Amoxicillin/Clavulanate potassium

Description

Amoxicillin and Clavulanate Potassium 600 mg/42.9 mg per 5 mL is an oral antibacterial combination that includes 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 basic 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-azabicyclo3.2.0heptane-2-carboxylic acid trihydrate.

Clavulanic acid, produced by the fermentation of Streptomyces clavuligerus, is a β-lactam that is structurally related to penicillins. It effectively inactivates a wide variety of β-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. Its chemical structure is characterized as potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo3.2.0-heptane-2-carboxylate.

Uses and Indications

Amoxicillin and Clavulanate Potassium 600 mg/42.9 mg per 5 mL is indicated for the treatment of pediatric patients with recurrent or persistent acute otitis media caused by specific pathogens. This formulation is effective against Streptococcus pneumoniae (penicillin minimum inhibitory concentrations MICs ≤ 2 mcg/mL), Haemophilus influenzae (including β-lactamase–producing strains), and Moraxella catarrhalis (including β-lactamase–producing strains). The targeted patient population includes those with the following risk factors: antibiotic exposure for acute otitis media within the preceding 3 months, and either age ≤ 2 years or daycare attendance.

For cases of acute otitis media due solely to S. pneumoniae, treatment with amoxicillin is appropriate. However, Amoxicillin and Clavulanate Potassium 600 mg/42.9 mg per 5 mL is not indicated for the treatment of acute otitis media caused by S. pneumoniae with penicillin MIC ≥ 4 mcg/mL.

Therapy may be initiated prior to the results of bacteriological studies when there is a clinical suspicion of infection involving both S. pneumoniae (penicillin MIC ≤ 2 mcg/mL) and the aforementioned β-lactamase–producing organisms.

Dosage and Administration

Pediatric patients aged 3 months and older are recommended to receive a dose of 90 mg/kg/day, divided into two administrations every 12 hours, for a duration of 10 days. The specific dosage based on body weight is as follows:

• For a body weight of 8 kg, administer 3.0 mL twice daily.

• For a body weight of 12 kg, administer 4.5 mL twice daily.

• For a body weight of 16 kg, administer 6.0 mL twice daily.

• For a body weight of 20 kg, administer 7.5 mL twice daily.

• For a body weight of 24 kg, administer 9.0 mL twice daily.

• For a body weight of 28 kg, administer 10.5 mL twice daily.

• For a body weight of 32 kg, administer 12.0 mL twice daily.

• For a body weight of 36 kg, administer 13.5 mL twice daily.

To minimize gastrointestinal intolerance, it is advised that Amoxicillin and Clavulanate Potassium 600 mg/42.9 mg per 5 mL be taken at the start of a meal. This timing may enhance the absorption of clavulanate potassium.

Contraindications

Amoxicillin and Clavulanate Potassium 600 mg/42.9 mg per 5 mL is contraindicated in patients with a history of allergic reactions to any penicillin, due to the risk of severe hypersensitivity reactions. Additionally, it is contraindicated in individuals with a previous history of cholestatic jaundice or hepatic dysfunction associated with Amoxicillin and Clavulanate Potassium, as this may exacerbate liver conditions. Furthermore, the use of ampicillin-class antibiotics is contraindicated in patients with mononucleosis, as it may lead to a higher incidence of rash and other adverse effects.

Warnings and Precautions

Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving penicillin therapy. These reactions are more prevalent in individuals with a history of penicillin hypersensitivity or sensitivity to multiple allergens. Prior to initiating therapy with Amoxicillin and Clavulanate Potassium 600 mg/42.9 mg per 5 mL, a thorough inquiry regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens is essential. Should an allergic reaction occur, the administration of Amoxicillin and Clavulanate Potassium 600 mg/42.9 mg per 5 mL must be discontinued immediately, and appropriate therapeutic measures should be instituted.

In cases of serious anaphylactic reactions, immediate emergency treatment with epinephrine is required. Additional interventions may include the administration of oxygen, intravenous steroids, and airway management, including intubation, as clinically indicated.

