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 acts as a beta-lactamase inhibitor. 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. Its chemical structure 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, has a molecular formula of C8H8KNO5 and a molecular weight of 237.25, with the chemical structure of potassium (Z)(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo3.2.0-heptane-2-carboxylate.

The formulation is available in various dosage forms, including tablets, oral suspension, and chewable tablets.

Amoxicillin and Clavulanate Potassium Tablets:

• 250 mg/125 mg: Each tablet contains 250 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid (equivalent to 149 mg of clavulanate potassium).

• 500 mg/125 mg: Each tablet contains 500 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid (equivalent to 149 mg of clavulanate potassium).

• 875 mg/125 mg: Each tablet contains 875 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid (equivalent to 149 mg of clavulanate potassium).

Amoxicillin and Clavulanate Potassium for Oral Suspension:

• 125 mg/31.25 mg: Each 5 mL contains 125 mg of amoxicillin as the trihydrate and 31.25 mg of clavulanic acid (equivalent to 37.23 mg of clavulanate potassium).

• 200 mg/28.5 mg: Each 5 mL contains 200 mg of amoxicillin as the trihydrate and 28.5 mg of clavulanic acid (equivalent to 34 mg of clavulanate potassium).

• 250 mg/62.5 mg: Each 5 mL contains 250 mg of amoxicillin as the trihydrate and 62.5 mg of clavulanic acid (equivalent to 74.5 mg of clavulanate potassium).

• 400 mg/57 mg: Each 5 mL contains 400 mg of amoxicillin as the trihydrate and 57 mg of clavulanic acid (equivalent to 68 mg of clavulanate potassium).

Amoxicillin and Clavulanate Potassium Chewable Tablets:

• 125 mg/31.25 mg: Each chewable tablet contains 125 mg of amoxicillin as the trihydrate and 31.25 mg of clavulanic acid (equivalent to 37.23 mg of clavulanate potassium).

• 200 mg/28.5 mg: Each chewable tablet contains 200 mg of amoxicillin as the trihydrate and 28.5 mg of clavulanic acid (equivalent to 34 mg of clavulanate potassium).

• 250 mg/62.5 mg: Each chewable tablet contains 250 mg of amoxicillin as the trihydrate and 62.5 mg of clavulanic acid (equivalent to 74.5 mg of clavulanate potassium).

• 400 mg/57 mg: Each chewable tablet contains 400 mg of amoxicillin as the trihydrate and 57 mg of clavulanic acid (equivalent to 68 mg of clavulanate potassium).

Inactive ingredients vary by formulation and include colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, titanium dioxide, flavorings, xanthan gum, mannitol, succinic acid, silica gel, sodium saccharin, glycine, and aspartame. Each dosage form contains a specific amount of potassium, with values ranging from 0.14 mEq to 0.63 mEq per dosage unit.

Uses and Indications

Amoxicillin and Clavulanate Potassium is 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.

This drug should be utilized only 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 and other antibacterial agents.

There are no teratogenic or nonteratogenic effects associated with Amoxicillin and Clavulanate Potassium.

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, based on the amoxicillin component. It is advised to use the 125 mg/5 mL oral suspension for this age group.

Contraindications

Use of Amoxicillin and Clavulanate Potassium 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 fatal outcomes, have been associated with the use of 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; therefore, patients should be monitored closely for any signs of rash. Should the rash progress, discontinuation of Amoxicillin and Clavulanate Potassium is necessary.

Drug-induced enterocolitis syndrome (DIES) has been reported in patients receiving amoxicillin, a component of Amoxicillin and Clavulanate Potassium. If DIES is suspected, the medication should be discontinued, and appropriate therapeutic measures should be initiated.

Patients with hepatic dysfunction or cholestatic jaundice should be closely monitored for signs and symptoms of hepatitis. In such cases, discontinuation of the medication is warranted, and liver function tests should be performed to assess hepatic status.

Clostridioides difficile-associated diarrhea (CDAD) is a potential complication; therefore, healthcare professionals should evaluate patients who present with diarrhea during treatment.

