Amoxicillin/Clavulanate potassium

Description

Amoxicillin and clavulanate potassium is an oral antibacterial combination comprising amoxicillin and clavulanate potassium, the potassium salt of clavulanic acid, which serves as 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 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, is a beta-lactam that shares structural similarities with penicillins and is capable of inactivating 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. Its chemical structure is potassium (Z)(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo3.2.0-heptane-2-carboxylate.

Each tablet of amoxicillin and clavulanate potassium contains 0.63 mEq of potassium and includes the following inactive ingredients: 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 and clavulanate potassium is indicated for the treatment of the following conditions: 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, 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 those that may be fatal, 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 hepatic dysfunction are at an increased risk for cholestatic jaundice. Should any signs or symptoms of hepatitis arise, discontinuation of amoxicillin and clavulanate potassium is necessary. Additionally, liver function tests should be monitored in patients who have pre-existing hepatic impairment to ensure safety during treatment.

Clostridium difficile-associated diarrhea (CDAD) is a potential complication associated with the use of this medication. 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 diagnosed with mononucleosis, as these individuals are prone to developing skin rashes when treated with this antibiotic combination.

Finally, clinicians should remain vigilant for the possibility of superinfections, including those caused by fungal or bacterial pathogens, during the course of therapy with amoxicillin and clavulanate potassium.

Side Effects

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 may occur, including serious (and potentially fatal) hypersensitivity reactions. In such cases, amoxicillin and clavulanate potassium should be discontinued immediately. Hepatic dysfunction and cholestatic jaundice have also been reported; discontinuation is advised if signs or symptoms of hepatitis appear, and liver function tests should be monitored in patients with pre-existing hepatic impairment.

Clostridium difficile-associated diarrhea (CDAD) is a significant concern, and patients experiencing diarrhea should be evaluated for this condition. Additionally, patients with mononucleosis who receive amoxicillin and clavulanate potassium may develop skin rashes, and the use of this medication is contraindicated in these individuals. The potential for superinfections with fungal or bacterial pathogens should be considered during therapy, particularly in patients at risk for overgrowth.

It is important to note that a history of serious hypersensitivity reactions, such as anaphylaxis or Stevens-Johnson syndrome, to amoxicillin and clavulanate potassium or other beta-lactams (including penicillins or cephalosporins) may increase the risk of adverse reactions. Furthermore, a history of cholestatic jaundice or hepatic dysfunction associated with amoxicillin and clavulanate potassium should be taken into account.

Rarely, interstitial nephritis resulting in oliguric renal failure has been reported following overdosage with amoxicillin and clavulanate potassium. Crystalluria, which in some cases has led to renal failure, has also 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 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 combination of amoxicillin and clavulanate potassium with allopurinol has been associated with an increased risk of rash. Caution is advised when these medications are prescribed together, and patients should be monitored for dermatological reactions.

Additionally, amoxicillin and clavulanate potassium may reduce the efficacy of oral contraceptives. Patients using hormonal contraceptives should be informed of this potential interaction and may need to consider 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 have been established in pediatric patients. Evidence supporting the use of this formulation in children is derived from studies involving amoxicillin and clavulanate potassium tablets in adults, along with data from a specific study in 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, 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, 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 to ensure appropriate dosing and to mitigate the risk of adverse effects.

Pregnancy

Pregnancy Category B indicates that 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 showed no evidence of harm to the fetus. The doses of amoxicillin in these studies were approximately 4 and 2 times the maximum recommended adult human oral dose of 875 mg every 12 hours, while the doses for clavulanate 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, 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 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 available 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 these patients 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, the treatment should be discontinued immediately. 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 and clavulanate potassium has been associated with interstitial nephritis, which may 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, it is essential to maintain adequate fluid intake and promote diuresis. This approach helps to reduce the likelihood of crystallization in the renal system. It is also important to note that renal impairment observed in these cases appears to be reversible upon cessation of the drug.

Patients with pre-existing renal impairment may experience elevated blood levels of amoxicillin and 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

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 hypersensitivity reactions, which include anaphylaxis, angioedema, and skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Additionally, there have been reports of liver function test abnormalities, characterized by elevations in liver enzymes (ALT, AST) and bilirubin levels. Cases of Clostridium difficile-associated diarrhea have also been reported, which may occur during or after treatment with antibiotics, including amoxicillin and clavulanate potassium. Other adverse reactions noted include renal impairment, specifically interstitial nephritis, as well as hematologic reactions such as thrombocytopenia and leukopenia.

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 that each dose is taken 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, rendering them untreatable by amoxicillin and clavulanate potassium or other antibacterial agents 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. However, they should be informed that watery and bloody stools, with or without accompanying stomach cramps and fever, can occur even up to 2 months after completing the treatment. If diarrhea is severe or persists for more than 2 to 3 days, patients should contact their physician.

It is essential to advise patients to keep the suspension refrigerated and to shake it well before use. When administering the suspension (liquid) to a child, a dosing spoon or medicine dropper should be utilized, and it is important to rinse the spoon or dropper after each use. Patients should follow their doctor’s instructions regarding the appropriate amount to use and the duration of treatment required 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 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 Cambridge Therapeutics Technologies, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)