Pseudomembranous colitis has been associated with nearly all antibacterial agents, including Amoxicillin and Clavulanate Potassium, and can range from mild to life-threatening. Clinicians should consider this diagnosis in patients who present with diarrhea following the administration of antibacterial agents. The alteration of normal colonic flora due to antibacterial treatment may lead to the overgrowth of Clostridium difficile, a primary cause of antibiotic-associated colitis. Upon establishing a diagnosis of pseudomembranous colitis, appropriate therapeutic measures should be initiated. Mild cases may respond to the discontinuation of the drug alone, while moderate to severe cases may require management with fluids, electrolytes, protein supplementation, and treatment with an antibacterial agent effective against C. difficile colitis.

Caution is advised when prescribing Amoxicillin and Clavulanate Potassium 600 mg/42.9 mg per 5 mL to patients with hepatic dysfunction. Although hepatic toxicity associated with this medication is typically reversible, rare cases of severe outcomes, including death, have been reported, primarily in patients with serious underlying conditions or those taking concomitant medications.

While Amoxicillin and Clavulanate Potassium is characterized by low toxicity typical of penicillin antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is recommended for patients undergoing therapy beyond the approved duration.

Patients with mononucleosis should not receive ampicillin-class antibiotics, as a significant percentage may develop an erythematous skin rash. The potential for superinfections with mycotic or bacterial pathogens should also be considered during therapy. If superinfections occur, typically involving Pseudomonas or Candida, the drug should be discontinued, and appropriate therapy should be initiated.

Prescribing Amoxicillin and Clavulanate Potassium 600 mg/42.9 mg per 5 mL in the absence of a proven or strongly suspected bacterial infection, or without a prophylactic indication, is unlikely to benefit the patient and may increase the risk of developing drug-resistant bacteria.

For patients receiving therapy for longer than the approved duration, periodic laboratory assessments of organ system functions, including renal, hepatic, and hematopoietic function, are advisable to ensure patient safety.

Side Effects

Adverse reactions associated with the use of the medication include a range of common and serious effects, as well as reactions leading to withdrawal from treatment.

Common adverse reactions observed in clinical trials include contact dermatitis (diaper rash) in 3.5% of patients, diarrhea in 2.9%, vomiting in 2.2%, moniliasis in 1.4%, and rash in 1.1%. Notably, diarrhea and vomiting were also among the adverse reactions that led to withdrawal from treatment, occurring in 2.5% and 1.4% of participants, respectively.

Gastrointestinal adverse reactions may include diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic or pseudomembranous colitis. Symptoms of pseudomembranous colitis may arise during or after antibiotic treatment.

Hypersensitivity reactions can manifest as skin rashes, pruritus, urticaria, angioedema, and serum sickness-like reactions, which may include urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever. Rarely, erythema multiforme, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, and exfoliative dermatitis (including toxic epidermal necrolysis) have been reported. Serious and occasionally fatal anaphylactic reactions can occur, particularly in patients with a history of penicillin hypersensitivity or sensitivity to multiple allergens.

Liver-related adverse reactions may include a moderate rise in AST (SGOT) and/or ALT (SGPT), with hepatic dysfunction reported infrequently. This dysfunction, which may involve increases in serum transaminases, serum bilirubin, and/or alkaline phosphatase, is more commonly observed in elderly patients, males, or those undergoing prolonged treatment. While the hepatic dysfunction is usually reversible, rare instances of death have been documented, with less than one death reported per estimated four million prescriptions worldwide.

Renal adverse reactions are rare and may include interstitial nephritis, hematuria, and crystalluria.

Hemic and lymphatic system effects can include anemia (including hemolytic anemia), thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, agranulocytosis, and slight thrombocytosis (less than 1% of patients). Additionally, increased prothrombin time has been noted in patients receiving amoxicillin and clavulanate potassium alongside anticoagulant therapy.

Central nervous system effects, though rare, may include agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity.

