Amoxicillin/Clavulanate potassium

Description

Amoxicillin and clavulanate potassium tablets, USP, and for oral suspension, USP, are an oral antibacterial combination consisting of amoxicillin and the beta-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The molecular formula for amoxicillin is C16H19N3O5S•3H2O, with a molecular weight of 419.46 g/mol. Chemically, amoxicillin is described 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. The molecular formula for clavulanate potassium is C8H8KNO5, with a molecular weight of 237.25 g/mol. Chemically, clavulanate potassium is potassium (Z)(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo3.2.0-heptane-2-carboxylate.

Amoxicillin and clavulanate potassium tablets are available in strengths of 250 mg/125 mg, 500 mg/125 mg, and 875 mg/125 mg. The oral suspension is available in strengths of 200 mg/28.5 mg and 400 mg/57 mg. Each tablet contains 0.63 mEq potassium. Each 5 mL of reconstituted 200 mg/28.5 mg oral suspension contains 0.14 mEq potassium, while each 5 mL of reconstituted 400 mg/57 mg oral suspension contains 0.29 mEq potassium.

Inactive ingredients in amoxicillin and clavulanate potassium tablets include colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, talc, titanium dioxide, triethyl citrate, ethylcellulose, cetyl alcohol, and sodium lauryl sulfate. Inactive ingredients in the oral suspension include aspartame, colloidal silicon dioxide, hydroxypropyl methylcellulose, mannitol, orange flavoring, precipitated silicon dioxide, succinic acid, xanthan gum, and golden syrup flavoring (caramel).

Uses and Indications

Amoxicillin and clavulanate potassium tablets and oral suspension 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.

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 as well as other antibacterial agents.

There are no teratogenic or nonteratogenic effects associated with this medication.

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 utilized.

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 less than 12 weeks of age, the recommended dosage is 30 mg/kg/day, divided and administered every 12 hours. It is advised to use the 125 mg/5 mL oral suspension for this population to ensure accurate dosing and administration.

Contraindications

Use of this product is contraindicated in patients with a history of serious hypersensitivity reactions, such as anaphylaxis or Stevens-Johnson syndrome, to amoxicillin and clavulanate potassium or to other beta-lactams, including 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, discontinuation of amoxicillin and clavulanate potassium is necessary.

Drug-induced enterocolitis syndrome (DIES) has been associated with the use of amoxicillin, a component of this combination therapy. Should symptoms indicative of DIES arise, the medication must be discontinued, and appropriate therapeutic measures should be initiated.

Patients with hepatic dysfunction are at an increased risk for cholestatic jaundice. It is essential to discontinue treatment if any signs or symptoms of hepatitis develop. 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 prone to developing skin rashes when treated with this medication.

Finally, healthcare providers should remain vigilant for the possibility of superinfections with fungal or bacterial pathogens during therapy, as overgrowth may occur. Regular assessment of the patient's clinical status is recommended to address any emerging infections promptly.

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, amoxicillin and clavulanate potassium should be discontinued immediately if such a reaction occurs. Severe cutaneous adverse reactions (SCAR) require close monitoring, and discontinuation is advised if any rash progresses. Drug-induced enterocolitis syndrome (DIES) necessitates discontinuation of the medication and appropriate therapeutic intervention if it occurs. Hepatic dysfunction and cholestatic jaundice have been noted, with recommendations to discontinue treatment if signs or symptoms of hepatitis arise, alongside monitoring liver function tests in patients with pre-existing hepatic impairment. Clostridioides difficile-associated diarrhea (CDAD) should be evaluated in patients presenting with diarrhea.

Additionally, patients with mononucleosis who are treated with amoxicillin and clavulanate potassium may develop skin rashes, and its use is contraindicated in these individuals. The potential for superinfections with fungal or bacterial pathogens should be considered during therapy, particularly in the context of overgrowth.

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 pharmacokinetic interactions that may affect the therapeutic efficacy of the antibiotic.

When used concurrently with oral anticoagulants, amoxicillin and clavulanate potassium may lead to an increased prolongation of prothrombin time. Clinicians should monitor prothrombin time closely and consider dosage adjustments of the anticoagulant as necessary to maintain therapeutic levels.

The concomitant use of amoxicillin and clavulanate potassium with allopurinol has been associated with an increased risk of rash. Patients should be monitored for dermatological reactions, and if a rash occurs, discontinuation of one or both agents should be considered.

Additionally, amoxicillin and clavulanate potassium may reduce the efficacy of oral contraceptives. Patients using hormonal contraceptives should be advised to consider alternative or additional non-hormonal 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 these formulations in children is derived from studies involving amoxicillin and clavulanate potassium tablets in adults, supplemented by data from a study specifically examining the oral suspension 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, with 14% being 75 years or older. Overall, no significant differences in safety or effectiveness were observed between 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 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 mitigate the risk of adverse effects and ensure appropriate dosing.

Pregnancy

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 harm to 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 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 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 indicates that overdosages of amoxicillin below 250 mg/kg are generally not associated with significant clinical symptoms. However, it is important to note that interstitial nephritis leading to oliguric renal failure has been documented in patients following an overdosage of amoxicillin and clavulanate potassium. Additionally, crystalluria has been reported, which in some instances has resulted in renal failure among both adult and pediatric patients.

To mitigate the risk of crystalluria, it is essential to maintain adequate fluid intake and promote diuresis. It should be noted that patients with impaired renal function may experience elevated blood levels of amoxicillin and clavulanate potassium due to decreased renal clearance.

In cases of severe overdosage, hemodialysis may be employed to facilitate the removal of amoxicillin and clavulanate potassium from circulation. Healthcare professionals should remain vigilant and monitor patients closely for any signs of complications associated with overdosage.

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, also yielded negative results 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 several adverse reactions reported voluntarily or through surveillance programs. These include anaphylaxis and serious skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Hepatic dysfunction has also been noted, encompassing cholestatic jaundice and hepatitis. Hematologic reactions, including thrombocytopenia, leukopenia, and agranulocytosis, have been reported, as well as renal impairment characterized by interstitial nephritis. Additionally, cases of Clostridium difficile-associated diarrhea have been documented. Allergic reactions, including angioedema and urticaria, were also observed. Other adverse reactions reported include nausea, vomiting, and abdominal pain.

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 dose. Each dose should be taken 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 cause allergic reactions in some individuals. Patients should be advised about the signs and symptoms of serious skin manifestations. They should be instructed to stop taking amoxicillin and clavulanate potassium immediately and promptly report any signs or symptoms of skin rash, mucosal lesions, or other indications of hypersensitivity.

It is important to inform patients that diarrhea is a common side effect associated with antibacterial medications, typically resolving upon discontinuation of the drug. However, patients should be made aware that they may develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after their last dose. If diarrhea is severe or persists for more than 2 or 3 days, patients should contact their physician as soon as possible.

Patients should be counseled 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 informed 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 likelihood of bacterial resistance, rendering amoxicillin and clavulanate potassium or other antibacterial drugs ineffective in the future.

Patients should be advised to keep the suspension refrigerated and to shake it well before use. When dosing a child with the liquid form of amoxicillin and clavulanate potassium, a calibrated oral syringe should be used, and it is essential to rinse the syringe 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. Any unused medicine should be discarded as per the guidance provided.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) 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. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

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 REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)