold. When prescribed for a bacterial infection, patients should be reminded that it is common to feel better early in the treatment. However, they must take the medication 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 bacterial resistance, making future infections harder to treat with amoxicillin and clavulanate potassium tablets or other antibacterial agents.

Storage and Handling

The product is supplied in accordance with the following 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 the reach of children to ensure safety.

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 Chartwell RX, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)