Amoxicillin/Clavulanate potassium

Description

Amoxicillin and Clavulanate Potassium for Oral Suspension USP, 600 mg/42.9 mg per 5 mL, is an oral antibacterial combination that includes the semisynthetic antibacterial amoxicillin and the beta-lactamase inhibitor clavulanate potassium, the potassium salt of clavulanic acid. Amoxicillin, an analog of ampicillin derived from 6-aminopenicillanic acid, has 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 beta-lactam that is structurally related to penicillins. It effectively inactivates a variety of beta-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, 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, providing a potassium content of 0.248 mEq per 5 mL. The formulation includes inactive ingredients such as aspartame, colloidal silicon dioxide, hypromellose, orange powder flavor, silicon dioxide, succinic acid, and xanthan gum. Each 5 mL of the reconstituted suspension contains approximately 9.73 mg of potassium.

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 includes cases due to 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).

This medication is specifically indicated for patients who have had antibacterial exposure for acute otitis media within the preceding 3 months, and who meet at least one of the following criteria: are aged 2 years or younger, or attend daycare.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL, as well as other antibacterial drugs, it should be utilized only to treat or prevent 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 into two administrations every 12 hours. The treatment course is to be continued for a total 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 throughout 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 the use of this medication.

Warnings and Precautions

Serious hypersensitivity reactions, including anaphylaxis, 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) may occur with the use of this medication. Healthcare professionals should monitor patients closely for any signs of rash, and if the rash progresses, discontinuation of the drug is warranted.

Drug-induced enterocolitis syndrome (DIES) has been associated with amoxicillin, a component of this formulation. Should symptoms indicative of DIES arise, it is essential to discontinue amoxicillin and clavulanate potassium for oral suspension 600 mg/42.9 mg per 5 mL and provide suitable therapy.

Patients with hepatic dysfunction are at 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) can manifest in patients taking this medication, ranging from mild diarrhea to severe, potentially fatal colitis. It is crucial to evaluate any patient who presents with diarrhea during or after treatment.

In patients 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 increased risk of developing a skin rash. Therefore, this medication should be avoided in such cases to prevent adverse reactions.

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. Common adverse reactions reported include coughing, vomiting, contact dermatitis (such as diaper rash), fever, upper respiratory tract infections, and diarrhea.

Serious adverse reactions, although less frequent, can occur and require immediate attention. These include serious hypersensitivity reactions, which may 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 been observed; patients should be monitored for signs or symptoms of hepatitis, and the medication should be discontinued if these occur. Clostridioides difficile-associated diarrhea (CDAD), which can range from mild diarrhea to fatal colitis, requires evaluation of patients if diarrhea develops. Additionally, patients with mononucleosis who are treated with this medication may develop skin rashes, and its use should be avoided in these individuals.

It is important to note that patients with 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) should not receive this medication. Similarly, those with a history of cholestatic jaundice or hepatic dysfunction associated with this drug should be cautious.

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. Rarely, interstitial nephritis resulting in oliguric renal failure has been reported following overdosage, as well as crystalluria, which in some instances has led to renal failure in both adult and pediatric patients.

Drug Interactions

Co-administration of amoxicillin and clavulanate potassium for oral suspension 600 mg/42.9 mg per 5 mL with oral anticoagulants may lead to an increased prolongation of prothrombin time. It is advisable to monitor prothrombin time closely in patients receiving this combination.

The use of probenecid alongside amoxicillin and clavulanate potassium is not recommended due to potential interactions that may affect therapeutic outcomes.

Additionally, concomitant use of allopurinol with amoxicillin and clavulanate potassium has been associated with an increased risk of rash. Caution is advised when these medications are prescribed together.

Furthermore, amoxicillin and clavulanate potassium for oral suspension may reduce the efficacy of oral contraceptives. Patients should be informed of this potential interaction 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 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

There is no specific information available regarding the use of this medication in geriatric patients, including dosage adjustments, safety concerns, or special precautions. Healthcare providers should exercise caution when prescribing this medication to elderly patients, as individual responses may vary. It is advisable to monitor these patients closely for any adverse effects or changes in efficacy.

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.

Reproduction studies conducted in pregnant rodents, administered 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 (600 mg/42.9 mg per 5 mL), revealed no evidence of harm to the fetus. Similarly, studies in pregnant rats and mice given 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, those treated with amoxicillin and clavulanate exhibited a significantly increased rate of proven neonatal necrotizing enterocolitis, with 1.9% in the amoxicillin and clavulanate group compared to 0.5% in the placebo group (p = 0.001). 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 are no specific statements regarding the use of this medication in nursing mothers or its effects during lactation. Additionally, there is no available data on the excretion of this medication in breast milk or its potential effects on breastfed infants. Healthcare professionals should consider the absence 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 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, 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 for oral suspension 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 and supportive measures should be instituted 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 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. To mitigate the risk of crystalluria, it is essential to maintain adequate fluid intake and diuresis in cases of overdosage.

Renal impairment observed in these situations 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 amoxicillin and clavulanate due to decreased renal clearance. Both amoxicillin and clavulanate 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 the combination of amoxicillin and clavulanate. In mutagenicity testing, amoxicillin and clavulanate in a 4:1 ratio formulation demonstrated non-mutagenic properties in both the Ames bacterial mutation assay and the yeast gene conversion assay. However, results from the mouse lymphoma assay indicated a weakly positive response, although the observed trend toward increased mutation frequencies occurred at concentrations that also resulted in decreased cell survival. The combination was negative in the mouse micronucleus test and in the dominant lethal assay in mice.

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

In terms of reproductive toxicity, amoxicillin and clavulanate in a 2:1 ratio formulation, 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), which equates to about 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 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, including interstitial nephritis, has been reported as well.

Other adverse reactions include angioedema, serum sickness, and various hypersensitivity reactions.

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 healthcare provider 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 to their healthcare provider.

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 cautioned that watery and bloody stools, with or without stomach cramps and fever, can occur even up to 2 months after completing the treatment. If such symptoms arise, patients should seek medical attention promptly.

Counsel patients that antibacterial drugs, including amoxicillin and clavulanate potassium for oral suspension 600 mg/42.9 mg per 5 mL, are effective only against bacterial infections and do not treat viral infections, such as the common cold. Patients should be advised to adhere strictly to the prescribed regimen, as skipping doses or failing to complete the full course of therapy may reduce the treatment's effectiveness 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 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 medication should be discarded.

For patients with phenylketonuria, it should be noted that each 5 mL of the 600 mg/42.9 mg per 5 mL suspension contains 7 mg of phenylalanine.

Storage and Handling

The product is supplied as a dry powder, which 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 to maintain its integrity.

Once reconstituted, the suspension must be stored under refrigeration. Any unused portion of the reconstituted suspension should be discarded after 10 days to ensure 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 Hikma Pharmaceuticals USA Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)