Amoxicillin/Clavulanate potassium

Description

Amoxicillin and clavulanate potassium tablets, USP, are an oral antibacterial combination comprising amoxicillin and clavulanate potassium, a beta-lactamase inhibitor. Amoxicillin, an analog of ampicillin, is derived from the penicillin nucleus, 6-aminopenicillanic acid. Its molecular formula is C16H19N3O5S•3H2O, with a molecular weight of 419.46 g/mol. The chemical structure of amoxicillin is (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 inactivates certain beta-lactamases by blocking their active sites. The molecular formula for clavulanate potassium is C8H8KNO5, with a molecular weight of 237.25 g/mol. 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 875 mg of amoxicillin USP 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, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, Surelease clear (aqueous ethyl cellulose dispersion), and titanium dioxide.

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.

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/125 mg or 875 mg/125 mg administered every 12 hours, or alternatively, 250 mg/125 mg or 500 mg/125 mg every 8 hours, depending on the amoxicillin component.

Pediatric patients aged 12 weeks (3 months) and older should receive a dosage of 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 utilize the 125 mg/31.25 mg per 5 mL oral suspension for this age group.

Healthcare professionals should ensure that the appropriate dosing regimen is selected based on the patient's weight, age, 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, the use of this medication is contraindicated in individuals with a history of cholestatic jaundice or hepatic dysfunction associated with amoxicillin and clavulanate potassium tablets.

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 the medication should be discontinued if the rash progresses.

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 should be conducted to rule out CDAD.

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 superinfections due to overgrowth of fungal or bacterial pathogens during therapy. Monitoring for signs of such infections is recommended to ensure timely intervention.

Side Effects

Patients may experience a range of adverse reactions while receiving amoxicillin and clavulanate potassium. 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 can be fatal; therefore, amoxicillin and clavulanate potassium should be discontinued immediately if such a reaction occurs. Severe cutaneous adverse reactions (SCAR) have also been reported, necessitating close monitoring and discontinuation of the medication if a rash progresses. Hepatic dysfunction and cholestatic jaundice are serious concerns, and patients should be monitored for signs or symptoms of hepatitis, with discontinuation of therapy if these occur. 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, and the use of this medication should be avoided in such cases. 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, as has 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 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 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 methods during treatment.

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 result in 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 under 12 weeks (less than 3 months) of age 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, and 14% were aged 75 years or older. No overall differences in safety or effectiveness were observed between these elderly patients and their younger counterparts. However, while clinical experience has not identified significant differences in responses between elderly and younger patients, it is important to note that greater sensitivity to the drug may be present in some older individuals.

Amoxicillin and clavulanate potassium is primarily excreted by the kidneys, which raises concerns regarding the risk of 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 potential adverse effects.

Pregnancy

Pregnancy Category B indicates that reproduction studies conducted in pregnant rats and mice, which received amoxicillin and clavulanate potassium (2:1 ratio formulation) 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 for amoxicillin (875 mg every 12 hours) and approximately 9 and 4 times for clavulanate (125 mg every 8 hours), based on body surface area.

Despite these findings, there are no adequate and well-controlled studies in pregnant women. Therefore, the use of amoxicillin and clavulanate potassium during pregnancy should be considered only if clearly needed, as animal reproduction studies are not always predictive of human response.

Additionally, it is not known whether the use of amoxicillin and clavulanate potassium in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood of the necessity for obstetrical intervention. Healthcare professionals should weigh the potential benefits against the risks when prescribing this medication to 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

There is no specific information regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in 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, 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. However, it is essential to remain vigilant for potential adverse effects, particularly in cases of higher doses.

Notably, interstitial nephritis leading to oliguric renal failure has been documented following overdosage with amoxicillin and clavulanate potassium. Additionally, crystalluria, which in some instances has progressed to renal failure, has been reported in both adult and pediatric populations after overdosage with these agents. To mitigate the risk of crystalluria, it is crucial to maintain adequate fluid intake and promote diuresis.

Renal impairment resulting from overdosage appears to be reversible upon cessation of the drug. It is important to note that patients with pre-existing renal dysfunction may experience elevated blood levels of amoxicillin and clavulanate potassium due to reduced renal clearance.

In cases of severe overdosage, hemodialysis may be employed to facilitate the removal of amoxicillin and clavulanate potassium from circulation, thereby aiding in the management of the patient's condition.

Nonclinical Toxicology

Long-term studies in animals have not been conducted to assess the carcinogenic potential of amoxicillin and clavulanate potassium. In mutagenicity testing, the 4:1 ratio formulation of amoxicillin and clavulanate 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 doses that also resulted in decreased cell survival. The formulation was negative in the mouse micronucleus test and the dominant lethal assay in mice.

Potassium clavulanate, when tested independently, was negative in both the Ames bacterial mutation assay and the mouse micronucleus test.

In terms of reproductive toxicity, the 2:1 ratio formulation of amoxicillin and clavulanate potassium, administered 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.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions reported voluntarily or through surveillance programs. These include severe allergic reactions, such as anaphylaxis, and severe cutaneous adverse reactions (SCAR), which encompass Stevens-Johnson syndrome and toxic epidermal necrolysis. Instances of hepatic dysfunction have been noted, including cases of cholestatic jaundice and hepatitis. Renal impairment, specifically interstitial nephritis, has also been reported.

Hematologic reactions, including thrombocytopenia, leukopenia, and hemolytic anemia, have been documented. Additionally, gastrointestinal disorders, particularly Clostridium difficile-associated diarrhea, have been observed. Other adverse reactions reported include angioedema, urticaria, and various hypersensitivity reactions.

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 product. 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 two months after completing the course of treatment. If diarrhea is severe or persists for more than 2 or 3 days, patients should contact their physician promptly.

It is essential to counsel patients 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 for a bacterial infection, patients should be reminded that it is common to feel better early in the treatment course; 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 bacterial resistance, rendering amoxicillin and clavulanate potassium tablets or other antibacterial drugs ineffective in the future.

Storage and Handling

The product is supplied in tightly closed, moisture-proof containers to ensure integrity and stability. It is recommended that patients store the product in a closed container to maintain its quality. The optimal storage temperature range is between 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Additionally, 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)