Amoxicillin/Clavulanate potassium

Description

Amoxicillin and clavulanate potassium tablets, USP, and for oral suspension, USP, are oral antibacterial formulations that combine amoxicillin, a penicillin analog, with clavulanate potassium, a beta-lactamase inhibitor. Amoxicillin is derived from 6-aminopenicillanic acid, with a molecular formula of C16H19N3O5S•3H2O and a molecular weight of 419.46. Its chemical structure is represented 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. Clavulanate potassium, with a molecular formula of C8H8KNO5 and a molecular weight of 237.25, is produced through the fermentation of Streptomyces clavuligerus. Its chemical structure is potassium (Z)(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo3.2.0-heptane-2-carboxylate.

The tablets are available in three strengths: 250 mg/125 mg, 500 mg/125 mg, and 875 mg/125 mg, containing amoxicillin as the trihydrate and clavulanic acid (equivalent to clavulanate potassium) in each tablet. The oral suspension is available in two strengths: 200 mg/28.5 mg and 400 mg/57 mg, with each 5 mL of reconstituted suspension containing the respective amounts of amoxicillin and clavulanic acid.

Inactive ingredients in the tablets include colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, talc, titanium dioxide, triethyl citrate, ethylcellulose, cetyl alcohol, and sodium lauryl sulfate. The 875 mg/125 mg tablet also contains crospovidone. Each tablet contains 0.63 mEq of potassium. The oral suspension contains aspartame, colloidal silicon dioxide, hydroxypropyl methylcellulose, mannitol, orange flavoring, precipitated silicon dioxide, succinic acid, xanthan gum, and golden syrup flavoring. The 200 mg/28.5 mg oral suspension contains 0.14 mEq of potassium per 5 mL, while the 400 mg/57 mg formulation contains 0.29 mEq of potassium per 5 mL.

Uses and Indications

Amoxicillin and clavulanate potassium tablets and oral suspension are 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 used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. There are no teratogenic or nonteratogenic effects associated with the use of amoxicillin and clavulanate potassium.

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, based on the amoxicillin component. It is advised to use the 125 mg/5 mL oral suspension for this age group.

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 or to 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.

Warnings and Precautions

Serious hypersensitivity reactions, including anaphylaxis, have been reported with the use of amoxicillin and clavulanate potassium. In the event of such a reaction, it is imperative to discontinue the medication immediately.

Severe Cutaneous Adverse Reactions (SCAR) may occur during treatment. Healthcare professionals should monitor patients closely for any signs of rash, and if the rash progresses, discontinuation of amoxicillin and clavulanate potassium is warranted.

Drug-induced enterocolitis syndrome (DIES) has been associated with amoxicillin, a component of this combination therapy. Should symptoms indicative of DIES arise, it is essential to discontinue the medication and initiate appropriate therapeutic measures.

Patients with hepatic dysfunction are at increased risk for cholestatic jaundice. If any signs or symptoms of hepatitis develop, the medication should be discontinued. 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 of antibiotic therapy. If a patient presents with diarrhea during treatment, a thorough evaluation is necessary to rule out CDAD.

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.

Finally, the possibility of superinfections due to overgrowth of fungal or bacterial pathogens should be considered during therapy. Monitoring for signs of such infections is recommended to ensure timely intervention.

Side Effects

Patients may experience a range of adverse reactions while receiving amoxicillin and clavulanate potassium. Common adverse reactions, occurring in 1% to 9% of patients, include diarrhea or loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%), and vaginitis (1%).

Serious adverse reactions have been reported and require immediate attention. These include serious hypersensitivity reactions, which may be fatal; in such cases, amoxicillin and clavulanate potassium should be discontinued. Severe cutaneous adverse reactions (SCAR) necessitate close monitoring, and discontinuation is advised if any rash progresses. Drug-induced enterocolitis syndrome (DIES) is another serious reaction that warrants discontinuation of the medication and initiation of appropriate therapy. Hepatic dysfunction and cholestatic jaundice have also been observed; patients should be monitored for signs or symptoms of hepatitis, and the drug should be discontinued if these occur. Clostridioides difficile-associated diarrhea (CDAD) should be evaluated if diarrhea develops during treatment. Additionally, patients with mononucleosis who receive this medication may develop skin rashes, and its use should be avoided in these individuals. The potential for superinfections with fungal or bacterial pathogens should also be considered during therapy.

