Amoxicillin/Clavulanate potassium

Description

Amoxicillin and Clavulanate Potassium for Oral Suspension, USP is an oral antibacterial combination that includes the semisynthetic antibacterial amoxicillin and the beta-lactamase inhibitor clavulanate potassium, which is the potassium salt of clavulanic acid. Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The chemical structure of amoxicillin 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, with a molecular formula of C16H19N3O5S • 3H2O and a molecular weight of 419.46. Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus, and its chemical structure is potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo3.2.0-heptane-2-carboxylate, with a molecular formula of C8H8KNO5 and a molecular weight of 237.25.

Each 5 mL of the oral suspension contains 600 mg of amoxicillin as the trihydrate and 42.9 mg of clavulanic acid, which is equivalent to 51.1 mg of clavulanate potassium. The potassium content per 5 mL is 0.23 mEq. Inactive ingredients include aspartame, citric acid, colloidal silicon dioxide, mannitol, hypromellose, PB82 spray dried orange 739 flavor, sodium citrate, sodium saccharin, and xanthan gum.

Uses and Indications

Amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL, 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. This indication specifically applies to cases caused by Streptococcus pneumoniae (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). Patients presenting with the following risk factors are particularly suited for this treatment: antibacterial exposure for acute otitis media within the preceding 3 months, age of 2 years or younger, or attendance at daycare.

Limitations of use include the fact that amoxicillin and clavulanate potassium for oral suspension is not indicated for the treatment of acute otitis media due to S. pneumoniae with penicillin MICs greater than or equal to 4 mcg/mL. Additionally, acute otitis media caused solely by S. pneumoniae can be effectively treated with amoxicillin alone. Therapy may be initiated prior to obtaining results from bacteriological studies if there is a reasonable suspicion that the infection may involve both S. pneumoniae (with penicillin MIC less than or equal to 2 mcg/mL) and the aforementioned beta-lactamase-producing organisms.

To mitigate the development of drug-resistant bacteria and preserve the efficacy of amoxicillin and clavulanate potassium for oral suspension, it 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 total daily dose should be divided into two administrations, given every 12 hours. The treatment course is to be continued for a 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, 600 mg/42.9 mg per 5 mL is contraindicated in patients with a history of serious hypersensitivity reactions, including anaphylaxis or Stevens-Johnson syndrome, to this medication 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 this medication.

Warnings and Precautions

Serious hypersensitivity reactions, including those that may be fatal, have been reported in patients receiving amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL. 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) require close monitoring. Should any rash develop or progress, the medication must be discontinued without delay.

Drug-induced enterocolitis syndrome (DIES) has also been associated with the use of amoxicillin, a component of this formulation. If DIES is suspected, the administration of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL should be halted, and suitable therapy should be initiated.

Patients with hepatic dysfunction or those exhibiting signs of cholestatic jaundice must be closely monitored. If symptoms of hepatitis arise, discontinuation of the medication is necessary, and liver function tests should be conducted in patients with pre-existing hepatic impairment.

Clostridioides difficile-associated diarrhea (CDAD) can occur, presenting a spectrum from mild diarrhea to potentially fatal colitis. It is essential to evaluate patients for CDAD if diarrhea develops during treatment.

In patients diagnosed with mononucleosis, the use of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL is contraindicated, as these patients are at an increased risk of developing a skin rash.

Side Effects

Patients receiving amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL may experience a range of adverse reactions. The most frequently reported adverse reactions include coughing, vomiting, contact dermatitis (such as diaper rash), fever, upper respiratory tract infection, and diarrhea.

Serious adverse reactions have been observed 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 management. Hepatic dysfunction and cholestatic jaundice have also been reported; patients should be monitored for signs and symptoms of hepatitis, and the medication should be discontinued if these occur. Additionally, Clostridioides difficile-associated diarrhea (CDAD) can range from mild diarrhea to fatal colitis, and patients should be evaluated if diarrhea develops. It is important to note that patients with mononucleosis who receive this medication may develop a skin rash, and its use should be avoided in these individuals.

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. Interstitial nephritis resulting in oliguric renal failure has been documented in a few cases 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

Coadministration of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL, with probenecid is not recommended due to potential interactions that may affect 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 use of allopurinol in conjunction with amoxicillin and clavulanate potassium 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.

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, 600 mg/42.9 mg per 5 mL, have been established in pediatric patients aged 3 months to 12 years weighing less than or equal to 40 kg for the treatment of acute otitis media and acute bacterial sinusitis. However, the safety and effectiveness of this formulation 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 have an increased risk of hepatic dysfunction when treated with amoxicillin and clavulanate potassium, particularly with the oral suspension formulation of 600 mg/42.9 mg per 5 mL. Experience with this specific formulation in adults is limited, and it is advised that elderly patients who have difficulty swallowing should not be administered this oral suspension in lieu of the 500 mg or 875 mg tablet forms.

