Amoxicillin/Clavulanate potassium

Description

Amoxicillin and clavulanate potassium for oral suspension USP, 600 mg/42.9 mg per 5 mL, is an oral antibacterial combination comprising the semisynthetic antibacterial amoxicillin and the beta-lactamase inhibitor clavulanate potassium, the potassium salt of clavulanic acid. Amoxicillin, an analog of ampicillin derived from the penicillin nucleus 6-aminopenicillanic acid, has a molecular formula of C₁₆H₁₉N₃O₅S•3H₂O and a molecular weight of 419.4 g/mol. Its chemical structure is defined as (2S,5R,6R)-6-((R)-2-amino-2-(4-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, is a beta-lactam structurally related to penicillins. It effectively inactivates a variety of beta-lactamases by blocking their active sites, particularly those that are plasmid-mediated and responsible for drug resistance to penicillins and cephalosporins. The molecular formula for clavulanate potassium is C₈H₈KNO₅, with a molecular weight of 237.3 g/mol, and its chemical structure is potassium (Z)-(2R,5R)-3-(2-Hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo3.2.0heptane-2-carboxylic acid.

Upon reconstitution, each 5 mL of the oral suspension contains 600 mg of amoxicillin, USP as the trihydrate, and 42.9 mg of clavulanic acid, equivalent to 51.1 mg of clavulanate potassium. Each dose also provides 0.23 mEq of potassium. Inactive ingredients include aspartame, citric acid anhydrous, colloidal silicon dioxide, hypromellose, mannitol, orange flavor, trisodium citrate dihydrate, and xanthan gum.

Uses and Indications

Amoxicillin and clavulanate potassium for oral suspension is indicated for the treatment of pediatric patients aged 3 months to 12 years, weighing less than or equal to 40 kg, who present with recurrent or persistent acute otitis media. This indication specifically applies to cases caused by the following bacterial pathogens: Streptococcus pneumoniae (with penicillin minimum inhibitory concentrations MICs less than or equal to 2 mcg/mL), Haemophilus influenzae (including beta-lactamase-producing strains), and Moraxella catarrhalis (including beta-lactamase-producing strains). Patients exhibiting the following risk factors are particularly suited for this treatment: antibacterial exposure for acute otitis media within the preceding 3 months, age of 2 years or younger, or attendance at daycare.

Amoxicillin and clavulanate potassium for oral suspension should be utilized exclusively for the treatment or prevention of infections that are proven or strongly suspected to be of bacterial origin.

Dosage and Administration

Pediatric patients aged 3 months to 12 years who weigh less than or equal to 40 kg should receive a dosage of 90 mg/kg/day. This dosage should be divided into two administrations every 12 hours. The treatment course is to be continued for a total duration of 10 days.

Healthcare professionals are advised to ensure accurate weight measurement to calculate the appropriate dosage and to monitor the patient for any adverse reactions throughout the treatment period.

Contraindications

Use of amoxicillin and clavulanate potassium for oral suspension is contraindicated in patients with a history of serious hypersensitivity reactions, including anaphylaxis or Stevens-Johnson syndrome, to amoxicillin, clavulanate potassium, or any 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 the use of amoxicillin and clavulanate potassium.

Warnings and Precautions

Serious hypersensitivity reactions, including those that may be fatal, 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 and initiate appropriate therapeutic measures.

Severe cutaneous adverse reactions (SCAR) have also been reported. Patients should be monitored closely for any signs of rash, and the medication should be discontinued if the rash progresses.

Drug-induced enterocolitis syndrome (DIES) has been documented in patients using amoxicillin, a component of amoxicillin and clavulanate potassium. Should symptoms of DIES arise, the medication must be discontinued, and suitable therapy should be initiated.

Patients with hepatic dysfunction are at risk for cholestatic jaundice. It is essential to discontinue the medication 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) can occur with the use of this medication, presenting as a spectrum from mild diarrhea to potentially fatal colitis. Healthcare professionals should evaluate patients promptly if diarrhea develops during treatment.

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.

Side Effects

Patients receiving amoxicillin and clavulanate potassium for oral suspension may experience a range of adverse reactions. The most frequently reported adverse reactions include coughing, vomiting, contact dermatitis (such as diaper rash), fever, upper respiratory tract infection, and diarrhea.