Important notes regarding additional adverse reactions 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 or 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 for decreased contraceptive effectiveness and advised to consider alternative or additional 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 and chewable tablets have been established in pediatric patients. Evidence supporting the use of these formulations in children is derived from studies involving amoxicillin and clavulanate potassium tablets in adults, supplemented by data from a study of the oral suspension in 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 unchanged in this age group. Therefore, dosing of amoxicillin and clavulanate potassium should be adjusted for pediatric patients aged less than 12 weeks (less than 3 months).

Geriatric Use

In clinical studies involving amoxicillin and clavulanate potassium, 32% of the 3,119 patients analyzed were aged 65 years or older, and 14% were aged 75 years or older. Overall, no significant differences in safety or effectiveness were observed between 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, which cannot be entirely ruled out based on current data.

Amoxicillin and clavulanate potassium is primarily excreted through the kidneys, and the risk of adverse reactions may be heightened in patients with impaired renal function. Given that geriatric 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 elderly patients to ensure appropriate dosing and minimize the risk of adverse effects.

Pregnancy

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 harm to the fetus. The amoxicillin doses in these studies were approximately 4 and 2 times the maximum recommended adult human oral dose of 875 mg every 12 hours, while the clavulanate doses were approximately 9 and 4 times the maximum recommended adult human oral dose of 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 lactating mothers.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to this patient population.

Hepatic Impairment

Patients with hepatic impairment should be closely monitored for liver function tests. In the event that signs or symptoms of hepatitis occur, it is recommended to discontinue treatment. Careful assessment of liver function is essential to ensure patient safety and to guide therapeutic decisions.

Overdosage

In the event of an overdosage, it is imperative to discontinue the medication immediately and provide symptomatic treatment along with supportive measures as necessary. A prospective study involving 51 pediatric patients at a poison-control center indicated that overdosages of amoxicillin below 250 mg/kg are generally not associated with significant clinical symptoms.

Potential Symptoms and Complications Overdosage of amoxicillin and clavulanate potassium has been linked to interstitial nephritis, which may result in oliguric renal failure. Additionally, crystalluria has been reported, occasionally leading to renal failure in both adult and pediatric populations.

Management Recommendations To mitigate the risk of crystalluria associated with amoxicillin and clavulanate potassium overdosage, it is essential to maintain adequate fluid intake and promote diuresis. Renal impairment observed in these cases is typically reversible upon cessation of the drug. It is important to note that patients with pre-existing renal impairment may experience elevated blood levels of the drug due to decreased renal clearance.

In cases of severe overdosage, hemodialysis may be employed to facilitate the removal of amoxicillin and clavulanate potassium from circulation. Healthcare professionals should monitor renal function and provide appropriate interventions as needed.

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 also negative in 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), when adjusted for body surface area.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions reported voluntarily or through surveillance programs. These include severe allergic reactions, such as anaphylaxis, and serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Hepatic dysfunction has also been noted, with cases of cholestatic jaundice and hepatitis reported.

Hematologic reactions, including thrombocytopenia, leukopenia, and agranulocytosis, have been documented. Additionally, gastrointestinal disorders, specifically Clostridium difficile-associated diarrhea, have been observed. Renal impairment, characterized by interstitial nephritis, has been reported as well. Other reactions include seizures and hyperactivity.

Patient Counseling

Patients should be informed that amoxicillin and clavulanate potassium may be taken every 8 hours or every 12 hours, depending on the prescribed dosage. It is important for patients to take each dose with a meal or snack to minimize the risk of gastrointestinal upset.

Healthcare providers should counsel patients that amoxicillin and clavulanate potassium contains a penicillin class drug, which can lead to 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 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 medications, typically resolving upon discontinuation of the drug. However, it is crucial to advise patients that they may experience watery and bloody stools (with or without stomach cramps and fever) even up to 2 months after completing the treatment. If diarrhea is severe or persists for more than 2 to 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, although they may feel better early in the treatment, it is vital to 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 liquid form of amoxicillin and clavulanate potassium to a child, a calibrated oral syringe should be used, 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 product is supplied in its original container to ensure integrity and stability. It is essential to store the dry powder 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. It is important to note that any unused suspension should be discarded after 10 days to maintain 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 Sandoz Inc. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)