Caution is warranted when prescribing amoxicillin and clavulanate potassium to geriatric patients with hepatic impairment. Regular monitoring of hepatic function is recommended, as increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase have been infrequently reported. These occurrences are more prevalent in elderly patients, males, and those undergoing prolonged treatment.

It is important to note that the onset of hepatic dysfunction may manifest during therapy or several weeks after discontinuation of treatment. While such dysfunction is typically reversible, it can be severe, and there have been reports of fatalities associated with this condition. Therefore, careful consideration and monitoring are essential when treating elderly patients with this medication.

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.

Reproductive studies conducted in pregnant rodents, which received 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, studies in pregnant rats and mice administered amoxicillin and clavulanate at oral doses up to 1200 mg/kg/day also showed no evidence of fetal harm.

It is important to note that the background risk of major birth defects and miscarriage for the indicated populations is unknown. 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, amoxicillin and clavulanate was associated with a significantly increased rate of proven neonatal necrotizing enterocolitis, with an incidence of 1.9% in the amoxicillin and clavulanate group compared to 0.5% in the placebo 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.

Lactation

There is no specific information available regarding the use of this drug in lactating mothers or its effects on breastfed infants. Healthcare professionals should consider the absence of data when advising lactating mothers about the use of this medication.

Renal Impairment

Patients with renal impairment have no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to this population. Regular assessment of renal function may be warranted to ensure safe and effective use of the medication in patients with reduced kidney function.

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 the treatment regimen.

Overdosage

Following an overdosage of amoxicillin and clavulanate potassium, patients have primarily exhibited gastrointestinal symptoms, including stomach and abdominal pain, vomiting, and diarrhea. In a minority of cases, additional symptoms such as rash, hyperactivity, or drowsiness have been reported.

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, healthcare professionals may consider inducing emesis or employing other methods to remove the drug from the stomach.

A prospective study indicates that overdosages of less than 250 mg/kg of amoxicillin are generally not associated with significant clinical symptoms and do not necessitate gastric emptying. However, it is important to monitor for potential complications, as interstitial nephritis leading to oliguric renal failure has been documented in a small number of patients following overdosage. Additionally, crystalluria, which can result in renal failure, has been observed in both adult and pediatric patients after amoxicillin overdosage.

To mitigate the risk of crystalluria, it is crucial to maintain adequate fluid intake and promote diuresis. Renal impairment associated with overdosage appears to be reversible upon cessation of the drug. It is also noteworthy that patients with impaired renal function may experience higher blood levels of amoxicillin and clavulanate due to decreased renal clearance.

Both amoxicillin and clavulanate can be effectively removed from the circulation through hemodialysis, which may be considered in cases of significant overdosage or renal impairment.

Nonclinical Toxicology

Long-term studies in animals have not been conducted to assess the carcinogenic potential of amoxicillin and clavulanate. In mutagenicity testing, the 4:1 ratio formulation of amoxicillin to clavulanate 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, also yielded negative results in the Ames bacterial mutation assay and the mouse micronucleus test.

In terms of reproductive toxicity, the 2:1 ratio formulation of amoxicillin to clavulanate, 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 (600 mg/42.9 mg per 5 mL dose, equating to 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. Notable among these are diarrhea, which may present as watery or bloody stools, and can occur even two or more months after discontinuation of the medication. Additionally, severe cutaneous adverse reactions (SCAR) have been reported, including serious skin manifestations.

Patients are advised to promptly report any signs or symptoms of skin rash, mucosal lesions, or other indications of hypersensitivity. It is important to note that antibacterial drugs, such as amoxicillin and clavulanate potassium, are indicated solely for the treatment of bacterial infections and are ineffective against viral infections.

Patient Counseling

Patients should be informed to take amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL, every 12 hours with a meal or snack to minimize the risk of gastrointestinal upset. They should be advised to contact their doctor if they experience severe diarrhea that lasts more than 2 or 3 days.

It is important to counsel patients that this medication 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 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, including amoxicillin and clavulanate potassium for oral suspension. This side effect typically resolves upon discontinuation of the medication. However, patients should be cautioned 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 such symptoms occur, patients should seek medical attention promptly.

For patients with phenylketonuria, it is essential to note that each 5 mL of the suspension contains 1.4 mg of phenylalanine.

Patients should be counseled that antibacterial drugs, including amoxicillin and clavulanate potassium for oral suspension, are effective only against bacterial infections and do not treat viral infections, such as the common cold. They should be advised that even if they 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.

Patients should be instructed 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 important to rinse the spoon or dropper after each use. Patients should follow their doctor’s instructions regarding the appropriate dosage and duration of treatment for their child and should discard any unused medication.

Storage and Handling

The dry powder should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. It is essential to dispense the product in its original container and ensure that the container remains tightly closed to maintain stability.

Once reconstituted, the suspension must be stored under refrigeration. Any unused suspension should be discarded after 10 days to ensure safety and efficacy. Additionally, it is crucial to keep this medication, as well as all other medications, out of the reach of children.

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 Teva Pharmaceuticals USA, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)