Amoxicillin and Clavulanate Potassium should be avoided in patients with mononucleosis, as these individuals are at risk of developing a skin rash upon administration of the medication.

The possibility of superinfections due to overgrowth of fungal or bacterial pathogens should be considered during therapy with Amoxicillin and Clavulanate Potassium.

It is important to note that high urine concentrations of amoxicillin may lead to false-positive results when testing for glucose in urine using CLINITEST®, Benedict's Solution, or Fehling's Solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be utilized for accurate assessment.

Additionally, following the administration of amoxicillin to pregnant women, a transient decrease in plasma concentrations of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been observed. This should be taken into consideration when prescribing Amoxicillin and Clavulanate Potassium to pregnant patients.

Side Effects

The most frequently reported adverse reactions in clinical trials included diarrhea or loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%), and vaginitis (1%). Less frequently reported adverse reactions, occurring in less than 1% of participants, included abdominal discomfort, flatulence, and headache. Notably, less than 3% of patients discontinued therapy due to drug-related adverse reactions. The overall incidence of adverse reactions, particularly diarrhea, was observed to increase with higher recommended doses.

Serious adverse reactions have been documented, including serious (and potentially fatal) hypersensitivity reactions. In such cases, it is imperative to discontinue Amoxicillin and Clavulanate Potassium 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 with the use of amoxicillin, necessitating the discontinuation of Amoxicillin and Clavulanate Potassium and the initiation of appropriate therapy if this occurs. Hepatic dysfunction and cholestatic jaundice may arise; therefore, discontinuation is warranted if signs or symptoms of hepatitis develop, and liver function tests should be monitored in patients with hepatic impairment. Additionally, Clostridioides difficile-associated diarrhea (CDAD) should be evaluated in patients presenting with diarrhea.

Patients with mononucleosis who receive Amoxicillin and Clavulanate Potassium are at risk of developing 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.

Additional adverse reactions of note include interstitial nephritis, which can result in oliguric renal failure, reported in patients following overdosage with Amoxicillin and Clavulanate Potassium. Crystalluria, which in some cases has led to renal failure, has been observed after overdosage in both adult and pediatric patients. Renal impairment appears to be reversible upon cessation of the drug. It is important to note that high blood levels of Amoxicillin and Clavulanate Potassium may occur more readily in patients with impaired renal function due to decreased renal clearance. Furthermore, Amoxicillin and Clavulanate Potassium can be removed from circulation by hemodialysis.

Drug Interactions

Co-administration of Amoxicillin and Clavulanate Potassium with certain medications may lead to significant interactions that require careful consideration.

Pharmacodynamic Interactions

The concomitant use of Amoxicillin and Clavulanate Potassium with oral anticoagulants has been observed to potentially increase the prolongation of prothrombin time. Clinicians should monitor prothrombin time closely in patients receiving this combination to ensure appropriate anticoagulation levels are maintained.

Additionally, the use of Amoxicillin and Clavulanate Potassium alongside allopurinol has been associated with an increased risk of rash. Patients should be monitored for dermatological reactions, and if a rash develops, discontinuation of one or both agents may be warranted.

Pharmacokinetic Interactions

Co-administration with probenecid is not recommended, as it may affect the pharmacokinetics of Amoxicillin and Clavulanate Potassium, potentially leading to altered therapeutic effects.

Furthermore, it is important to note that Amoxicillin and Clavulanate Potassium may reduce the efficacy of oral contraceptives. Patients using hormonal contraceptives should be advised to consider alternative or additional contraceptive methods during treatment to prevent unintended pregnancy.

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 this medication in children includes studies conducted with Amoxicillin and Clavulanate Potassium Tablets in adults, as well as a specific 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 under 12 weeks (less than 3 months) of age to ensure safety and efficacy.

Geriatric Use

In clinical studies of 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 younger subjects. 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 by the kidneys, which raises concerns regarding the risk of adverse reactions in patients with impaired renal function. Given that geriatric 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 elderly patients to ensure appropriate dosing and to mitigate potential risks associated with renal impairment.