Miscellaneous adverse reactions include tooth discoloration (brown, yellow, or gray staining), which has been reported rarely, primarily in pediatric patients. In most cases, discoloration was reduced or eliminated with brushing or dental cleaning.

It is important to note that pseudomembranous colitis has been reported with nearly all antibacterial agents, including amoxicillin/clavulanate potassium, and can range in severity from mild to life-threatening.

Drug Interactions

Probenecid is known to decrease the renal tubular secretion of amoxicillin. When amoxicillin and clavulanate potassium 600 mg/42.9 mg per 5 mL is administered concurrently with probenecid, there may be an increase in blood levels of amoxicillin, leading to prolonged effects. Therefore, co-administration of probenecid with this formulation is not recommended.

In patients receiving amoxicillin alongside oral anticoagulants, there have been rare reports of abnormal prolongation of prothrombin time, indicated by an increased international normalized ratio (INR). It is advised that appropriate monitoring of INR levels be conducted when these medications are used together. Adjustments to the dosage of oral anticoagulants may be necessary to maintain the desired anticoagulation effect.

The concurrent use of allopurinol with ampicillin has been associated with a significantly higher incidence of rashes compared to patients receiving ampicillin alone. While it remains unclear whether this increased incidence is attributable to allopurinol or the hyperuricemia in these patients, there is no available data regarding the concurrent administration of allopurinol with amoxicillin and clavulanate potassium 600 mg/42.9 mg per 5 mL.

Similar to other broad-spectrum antibiotics, amoxicillin/clavulanate may diminish the effectiveness of oral contraceptives, and patients should be counseled accordingly.

Regarding laboratory test interactions, the oral administration of amoxicillin and clavulanate potassium can lead to elevated urine concentrations of amoxicillin. This may result in false-positive results for glucose when using CLINITEST®, Benedict’s Solution, or Fehling’s Solution. To avoid this issue, it is recommended that glucose testing utilize enzymatic glucose oxidase reactions, such as CLINISTIX®.

Additionally, following the administration of ampicillin to pregnant women, a transient decrease in plasma concentrations of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been observed. This effect may also be applicable to amoxicillin and clavulanate potassium 600 mg/42.9 mg per 5 mL.

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 efficacy of Amoxicillin and Clavulanate Potassium 600 mg/42.9 mg per 5 mL have not been established in infants younger than 3 months. However, this formulation has demonstrated safety and efficacy for the treatment of acute otitis media in infants and children aged 3 months to 12 years. Additionally, it has been shown to be safe and effective for treating acute bacterial sinusitis in pediatric patients within the same age range.

Geriatric Use

Elderly patients may require special consideration when prescribed Amoxicillin and Clavulanate Potassium 600 mg/42.9 mg per 5 mL, particularly those with evidence of hepatic dysfunction. While hepatic toxicity associated with this medication is generally reversible, there have been rare reports of fatalities (less than 1 death per estimated 4 million prescriptions worldwide), typically linked to serious underlying conditions or concomitant medications. Therefore, caution is advised in this population, especially in those with pre-existing liver issues.

Hepatic dysfunction, characterized by increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been infrequently reported with the use of Amoxicillin and Clavulanate Potassium, with a higher incidence noted among elderly patients, males, and those undergoing prolonged treatment. Regular monitoring of liver function is recommended for geriatric patients receiving this therapy.

For patients on extended courses of treatment, periodic assessment of organ system functions—including renal, hepatic, and hematopoietic function—is advisable to ensure safety and efficacy. Additionally, healthcare providers should remain vigilant for the possibility of superinfections with mycotic or bacterial pathogens during therapy. Should superinfections occur, typically involving Pseudomonas or Candida, discontinuation of the drug and initiation of appropriate therapy is warranted.

Elderly patients receiving Amoxicillin and Clavulanate Potassium alongside oral anticoagulants should be monitored closely for abnormal prolongation of prothrombin time, as increased international normalized ratio (INR) has been reported rarely in this context. Dose adjustments of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

Furthermore, renal impairment associated with the use of this medication appears to be reversible upon cessation of therapy. Elderly patients with impaired renal function may experience higher blood levels of both amoxicillin and clavulanate due to decreased renal clearance. It is important to note that both components of this medication are removed from circulation by hemodialysis, necessitating careful consideration of renal function in this patient population.

