Amoxicillin/Clavulanate potassium

Description

Amoxicillin and clavulanate potassium for oral suspension, USP is an oral antibacterial combination comprising amoxicillin and the beta-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. Its chemical structure is (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 is produced through the fermentation of Streptomyces clavuligerus and is a beta-lactam related to penicillins, 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.

Upon reconstitution, each 5 mL of the oral suspension contains either 125 mg of amoxicillin as the trihydrate and 31.25 mg of clavulanic acid (equivalent to 37.23 mg of clavulanate potassium) or 250 mg of amoxicillin as the trihydrate and 62.5 mg of clavulanic acid (equivalent to 74.5 mg of clavulanate potassium). The product appears as a white to off-white granular powder, transforming into a white to pale yellow suspension with an orange flavor after reconstitution.

Inactive ingredients include aspartame, colloidal silicon dioxide, hypromellose, orange flavor, silicon dioxide, succinic acid, and xanthan gum. The orange flavor component consists of corn syrup, gum arabic, and natural and artificial flavors. Each 5 mL of the reconstituted 125 mg/31.25 mg oral suspension contains 0.16 mEq of potassium, while the 250 mg/62.5 mg formulation contains 0.31 mEq of potassium.

Uses and Indications

Amoxicillin and clavulanate potassium for oral suspension 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 utilized only for the treatment or prevention of infections that are proven or strongly suspected to be caused by bacteria. This approach is essential to reduce the development of drug-resistant bacteria and to maintain the effectiveness of amoxicillin and clavulanate potassium as well as other antibacterial agents.

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 utilize the 125 mg/31.25 mg per 5 mL oral suspension for this age group.

Healthcare professionals should ensure that the appropriate dosing regimen is selected based on the patient's weight and age, and that the method of administration is consistent with the recommended guidelines.

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 fatal outcomes, 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.

Severe Cutaneous Adverse Reactions (SCAR) may occur; therefore, patients should be monitored closely for any signs of rash. Should the rash progress, discontinuation of the medication is necessary.

Drug-induced enterocolitis syndrome (DIES) has been reported in patients using amoxicillin, a component of this formulation. If DIES is suspected, the medication should be discontinued, and appropriate therapeutic measures 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 arise. Additionally, liver function tests should be monitored in patients with pre-existing hepatic impairment to ensure safety.

Clostridioides difficile-associated diarrhea (CDAD) is a potential complication; therefore, healthcare professionals should evaluate patients who present with diarrhea during treatment.

In patients diagnosed with mononucleosis, the use of amoxicillin and clavulanate potassium is contraindicated due to the risk of developing a skin rash.

Finally, clinicians should remain vigilant for the possibility of superinfections with fungal or bacterial pathogens during therapy, as overgrowth may occur.

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 the medication should be discontinued if any rash progresses. Drug-induced enterocolitis syndrome (DIES) necessitates discontinuation of the drug and appropriate therapeutic intervention. Hepatic dysfunction and cholestatic jaundice have been noted, and discontinuation is advised 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) should be evaluated if diarrhea occurs during treatment. Additionally, patients with mononucleosis who receive this medication 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.

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, including penicillins and cephalosporins. A history of cholestatic jaundice or hepatic dysfunction associated with this medication 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 need for alternative or additional contraceptive methods during treatment with this antibiotic combination.

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 amoxicillin and clavulanate potassium for oral suspension in this population is derived from studies involving adult patients, supplemented by data from a study specifically examining 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 unaffected in this age group. Therefore, dosing of amoxicillin and clavulanate potassium for oral suspension should be adjusted for pediatric patients under 12 weeks (less than 3 months) of age to ensure safety and efficacy.

Geriatric Use

In an analysis of clinical studies involving 3,119 patients treated with amoxicillin and clavulanate potassium, 32% 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

Pregnancy Category B. 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 teratogenic effects or harm to the fetus. The doses of amoxicillin in these studies were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours), while the doses for clavulanate were approximately 9 and 4 times the maximum recommended adult human oral dose (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 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, 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

In the event of an overdosage, it is imperative to discontinue the medication immediately. Symptomatic treatment and supportive measures should be instituted as necessary to manage the patient's condition effectively.

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. However, it is essential to remain vigilant for potential adverse effects, particularly in cases of higher dosages.

Notably, interstitial nephritis leading to oliguric renal failure has been documented following overdosage with amoxicillin and clavulanate potassium. Additionally, crystalluria has been reported, which in some instances has progressed to renal failure in both adult and pediatric populations. To mitigate the risk of crystalluria associated with amoxicillin and clavulanate potassium overdosage, it is crucial to maintain adequate fluid intake and promote diuresis.

Renal impairment observed in these cases appears to be reversible upon cessation of the drug. It is important to note that patients with pre-existing renal dysfunction may experience elevated blood levels of amoxicillin and clavulanate potassium due to decreased renal clearance.

For patients experiencing severe overdosage, hemodialysis may be employed as a method to remove amoxicillin and clavulanate potassium from circulation, thereby aiding in the management of the overdosage.

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 did not affect fertility or 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), based on body surface area calculations.

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 have been reported, which may include cases of watery and bloody stools. These gastrointestinal events can occur 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 for oral suspension may be administered every 8 hours or every 12 hours, depending on the prescribed dosage. It is important that each dose is taken with a meal or snack to minimize the risk of gastrointestinal upset.

Healthcare providers should counsel patients regarding the potential for allergic reactions, as amoxicillin and clavulanate potassium contains a penicillin class drug. 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 initial signs or symptoms of skin rash, mucosal lesions, or other indications of hypersensitivity.

Patients should also be advised that diarrhea is a common side effect associated with antibacterial medications, typically resolving upon discontinuation of the drug. However, it is crucial to inform patients that they may experience watery and bloody stools, with or without accompanying stomach cramps and fever, even up to two 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 promptly.

It is essential to counsel patients 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 improvement early in the treatment. However, they must adhere strictly to the prescribed regimen, as skipping doses or failing to complete the full course may reduce the effectiveness of the treatment and increase the risk of bacterial resistance to amoxicillin and clavulanate potassium and other antibacterial agents in the future.

Patients should be advised to store the suspension in the refrigerator and to shake it well before use. When administering the suspension to a child, a calibrated oral syringe should be utilized, and it is important 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 medication should be discarded.

Storage and Handling

The dry powder formulation is supplied in a container that should be stored at a temperature range of 20º to 25ºC (68º to 77ºF), in accordance with USP Controlled Room Temperature guidelines. Once reconstituted, the suspension must be stored under refrigeration. It is important to discard any unused suspension after 10 days to ensure safety and efficacy. Additionally, this product should be kept out of the reach of children to prevent accidental ingestion.

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)