Serious adverse reactions have been observed and require immediate attention. These include serious hypersensitivity reactions, which can be fatal; in such cases, amoxicillin and clavulanate potassium should be discontinued, and appropriate therapy should be initiated. Severe cutaneous adverse reactions (SCAR) necessitate close monitoring, with discontinuation of the medication if any rash progresses. Drug-induced enterocolitis syndrome (DIES) is another serious reaction that warrants discontinuation of the drug and appropriate therapeutic measures. Hepatic dysfunction and cholestatic jaundice have also been reported; if signs or symptoms of hepatitis occur, the medication should be discontinued, and liver function tests should be monitored in patients with pre-existing hepatic impairment. Additionally, Clostridioides difficile-associated diarrhea (CDAD), which can range from mild diarrhea to fatal colitis, should be evaluated if diarrhea occurs. It is important to note that patients with mononucleosis who receive this medication may develop a skin rash, and its use should be avoided in these individuals.

Other important considerations include a history of serious hypersensitivity reactions, such as anaphylaxis or Stevens-Johnson syndrome, to amoxicillin and clavulanate potassium or any other beta-lactams, including penicillins or cephalosporins. A history of cholestatic jaundice or hepatic dysfunction associated with this medication is also significant.

In cases of overdosage, patients have primarily experienced gastrointestinal symptoms, including stomach and abdominal pain, vomiting, and diarrhea. Some patients have also reported rash, hyperactivity, or drowsiness. Rarely, interstitial nephritis resulting in oliguric renal failure has been documented following overdosage with amoxicillin. Furthermore, crystalluria, which in some instances has led to renal failure, has been reported in both adult and pediatric patients after amoxicillin overdosage.

Drug Interactions

Co-administration of amoxicillin and clavulanate potassium for oral suspension 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. Clinicians should monitor prothrombin time closely and consider dosage adjustments of the anticoagulant as necessary.

The concomitant use of allopurinol with amoxicillin and clavulanate potassium is associated with an increased risk of rash. Patients should be monitored for dermatological reactions, and if a rash occurs, discontinuation of one or both medications 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 have been established in pediatric patients aged 3 months to 12 years, specifically for those weighing less than or equal to 40 kg, in the treatment of acute otitis media and acute bacterial sinusitis. However, the safety and effectiveness of this medication have not been established in pediatric patients younger than 3 months of age or in those aged 3 months to 12 years who weigh more than 40 kg. Caution is advised when considering treatment in these populations.

Geriatric Use

Elderly patients may exhibit altered pharmacokinetics and increased susceptibility to adverse effects when treated with amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL. The safety and effectiveness of this formulation have not been established in adults and pediatric patients weighing more than 40 kg.

In geriatric patients, hepatic dysfunction is more frequently observed, particularly in those with a history of prolonged treatment. This dysfunction may manifest as increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase levels. It is important to monitor hepatic function at regular intervals in elderly patients, especially those with existing hepatic impairment, as the hepatic dysfunction, which can be severe, is typically reversible upon discontinuation of the medication.

Additionally, caution is warranted when administering this medication to elderly patients with evidence of hepatic dysfunction. Serious hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving beta-lactam antibacterials, and these reactions are more likely to occur in individuals with a history of penicillin hypersensitivity or sensitivity to multiple allergens.

Elderly patients with renal impairment may experience increased blood levels of both amoxicillin and clavulanate due to decreased renal clearance, which can occur more readily in this population. Therefore, careful consideration of renal function and potential dose adjustments may be necessary to mitigate the risk of adverse effects in geriatric patients.

Pregnancy

Available data from published epidemiologic studies and pharmacovigilance case reports over several decades of use with amoxicillin and clavulanate during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal outcomes. However, a study involving women with preterm prelabor rupture of membranes (PPROM) indicated that prophylactic treatment with amoxicillin and clavulanate may be associated with an increased risk of necrotizing enterocolitis in neonates. Specifically, in a randomized, controlled trial of 4,826 pregnant women with premature rupture of fetal membranes, the use of amoxicillin and clavulanate was linked to a significantly higher rate of proven neonatal necrotizing enterocolitis, with an incidence of 1.9% in the amoxicillin and clavulanate group compared to 0.5% in the placebo group (p = 0.001).

Reproduction studies conducted in pregnant rodents, including rats and mice, administered doses of amoxicillin and clavulanate up to approximately 2 times the amount of amoxicillin and 15 times the amount of clavulanate in the Maximum Human Recommended Dose (MHRD) for oral suspension, revealed no evidence of harm to the fetus. Similarly, studies in pregnant rats and mice given amoxicillin and clavulanate at oral doses up to 1200 mg/kg/day also showed no evidence of fetal harm.

It is important to note that the background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Therefore, healthcare professionals should weigh the potential benefits and risks when considering the use of amoxicillin and clavulanate in pregnant patients.

