Amoxicillin/Clavulanate potassium

Description

Amoxicillin and clavulanate potassium for oral suspension, USP 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 419.46 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, 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 237.25 g/mol, and its chemical structure is potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo3.2.0-heptane-2-carboxylate.

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. The product appears as a white to off-white granular powder that transforms into a white to pale yellow suspension with a strawberry flavor. Each 5 mL of the reconstituted suspension contains 9 mg of potassium. Inactive ingredients include aspartame, colloidal silicon dioxide, hypromellose, silicon dioxide, strawberry cream permaseal, succinic acid, 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, with recurrent or persistent acute otitis media caused by specific bacterial pathogens. These pathogens include 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).

Risk factors associated with these indications include prior antibacterial exposure for acute otitis media within the preceding 3 months, being aged 2 years or younger, and attendance at daycare facilities.

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 during 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 for oral suspension. In the event of such a reaction, it is imperative to discontinue the medication immediately and initiate appropriate therapeutic measures.

Healthcare professionals should remain vigilant for severe cutaneous adverse reactions (SCAR) during treatment. Close monitoring is essential, and the medication should be discontinued if any rash progresses.

Additionally, drug-induced enterocolitis syndrome (DIES) has been reported in patients receiving amoxicillin, a component of this formulation. Should symptoms of DIES manifest, it is crucial to discontinue amoxicillin and clavulanate potassium for oral suspension and provide suitable therapy.

Patients with hepatic dysfunction may experience cholestatic jaundice. In such cases, the medication should be discontinued if any signs or symptoms of hepatitis arise. Regular monitoring of liver function tests is recommended for patients with pre-existing hepatic impairment to ensure safety.

Clostridioides difficile-associated diarrhea (CDAD) can occur, presenting a spectrum from mild diarrhea to potentially fatal colitis. Healthcare providers should evaluate patients promptly if diarrhea develops during treatment.

It is also important to note that patients with mononucleosis who are treated with amoxicillin and clavulanate potassium for oral suspension are at risk of developing a skin rash. Therefore, the use of this medication should be avoided in these patients to prevent adverse reactions.

Side Effects

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

Serious adverse reactions, although less frequent, 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) have also been noted, necessitating close monitoring and discontinuation of the medication if a rash progresses. Additionally, drug-induced enterocolitis syndrome (DIES) may occur, warranting discontinuation of the drug and appropriate therapeutic measures.

Hepatic dysfunction and cholestatic jaundice have been observed, with recommendations to discontinue the medication if signs or symptoms of hepatitis arise. Liver function tests should be monitored in patients with pre-existing hepatic impairment. Clostridioides difficile-associated diarrhea (CDAD), which can range from mild diarrhea to fatal colitis, should prompt evaluation of patients if diarrhea occurs. It is also important to note that patients with mononucleosis who are treated with amoxicillin and clavulanate potassium may develop skin rashes; therefore, the use of this medication in such patients should be avoided.

Additional 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.

In cases of overdosage, patients have primarily experienced gastrointestinal symptoms, including stomach and abdominal pain, vomiting, and diarrhea. Other reported symptoms include rash, hyperactivity, or drowsiness in a small number of patients. Rarely, interstitial nephritis resulting in oliguric renal failure and crystalluria, which may lead to renal failure, have been documented following overdosage in both adult and pediatric patients.

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 therapeutic outcomes.

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 need for 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 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 experience unique safety and efficacy considerations when using amoxicillin and clavulanate potassium for oral suspension. The safety and effectiveness of this medication have not been established in adults and pediatric patients weighing more than 40 kg. Therefore, caution is advised when prescribing this medication to geriatric patients.

In elderly patients, there is an increased risk of hepatic dysfunction, which may manifest as elevations in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase. Such hepatic dysfunction has been reported more frequently in this population, particularly among males or those undergoing prolonged treatment. Consequently, it is essential to monitor hepatic function at regular intervals in geriatric patients, especially those with pre-existing hepatic impairment.

Amoxicillin and clavulanate potassium for oral suspension should be used with caution in patients exhibiting signs of hepatic dysfunction. While hepatic toxicity associated with this medication is generally reversible, careful monitoring and potential dose adjustments may be necessary to ensure patient safety.

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.

Reproduction studies conducted in pregnant rodents, administered doses up to approximately 2 times the amount of amoxicillin and 15 times the amount of clavulanate in the Maximum Human Recommended Dose (MHRD) of amoxicillin and clavulanate potassium for oral suspension, revealed no evidence of harm to the fetus. Similarly, reproduction 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.

The background risk of major birth defects and miscarriage for the indicated populations remains unknown. It is important to note that 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.

In a randomized, controlled trial involving 4,826 pregnant women with premature rupture of fetal membranes, those treated with amoxicillin and clavulanate exhibited a significantly increased rate of proven neonatal necrotizing enterocolitis, with rates of 1.9% in the amoxicillin and clavulanate only group compared to 0.5% in the placebo group, and 1.8% in any amoxicillin and clavulanate group versus 0.7% in the no amoxicillin and clavulanate group.

Given these findings, healthcare professionals should weigh the potential benefits against the risks when considering the use of amoxicillin and clavulanate in pregnant patients, particularly those with PPROM.

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 individuals 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, the treatment should be discontinued immediately. It is essential to assess liver function regularly to ensure the safety and efficacy of the therapy in this population.

Overdosage

Following an overdosage of amoxicillin and clavulanate potassium, patients have primarily exhibited gastrointestinal symptoms, which include stomach and abdominal pain, vomiting, and diarrhea. Additionally, a small number of patients have reported symptoms such as rash, hyperactivity, or drowsiness.

In the event of an overdosage, it is recommended to discontinue the administration of amoxicillin and clavulanate potassium for oral suspension. 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. Furthermore, crystalluria, which in some cases 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 the 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

Postmarketing experience has identified several adverse reactions associated with the use of the antibacterial drug. Notably, severe cutaneous adverse reactions (SCAR) have been reported. Additionally, instances of diarrhea, which may be watery and bloody, have been documented, occurring even as late as two or more months following the last dose of the medication. These events were reported voluntarily or through surveillance programs.

Patient Counseling

Patients should be informed to take amoxicillin and clavulanate potassium for oral suspension every 12 hours with a meal or snack to minimize the risk of gastrointestinal upset. In the event that diarrhea develops and is severe or persists for more than 2 or 3 days, patients should be advised to contact their healthcare provider.

It is important to counsel patients that amoxicillin and clavulanate potassium for oral suspension 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 promptly report any initial signs or symptoms of skin rash, mucosal lesions, or other indications of hypersensitivity.

Patients should also be informed that diarrhea is a common side effect associated with antibacterial drugs, typically resolving upon discontinuation of the medication. However, it is crucial to alert patients that they may experience watery and bloody stools (with or without stomach cramps and fever) even as late as 2 months after completing the course of the antibacterial drug. If such symptoms occur, patients should seek medical attention as soon as possible.

Counsel patients that antibacterial drugs, including amoxicillin and clavulanate potassium for oral suspension, 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 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, rendering amoxicillin and clavulanate potassium for oral suspension 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 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 healthcare provider's instructions regarding the appropriate dosage and duration of treatment for their child, and any unused medicine should be discarded.

Additionally, patients with phenylketonuria should be counseled that each 5 mL of amoxicillin and clavulanate potassium for oral suspension contains 7.02 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). 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 Aurobindo Pharma Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)