Pregnancy

Pregnant patients should be informed that Amoxicillin and Clavulanate Potassium is classified as Pregnancy Category B. Reproductive studies conducted in pregnant rats and mice, using a 2:1 ratio formulation of amoxicillin to clavulanate at oral doses up to 1200 mg/kg/day, demonstrated no evidence of fetal harm associated with the administration of Amoxicillin and Clavulanate Potassium. The doses of amoxicillin administered 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.

It is important to note that 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 should weigh the potential benefits against any possible 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 lactating mothers.

Renal Impairment

Amoxicillin is primarily eliminated by the kidney, and dosage adjustment is usually required in patients with severe renal impairment, specifically those with a glomerular filtration rate (GFR) of less than 30 mL/min. Healthcare professionals should refer to the specific recommendations for patients with renal impairment to ensure appropriate dosing and monitoring in this 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.

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 instances, hemodialysis may be employed to facilitate the removal of the drug from circulation.

Nonclinical Toxicology

Pregnancy Category B. Reproduction studies conducted in pregnant rats and mice administered Amoxicillin and Clavulanate Potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses up to 1200 mg/kg/day demonstrated no evidence of fetal harm attributable to Amoxicillin and Clavulanate Potassium. The amoxicillin doses in rats and mice, adjusted for body surface area, were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours), respectively. For clavulanate, these dose 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. Due to the limitations of animal reproduction studies in predicting human response, this drug should be utilized during pregnancy only if clearly necessary.

Long-term studies in animals have not been conducted to assess the carcinogenic potential of Amoxicillin and Clavulanate Potassium. In mutagenicity assessments, Amoxicillin and Clavulanate Potassium (4:1 ratio formulation of amoxicillin:clavulanate) was found to be non-mutagenic in the Ames bacterial mutation assay and the yeast gene conversion assay. It exhibited weak positivity in the mouse lymphoma assay; however, the observed trend toward increased mutation frequencies in this assay occurred at doses that were also linked to decreased cell survival. The compound was negative in the mouse micronucleus test and in the dominant lethal assay in mice. Potassium clavulanate alone was evaluated in the Ames bacterial mutation assay and the mouse micronucleus test, yielding negative results in both assays.

Amoxicillin and Clavulanate Potassium (2:1 ratio formulation of amoxicillin:clavulanate) administered at oral doses up to 1,200 mg/kg/day did not affect fertility or reproductive performance in rats. Based on body surface area, this dose of amoxicillin is approximately 4 times the maximum recommended adult human oral dose (875 mg every 12 hours), while the dose for clavulanate is approximately 9 times higher than the maximum recommended adult human oral dose (125 mg every 8 hours), also adjusted for body surface area.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions associated with the use of the antibacterial. Notably, severe cutaneous adverse reactions (SCAR) have been reported. Additionally, instances of diarrhea have been documented, including cases characterized by watery and bloody stools. These gastrointestinal events may occur even two or more months following the discontinuation of the antibacterial.

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 Amoxicillin and Clavulanate Potassium contains a penicillin class drug, which can lead to allergic reactions in some individuals. Patients should be made aware of the signs and symptoms of serious skin manifestations. 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 stomach cramps and fever) even weeks 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, 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 even if they feel better early in the treatment, it is vital to 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.

Patients should be advised to store the suspension refrigerated and to shake it well before use. When administering the suspension to a child, a calibrated oral syringe should be used, and it is important to rinse the syringe 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.

Storage and Handling

Tablets and dry powder should be stored at or below 25°C (77°F). Once reconstituted, the suspension must be kept under refrigeration. Any unused suspension should be discarded after 10 days to ensure safety and efficacy. The product should be dispensed in a tight container, in accordance with USP guidelines. Additionally, it is essential to keep this product out of the reach of children to prevent accidental ingestion.

Additional Clinical Information

High urine concentrations of amoxicillin may lead to false-positive results for glucose in urine when using CLINITEST®, Benedict's Solution, or Fehling's Solution. Clinicians are advised to utilize glucose tests that rely on enzymatic glucose oxidase reactions for accurate results. Additionally, administration of amoxicillin to pregnant women has been associated with a transient decrease in plasma concentrations of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol.

FDA Insert (PDF)

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

View full prescribing information (PDF)