Amoxicillin/Clavulanate potassium

Description

Amoxicillin and clavulanate potassium tablets, USP, are oral antibacterial combinations comprising amoxicillin and clavulanate potassium, the potassium salt of clavulanic acid. 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 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, and 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 three strengths: 250 mg/125 mg, 500 mg/125 mg, and 875 mg/125 mg. Each tablet contains 250 mg, 500 mg, or 875 mg of amoxicillin as the trihydrate, respectively, along with 125 mg of clavulanic acid, which is equivalent to 149 mg of clavulanate potassium. Each tablet also contains 0.63 mEq of potassium.

Inactive ingredients include colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, talc, titanium dioxide, triethyl citrate, ethylcellulose, cetyl alcohol, and sodium lauryl sulfate. The 875 mg/125 mg tablet additionally contains crospovidone.

Uses and Indications

Amoxicillin and clavulanate potassium tablet 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 used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. 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.

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, 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 warranted.

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, it is essential to discontinue the medication and initiate appropriate therapeutic measures.

Patients with hepatic dysfunction or those exhibiting signs of cholestatic jaundice should be closely monitored. Liver function tests are recommended for patients with pre-existing hepatic impairment, and the medication should be discontinued if any signs or symptoms of hepatitis develop.

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

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

Additionally, healthcare providers should remain vigilant for the possibility of superinfections due to overgrowth of fungal or bacterial pathogens during therapy, necessitating appropriate clinical management.

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 during treatment.

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 also be considered during therapy.

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 amoxicillin and clavulanate potassium is also significant. Furthermore, 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 appropriate 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 for decreased contraceptive effectiveness and advised 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 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 additional 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, 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 in reported clinical experiences.

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

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 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 monitoring of renal function may be warranted in patients with reduced kidney function to ensure safety and efficacy.

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 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 can 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 4:1 ratio formulation of amoxicillin and clavulanate was found to be non-mutagenic 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 formulation was negative in the mouse micronucleus test and in the dominant lethal assay in mice.

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

In terms of reproductive toxicity, the 2:1 ratio formulation of amoxicillin and clavulanate potassium, administered at oral doses of up to 1,200 mg/kg/day, demonstrated no adverse effects on fertility and 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. Notably, severe cutaneous adverse reactions (SCAR) have been documented. Additionally, instances of diarrhea, including cases characterized by watery and bloody stools, have been reported, occurring even as late as 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. 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 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 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 cautioned that they may experience watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after completing the course of treatment. If diarrhea is severe or persists for more than 2 or 3 days, patients should contact their physician without delay.

Patients should be advised 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 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 risk of bacterial resistance, making future infections harder to treat with amoxicillin and clavulanate potassium or other antibacterial drugs.

Patients should also be advised to keep the suspension refrigerated and to shake it well before use. When administering the suspension (liquid) to a child, a calibrated oral syringe should be used, and it is essential 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

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 Northstar RxLLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)