Pregnancy

The use of AMOXICILLIN AND CLAVULANATE POTASSIUM during pregnancy has not been well studied, and it is not known whether its administration during labor or delivery has immediate or delayed adverse effects on the fetus. There is insufficient data to determine if this medication prolongs the duration of labor or increases the likelihood of requiring obstetrical interventions, such as forceps delivery or resuscitation of the newborn.

In a single study involving women with premature rupture of fetal membranes, prophylactic treatment with AMOXICILLIN AND CLAVULANATE POTASSIUM was associated with an increased risk of necrotizing enterocolitis in neonates. Given these findings, healthcare professionals should weigh the potential benefits against the risks when considering the use of this medication in pregnant patients. Caution is advised, particularly in the context of obstetric complications.

Lactation

Ampicillin-class antibiotics, including amoxicillin and clavulanate potassium, are excreted in human milk. Therefore, caution should be exercised when administering this medication to lactating mothers. The potential effects on breastfed infants have not been fully established, and healthcare professionals should consider the benefits of breastfeeding alongside the potential risks associated with the use of this antibiotic in nursing women.

Renal Impairment

Patients with renal impairment should use Amoxicillin and Clavulanate Potassium 600 mg/42.9 mg per 5 mL with caution, particularly in those with evidence of hepatic dysfunction. It is important for healthcare professionals to monitor renal function closely in these patients to ensure safe and effective use of the medication. Dosing adjustments may be necessary based on the degree of renal impairment, and careful consideration should be given to the potential for altered pharmacokinetics in this population.

Hepatic Impairment

Patients with hepatic impairment should use Amoxicillin and Clavulanate Potassium 600 mg/42.9 mg per 5 mL with caution. While hepatic toxicity associated with the use of this medication is typically reversible, it is important to monitor liver function closely in these patients.

Although rare, there have been reports of fatalities linked to the use of amoxicillin/clavulanate potassium, with less than one death reported per an estimated four million prescriptions worldwide. These cases have generally occurred in patients with serious underlying diseases or those taking concomitant medications that may exacerbate liver dysfunction. Therefore, careful consideration of the patient's overall health status and concurrent therapies is advised when prescribing this medication to individuals with compromised liver function.

Overdosage

Following an overdosage of Amoxicillin and Clavulanate Potassium 600 mg/42.9 mg per 5 mL, patients have primarily exhibited gastrointestinal symptoms. These symptoms 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 administration of Amoxicillin and Clavulanate Potassium. Symptomatic treatment should be initiated, and supportive measures should be implemented 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 amoxicillin overdosage. 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

Reproduction studies conducted in pregnant rats and mice administered AMOXICILLIN AND CLAVULANATE POTASSIUM at oral dosages up to 1,200 mg/kg/day (4.9 and 2.8 times the maximum adult human oral dose based on body surface area, respectively) demonstrated no evidence of teratogenic effects on the fetus. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human outcomes, this drug should be used during pregnancy only if clearly needed.

In terms of non-teratogenic effects, AMOXICILLIN AND CLAVULANATE POTASSIUM, when given at oral doses of up to 1,200 mg/kg/day (5.7 times the maximum adult human dose based on body surface area), did not adversely affect fertility or reproductive performance in rats treated with a 2:1 ratio formulation of amoxicillin to clavulanate.

Long-term studies in animals have not been conducted to assess the carcinogenic potential of AMOXICILLIN AND CLAVULANATE POTASSIUM. The mutagenic potential of this compound was evaluated through various in vitro assays, including the Ames test, a human lymphocyte cytogenetic assay, a yeast test, and a mouse lymphoma forward mutation assay, as well as in vivo assessments using mouse micronucleus tests and a dominant lethal test. All tests returned negative results, except for the in vitro mouse lymphoma assay, which indicated weak activity at very high, cytotoxic concentrations.

