Amoxicillin/Clavulanate potassium

Description

Amoxicillin and clavulanate potassium for oral suspension, USP is a combination antibacterial formulation comprising the semisynthetic antibiotic amoxicillin and the β-lactamase inhibitor 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 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-azabicyclo 3.2.0 heptane-2-carboxylic acid trihydrate.

Clavulanic acid, produced through the fermentation of Streptomyces clavuligerus, is a β-lactam compound structurally related to penicillins. It effectively inactivates a range of β-lactamases by obstructing their active sites, particularly targeting plasmid-mediated β-lactamases that confer 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 as the trihydrate and 42.9 mg of clavulanic acid, equivalent to 51.1 mg of clavulanate potassium. Each 5 mL of the suspension also provides 0.23 mEq of potassium. The dry powder appears as a white to yellowish white crystalline powder, while the reconstituted suspension is characterized as an almost white to yellow, homogeneous liquid. Inactive ingredients include caramel flavor, carboxymethyl cellulose sodium, citric acid, colloidal silicon dioxide, microcrystalline cellulose, orange flavor, raspberry flavor, saccharin sodium, silicon dioxide, sodium citrate, 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 β-lactamase–producing strains), and Moraxella catarrhalis (including β-lactamase–producing strains).

The use of amoxicillin and clavulanate potassium for oral suspension is recommended for patients exhibiting specific risk factors, which include antibacterial exposure for acute otitis media within the preceding 3 months, and either being 2 years of age or younger or attending daycare.

This drug should be utilized solely for the treatment or prevention of infections that are proven or strongly suspected to be caused by bacteria.

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 and administered every 12 hours for a total duration of 10 days.

Healthcare professionals are advised to calculate the total daily dose based on the patient's weight and ensure that the medication is administered at consistent intervals to maintain effective therapeutic levels.

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 for oral suspension 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 amoxicillin and clavulanate potassium for oral suspension.

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.

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 receiving amoxicillin, a component of this formulation. Should symptoms of DIES arise, it is essential 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 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, presenting a spectrum of severity from mild diarrhea to potentially fatal colitis. Healthcare professionals should evaluate patients for CDAD if they present with diarrhea during or after treatment.

It is crucial to avoid prescribing amoxicillin and clavulanate potassium for oral suspension to patients with mononucleosis, as these individuals are at risk of developing a skin rash upon administration of the medication.

Side Effects

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

Serious adverse reactions have been reported 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 a 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 observed; 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, requires evaluation if diarrhea develops. It is important to note that patients with mononucleosis who are treated with amoxicillin and clavulanate potassium may develop a skin rash, and the use of this medication should be avoided in such cases.

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.

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 for oral suspension 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 experience an increased risk of hepatic dysfunction when treated with amoxicillin and clavulanate potassium for oral suspension. Reports indicate that hepatic dysfunction, characterized by elevations in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, occurs more frequently in this population, particularly among males and those undergoing prolonged treatment.

Due to these considerations, amoxicillin and clavulanate potassium for oral suspension should be used with caution in geriatric patients who exhibit evidence of hepatic dysfunction. It is important to note that hepatic toxicity associated with this medication is generally reversible upon discontinuation.

Healthcare providers are advised to monitor liver function tests in elderly patients with hepatic impairment to ensure safety during treatment. Additionally, the safety and effectiveness of amoxicillin and clavulanate potassium for oral suspension have not been established in adults and pediatric patients weighing more than 40 kg.

It is crucial to be aware that fatalities have been reported in cases involving serious underlying diseases or the use of concomitant medications, underscoring the need for careful assessment and monitoring in this vulnerable population.

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, the rate of proven neonatal necrotizing enterocolitis was significantly higher in the amoxicillin and clavulanate group (1.9%) compared to the placebo group (0.5%) with a p-value of 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. These findings suggest that amoxicillin and clavulanate may be safe for use during pregnancy, although 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, with the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies in the U.S. general population being 2 to 4% and 15 to 20%, respectively.

Healthcare professionals should weigh the potential benefits of amoxicillin and clavulanate against the risks when prescribing to pregnant patients, particularly in cases of 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 the drug 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 patient safety and to make any necessary adjustments to therapy based on the patient's hepatic status.

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 experiencing rash, hyperactivity, or drowsiness.

In the event of an overdosage, it is recommended to discontinue the use 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 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 the circulation through hemodialysis.

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 potassium 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 concentrations. The formulation was negative in the mouse micronucleus test and the dominant lethal assay in mice.

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

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, 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 corresponds to approximately 15 times 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. 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 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 report any signs or symptoms of skin rash, mucosal lesions, or other indications of hypersensitivity promptly.

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 course of treatment. If such symptoms arise, 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. However, they must take the medication 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.

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 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 medicine should be discarded.

Storage and Handling

The reconstituted suspension must be stored under refrigeration. Any unused suspension should be discarded after 10 days to ensure safety and efficacy. The dry powder for oral suspension should be stored at a temperature range of 20ºC to 25°C (68ºF to 77°F), in accordance with USP Controlled Room Temperature guidelines. It is essential to dispense the product in its original container to maintain its integrity and stability.

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 Sandoz Inc. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)