Amoxicillin/Clavulanate potassium

Description

Amoxicillin and clavulanate potassium tablets, USP, are oral antibacterial formulations that combine amoxicillin, a penicillin analog, with clavulanate potassium, a beta-lactamase inhibitor. Amoxicillin is derived from 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 through the fermentation of Streptomyces clavuligerus, has a molecular formula of C8H8KNO5 and 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.

The tablets are available in two strengths: 500 mg/125 mg and 875 mg/125 mg. Each 500 mg/125 mg tablet contains 500 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid (equivalent to 149 mg of clavulanate potassium). Each 875 mg/125 mg tablet contains 875 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid (also equivalent to 149 mg of clavulanate potassium).

Inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, talc, titanium dioxide, polyvinyl alcohol, polyethylene glycol, methacrylic acid copolymer, and sodium bicarbonate. Each tablet contains 0.63 mEq of potassium.

Uses and Indications

Amoxicillin and clavulanate potassium tablets, oral suspension, and chewable tablets are indicated for the treatment of various infections in both adults and pediatric patients. These infections include lower respiratory tract infections, acute bacterial otitis media, sinusitis, skin and skin structure infections, and urinary tract infections.

This drug 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 amoxicillin and clavulanate potassium as well as other antibacterial agents.

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.

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, not exceeding the adult dose.

For neonates and infants less than 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, including anaphylaxis or Stevens-Johnson syndrome, to amoxicillin and clavulanate potassium or to other beta-lactams such as 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.

Severe Cutaneous Adverse Reactions (SCAR) may occur during treatment. Healthcare professionals should monitor patients closely for any signs of rash, and if the rash progresses, amoxicillin and clavulanate potassium should be discontinued.

Drug-induced enterocolitis syndrome (DIES) has been associated with the use of amoxicillin, a component of this combination therapy. Should symptoms of DIES arise, it is essential to discontinue the medication and initiate appropriate therapeutic measures.

Patients with hepatic dysfunction are at increased risk for cholestatic jaundice. If any signs or symptoms of hepatitis develop, the medication should be discontinued. Additionally, liver function tests should be monitored in patients with pre-existing hepatic impairment to ensure safety.

Clostridioides difficile-associated diarrhea (CDAD) is a potential complication of antibiotic therapy. If a patient presents with diarrhea during treatment, a thorough evaluation is warranted to rule out CDAD.

Amoxicillin and clavulanate potassium should be avoided in patients with mononucleosis, as these individuals are at risk of developing a skin rash when treated with this medication.

Finally, the possibility of superinfections due to overgrowth of fungal or bacterial pathogens should be considered during therapy. Monitoring for signs of such infections is recommended to ensure timely intervention.

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; in such cases, amoxicillin and clavulanate potassium should be discontinued immediately. Severe cutaneous adverse reactions (SCAR) require close monitoring, and discontinuation is advised if any rash progresses. Drug-induced enterocolitis syndrome (DIES) has also been reported; if this occurs, the medication should be discontinued, and appropriate therapy should be initiated. Hepatic dysfunction and cholestatic jaundice necessitate discontinuation of the drug if signs or symptoms of hepatitis arise, and liver function tests should be monitored in patients with pre-existing hepatic impairment. Additionally, Clostridioides difficile-associated diarrhea (CDAD) should be evaluated if diarrhea occurs during treatment.

Patients with mononucleosis who are treated with amoxicillin and clavulanate potassium may develop skin rashes, and the use of this medication in such patients is not recommended. 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, 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 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, along with 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 neonates and young infants, it is important to note that renal function may be incompletely developed, potentially leading to delayed elimination of amoxicillin. However, the elimination of clavulanate remains unaffected in this age group. Therefore, dosing adjustments are necessary 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, and 14% were aged 75 years or older. Overall, no significant differences in safety or effectiveness were observed between these 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.

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 in geriatric patients to mitigate the risk of adverse effects and ensure appropriate dosing.

Pregnancy

Pregnancy Category B. 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 on the fetus. The amoxicillin doses in these studies were approximately 4 and 2 times the maximum recommended adult human oral dose of 875 mg every 12 hours, while the clavulanate doses were approximately 9 and 4 times the maximum recommended adult human oral dose of 125 mg every 8 hours.

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, amoxicillin and clavulanate potassium should be used during pregnancy only if clearly needed. Healthcare professionals are advised to 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 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 assessment of renal function may be warranted to ensure safe and effective use of the medication in patients with reduced kidney function.

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 therapy based on the results of these evaluations.

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, serious complications can arise from higher doses. Interstitial nephritis leading to oliguric renal failure has been documented in patients following an overdosage of amoxicillin and clavulanate potassium. Additionally, crystalluria, which may progress 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 essential 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 impairment 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 the drug from circulation.

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 combination of amoxicillin and clavulanate potassium (4:1 ratio formulation) demonstrated non-mutagenic properties 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 compound was found to be negative in the mouse micronucleus test and in the dominant lethal assay in mice.

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

In terms of reproductive toxicity, amoxicillin and clavulanate potassium (2:1 ratio formulation) administered at oral doses of up to 1,200 mg/kg/day did not adversely affect fertility or 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 cases of severe cutaneous adverse reactions (SCAR) associated with the use of amoxicillin and clavulanate potassium. Additionally, reports of hypersensitivity reactions, including anaphylaxis, have been noted. Instances of liver injury, such as cholestatic jaundice and hepatitis, have also been reported following the administration of this medication. Furthermore, gastrointestinal adverse reactions, including severe diarrhea and colitis, have occurred in some patients. Postmarketing data has indicated the occurrence of renal impairment, including acute interstitial nephritis, in certain individuals taking amoxicillin and clavulanate potassium.

Patient Counseling

Patients should be informed that amoxicillin and clavulanate potassium may be administered 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 regarding the potential for allergic reactions, as amoxicillin and clavulanate potassium contains 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 two months after completing the course of treatment. If diarrhea is severe or persists for more than 2 to 3 days, patients should be encouraged to contact their physician promptly.

Additionally, patients should be counseled that antibacterial drugs, including amoxicillin and clavulanate potassium, 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 improvement early in the treatment. However, it is essential to take the medication exactly as directed, without skipping doses or discontinuing the full course of therapy. Failure to adhere to the prescribed regimen may reduce the effectiveness of the treatment and increase the risk of bacterial resistance, rendering amoxicillin and clavulanate potassium or other antibacterial drugs ineffective in the future.

Storage and Handling

The product is supplied in its original container to ensure integrity and stability. It must be stored at or below 25°C (77°F) to maintain its efficacy. Additionally, it is essential to keep the product out of the reach of children to ensure safety during handling and storage.

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 Devatis, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)