Postmarketing Experience

Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity or sensitivity to multiple allergens. Pseudomembranous colitis has been documented with nearly all antibacterial agents, including amoxicillin/clavulanate potassium, with severity ranging from mild to life-threatening.

Hepatic dysfunction, characterized by increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been infrequently reported in association with amoxicillin and clavulanate potassium. This condition has been observed more commonly in elderly patients, males, or those undergoing prolonged treatment. The onset of hepatic dysfunction may occur during therapy or several weeks after discontinuation, and while it can be severe, it is usually reversible.

On rare occasions, deaths have been reported, with an estimated incidence of less than one death per four million prescriptions worldwide. These cases have generally involved patients with serious underlying diseases or those taking concomitant medications. Interstitial nephritis and hematuria have been reported rarely, along with crystalluria.

Hematological reactions, including anemia (notably hemolytic anemia), thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis, have been associated with penicillin therapy. These reactions are typically reversible upon discontinuation of the medication and are believed to be hypersensitivity phenomena.

The most commonly reported side effects with a probable or suspected relationship to amoxicillin and clavulanate potassium 600 mg/42.9 mg per 5 mL include contact dermatitis, diarrhea, vomiting, moniliasis, and rash. Diarrhea and vomiting were the most common adverse experiences leading to withdrawal, with a probable or suspected relationship to the medication.

Patient Counseling

Healthcare providers should advise patients to take Amoxicillin and Clavulanate Potassium 600 mg/42.9 mg per 5 mL every 12 hours with a meal or snack to minimize the risk of gastrointestinal upset. Patients should be informed that diarrhea is a common side effect associated with antibiotic use, and if they experience severe diarrhea or if it lasts more than 2 or 3 days, they should contact their doctor. It is important to note that patients may develop watery and bloody stools, with or without stomach cramps and fever, even up to 2 months after completing the antibiotic course. In such cases, patients should seek medical attention promptly.

Patients should be instructed to keep the suspension refrigerated and to shake the bottle well before each use. When administering the suspension to children, healthcare providers should recommend using a dosing spoon or medicine dropper, ensuring that the spoon or dropper is rinsed after each use. It is essential to follow the physician's instructions regarding the appropriate dosage and duration of treatment, as bottles may contain more liquid than necessary. Any unused medicine should be discarded.

Healthcare providers should counsel patients that antibacterial medications, including Amoxicillin and Clavulanate Potassium, are effective only against bacterial infections and do not treat viral infections, such as the common cold. Patients should be reminded that even if they start to feel better early in the treatment, it is crucial to take the medication exactly as prescribed. 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.

Additionally, healthcare providers should inform patients who are phenylketonurics that each 5 mL of the suspension contains 7 mg of phenylalanine.

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 or below 25°C (77°F). It is essential to dispense the product in its original container to maintain its integrity and stability.

Additional Clinical Information

Oral administration of Amoxicillin and Clavulanate Potassium 600 mg/42.9 mg per 5 mL results in high urine concentrations of amoxicillin, which may lead to false-positive glucose test results when using CLINITEST, Benedict’s Solution, or Fehling’s Solution. Clinicians are advised to utilize glucose tests based on enzymatic glucose oxidase reactions, such as CLINISTIX, to avoid this issue.

Patients should take Amoxicillin and Clavulanate Potassium every 12 hours with a meal or snack to minimize gastrointestinal upset. It is important to counsel patients about the potential for diarrhea, which is common with antibiotic use and may persist even after treatment has ended. Patients should seek medical attention if they experience severe diarrhea or develop watery and bloody stools. The suspension should be refrigerated, shaken well before use, and administered with a dosing spoon or medicine dropper. Additionally, patients should be informed that this antibiotic is effective only against bacterial infections and that completing the full course of therapy is crucial to prevent resistance. Each 5 mL dose contains 7 mg of phenylalanine, which is relevant for phenylketonurics.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Amoxicillin and Clavulanate Potassium as submitted by Aidarex Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)