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 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 is produced through the fermentation of Streptomyces clavuligerus and is structurally related to penicillins. It possesses the ability to inactivate certain beta-lactamases by blocking their active sites, with a molecular formula of C₈H₈KNO₅ and a molecular weight of 237.25 g/mol. The chemical structure of clavulanate potassium is potassium (Z)(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo3.2.0-heptane-2-carboxylate.

The formulation includes various inactive ingredients depending on the dosage form. For tablets, the inactive components are colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide, with each tablet containing 0.63 mEq potassium. The powder for oral suspension is available in concentrations of 125 mg/5 mL and 250 mg/5 mL, containing colloidal silicon dioxide, flavorings, xanthan gum, mannitol, succinic acid, silica gel, and sodium saccharin. Higher concentrations of 200 mg/5 mL and 400 mg/5 mL also include similar inactive ingredients with slight variations.

Chewable tablets are available in strengths of 125 mg and 250 mg, containing colloidal silicon dioxide, flavorings, magnesium stearate, mannitol, sodium saccharin, glycine, and D&C Yellow No.10, with each 125-mg chewable tablet and each 5 mL of reconstituted 125/5 mL oral suspension containing 0.16 mEq potassium, and each 250-mg chewable tablet and each 5 mL of reconstituted 250/5 mL oral suspension containing 0.32 mEq potassium. Additionally, chewable tablets of 200 mg and 400 mg contain similar inactive ingredients with FD&C Red No. 40, with each 200-mg chewable tablet and each 5 mL of reconstituted 200/5 mL oral suspension containing 0.14 mEq potassium, and each 400-mg chewable tablet and each 5 mL of reconstituted 400/5 mL oral suspension containing 0.29 mEq potassium.

Uses and Indications

Amoxicillin and Clavulanate Potassium is indicated for the treatment of the following infections: 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 alternatively, 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 and administered every 12 hours, or 20 to 40 mg/kg/day, divided and administered every 8 hours, not exceeding the adult dosage.

For neonates and infants under 12 weeks of age, the recommended dosage is 30 mg/kg/day, divided and administered every 12 hours. It is advised to utilize the 125 mg/5 mL oral suspension for this age group.

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, the administration of the medication should be discontinued immediately. Healthcare professionals are advised to monitor patients closely for any signs of hypersensitivity during treatment (5.1).

Patients with pre-existing hepatic dysfunction are at an increased risk for developing cholestatic jaundice. If any signs or symptoms of hepatitis manifest, the use of Amoxicillin and Clavulanate Potassium should be discontinued. It is essential to monitor liver function tests in patients with hepatic impairment to ensure timely detection of any adverse effects (5.2).

Clostridium difficile-associated diarrhea (CDAD) has been associated with the use of antibiotics, including Amoxicillin and Clavulanate Potassium. Healthcare providers should evaluate patients who present with diarrhea during or after treatment, as this may indicate the presence of CDAD. Prompt assessment and management are crucial (5.3).

In patients diagnosed with mononucleosis, the administration of Amoxicillin and Clavulanate Potassium may lead to the development of a skin rash. Therefore, it is recommended to avoid the use of this medication in individuals with mononucleosis to prevent adverse skin reactions (5.4).

The potential for superinfections, including those caused by fungal or bacterial pathogens, should be considered during the course of therapy with Amoxicillin and Clavulanate Potassium. Healthcare professionals should remain vigilant for signs of overgrowth and manage any superinfections appropriately (5.5).

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 have also been reported. These include serious hypersensitivity reactions, which may be fatal; therefore, it is imperative to discontinue Amoxicillin and Clavulanate Potassium if such a reaction occurs. Hepatic dysfunction and cholestatic jaundice have been noted, necessitating discontinuation if signs or symptoms of hepatitis arise, along with monitoring of liver function tests in patients with pre-existing hepatic impairment. Additionally, Clostridium difficile-associated diarrhea (CDAD) should be evaluated if diarrhea occurs during treatment. Patients with mononucleosis who receive this medication may develop skin rashes, and its use is contraindicated in these individuals. 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, including penicillins and cephalosporins. A history of cholestatic jaundice or hepatic dysfunction associated with this medication is also significant. Furthermore, 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 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. Monitoring of prothrombin time is advised 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.