Lactation

There is no specific information available regarding the use of this medication in nursing mothers or its effects on lactation. Additionally, no data are provided concerning the excretion of this medication in breast milk or its potential effects on breastfed infants. Healthcare professionals should consider the lack of information when advising lactating mothers about the use of this medication.

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 the safety and efficacy of the therapy in this population.

Overdosage

Following overdosage of amoxicillin and clavulanate potassium for oral suspension, patients have primarily exhibited gastrointestinal symptoms, including stomach and abdominal pain, vomiting, and diarrhea. In a minority of cases, additional symptoms such as rash, hyperactivity, or drowsiness have been reported.

In the event of an overdosage, it is recommended to discontinue the administration of amoxicillin and clavulanate potassium. Symptomatic treatment and supportive measures should be instituted as necessary. If the overdosage has occurred very recently and there are no contraindications, an attempt at emesis or other methods to remove the drug from the stomach may be considered. 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 and do not necessitate gastric emptying.

There have been reports of interstitial nephritis leading to oliguric renal failure in a small number of patients following overdosage with amoxicillin. Additionally, crystalluria, which in some instances has resulted in renal failure, has been documented in both adult and pediatric patients after amoxicillin overdosage. To mitigate the risk of crystalluria, it is essential to maintain adequate fluid intake and diuresis.

Renal impairment observed in these cases appears to be reversible upon cessation of the drug. It is important to note that patients with impaired renal function may experience higher blood levels of the drug due to decreased renal clearance of both amoxicillin and clavulanate. Both compounds can be effectively removed from circulation through hemodialysis.

Nonclinical Toxicology

Long-term studies in animals have not been conducted to assess the carcinogenic potential of the combination of amoxicillin and clavulanate. In mutagenicity testing, amoxicillin and clavulanate in a 4:1 ratio formulation demonstrated non-mutagenic properties in both the Ames bacterial mutation assay and the yeast gene conversion assay. However, results from the mouse lymphoma assay indicated a weakly positive response, with increased mutation frequencies observed at concentrations that also resulted in decreased cell survival. The combination was negative in the mouse micronucleus test and the dominant lethal assay in mice.

Clavulanate potassium, when tested alone, also yielded negative results in the Ames bacterial mutation assay and the mouse micronucleus test.

In terms of reproductive toxicity, amoxicillin and clavulanate in a 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, when adjusted for body surface area based on a 20 kg child, is approximately twice the recommended clinical dose of amoxicillin and clavulanate potassium for oral suspension, which is 90/6.4 mg/kg/day. For clavulanate, the dose used in the study is approximately 15 times higher than the recommended clinical daily dose, also calculated based on body surface area.

Postmarketing Experience

No specific postmarketing experience details have been reported. As such, there are no additional adverse events or rare case reports to summarize at this time.

Patient Counseling

Patients should be informed to take amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL, every 12 hours with a meal or snack to minimize the risk of gastrointestinal upset. They should be advised to contact their healthcare provider if they experience severe diarrhea that lasts more than 2 or 3 days.

It is important to counsel patients that this medication contains a penicillin class drug, which may cause allergic reactions in some individuals. Patients should be made aware of the signs and symptoms of serious skin reactions. They should be instructed to discontinue the medication immediately and report any signs of skin rash, mucosal lesions, or other indications of hypersensitivity to their healthcare provider.

Patients should also be informed that diarrhea is a common side effect associated with antibacterial drugs, typically resolving upon discontinuation of the medication. However, they should be aware that watery and bloody stools, with or without stomach cramps and fever, can occur even up to 2 months after completing the treatment. If such symptoms arise, patients should seek medical attention promptly.

Counsel patients that antibacterial drugs, including amoxicillin and clavulanate potassium for oral suspension, are effective only against bacterial infections and do not treat viral infections, such as the common cold. Patients should be advised to adhere strictly to the prescribed regimen, as skipping doses or failing to complete the full course of therapy may reduce the treatment's effectiveness and increase the risk of bacterial resistance.

Patients should be instructed to keep the suspension refrigerated and to shake it well before use. When administering the suspension to a child, a dosing spoon or medicine dropper should be used, and it is essential to rinse the spoon or dropper 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 medication should be discarded.

For patients with phenylketonuria, it should be noted that each 5 mL of the suspension contains 9 mg of phenylalanine.

Storage and Handling

The dry powder for oral suspension is supplied in its original container. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines.

Once reconstituted, the suspension must be stored under refrigeration. Any unused suspension should be discarded after 10 days to ensure safety and efficacy.

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 Micro Labs Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)