Additionally, Amoxicillin and Clavulanate Potassium may reduce the efficacy of oral contraceptives. Patients should be informed of this potential interaction and advised to consider alternative or additional contraceptive measures 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 Powder for Oral Suspension and Chewable Tablets have been established in pediatric patients. Evidence supporting the use of Amoxicillin and Clavulanate Potassium in this population is derived from studies involving Amoxicillin and Clavulanate Potassium Tablets in adults, along with additional data from a study of the Powder for Oral Suspension in pediatric patients aged 2 months to 12 years with acute otitis media.

In neonates and young infants, renal function is incompletely developed, which may lead to delayed elimination of amoxicillin; however, the elimination of clavulanate remains unaltered in this age group. Therefore, dosing of Amoxicillin and Clavulanate Potassium should be modified for pediatric patients aged less than 12 weeks (less than 3 months).

Geriatric Use

In clinical studies of Amoxicillin and Clavulanate Potassium, 32% of the 3,119 patients analyzed were aged 65 years and older, with 14% being 75 years and 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 consider that some older individuals may exhibit greater sensitivity to the drug.

Amoxicillin and Clavulanate Potassium is primarily excreted by 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

Pregnant patients should be informed that Amoxicillin and Clavulanate Potassium is classified as Pregnancy Category B. Reproduction 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 harm to the fetus attributable to the drug. The amoxicillin doses 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 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 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/clavulanate potassium by nursing mothers may lead to sensitization of breastfed infants. Therefore, caution should be exercised when administering amoxicillin/clavulanate potassium to a lactating mother.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

Hepatic Impairment

Patients with hepatic impairment should be closely monitored for liver function tests. In the event of hepatic dysfunction or the development of cholestatic jaundice, it is recommended to discontinue treatment if signs or symptoms of hepatitis occur. Regular assessment of liver function is essential to ensure patient safety and to guide any necessary adjustments in therapy.

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 are generally not associated with significant clinical symptoms.

Potential Symptoms and Complications

Overdosage of amoxicillin/clavulanate potassium has been associated with interstitial nephritis, which can lead to oliguric renal failure. Additionally, crystalluria has been reported, which in some instances may progress to renal failure in both adult and pediatric populations.

Management Recommendations

To mitigate the risk of crystalluria following an overdosage of amoxicillin/clavulanate potassium, it is essential to maintain adequate fluid intake and promote diuresis. This approach helps to reduce the likelihood of crystallization in the renal system.

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/clavulanate potassium due to decreased 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, 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 decreased cell survival at the tested doses. Additionally, Amoxicillin and Clavulanate Potassium yielded negative results in the mouse micronucleus test and the dominant lethal assay in mice.

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

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 diarrhea as a common adverse event associated with the use of antibacterials, typically resolving upon discontinuation of the medication. Notably, there have been reports of patients developing watery and bloody stools, with or without accompanying symptoms such as stomach cramps and fever, even up to two months after the last dose of the antibacterial. In instances where diarrhea is severe or persists for more than two to three days, it is advised that patients seek medical attention.

Additionally, it is important for patients to be informed that Amoxicillin and Clavulanate Potassium contains a penicillin-class drug, which may lead to allergic reactions in susceptible individuals.

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 intended 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 likelihood of bacteria developing resistance, rendering Amoxicillin and Clavulanate Potassium or other antibacterial drugs ineffective 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. They should be informed that in some cases, watery and bloody stools may occur, 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.

For those receiving the suspension form of Amoxicillin and Clavulanate Potassium, patients should be advised to keep the medication refrigerated and to shake it well before use. When administering the suspension to a child, a dosing spoon or medicine dropper should be utilized, and it is essential 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

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. It is essential to dispense the product in its original container to maintain integrity. Additionally, the product should be kept out of the reach of children to prevent accidental ingestion.

Additional Clinical Information

Patients should be informed that Amoxicillin and Clavulanate Potassium Chewable tablets and Powder for Oral Solution contain aspartame, which includes phenylalanine. Specifically, each 200-mg chewable tablet contains 2.1 mg of phenylalanine, while each 400-mg chewable tablet contains 4.2 mg. Additionally, each 5 mL of the 200 mg/5 mL or 400 mg/5 mL oral suspension contains 7 mg of phenylalanine. It is important to note that other formulations of Amoxicillin and Clavulanate Potassium do not contain phenylalanine.

No further information is available regarding laboratory tests, abuse potential, route, method, and frequency of administration, or postmarketing experience.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Amoxicillin and Clavulanate Potassium as submitted by Dr. Reddy's Laboratories Inc. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)