Amoxicillin/Clavulanate potassium

Description

Amoxicillin and clavulanate potassium for oral suspension, USP is an oral antibacterial combination comprising the semisynthetic antibacterial amoxicillin and the beta-lactamase inhibitor clavulanate potassium, the potassium salt of clavulanic acid. Amoxicillin, an analog of ampicillin derived from the penicillin nucleus 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-azabicyclo 3.2.0 heptane-2-carboxylic acid trihydrate.

Clavulanic acid, produced by the fermentation of Streptomyces clavuligerus, is a beta-lactam 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.

Each 5 mL of reconstituted suspension contains 600 mg of amoxicillin as the trihydrate and 42.9 mg of clavulanic acid as the potassium salt, with a potassium content of 0.23 mEq (equivalent to 9 mg). The dry powder appears as a white to yellowish white crystalline powder, while the suspension is characterized as an almost white to yellow, homogeneous mixture. Inactive ingredients include caramel flavor, carboxymethyl cellulose sodium, citric acid, colloidal silicon dioxide, microcrystalline cellulose, orange flavor, raspberry flavor, saccharin sodium, silicon dioxide, sodium citrate, and xanthan gum.

Uses and Indications

Amoxicillin and clavulanate potassium for oral suspension, USP is indicated for the treatment of pediatric patients with recurrent or persistent acute otitis media caused by specific pathogens. This medication is effective against Streptococcus pneumoniae (penicillin minimum inhibitory concentrations MICs ≤2 mcg/mL), Haemophilus influenzae (including beta-lactamase–producing strains), and Moraxella catarrhalis (including beta-lactamase-producing strains).

This drug is particularly indicated for patients who present with risk factors such as antibacterial drug exposure for acute otitis media within the preceding 3 months, and either being 2 years of age or younger, or attending daycare.

No teratogenic or nonteratogenic effects have been reported with the use of this medication.

Dosage and Administration

Pediatric patients weighing less than 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 duration is recommended 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 effects during the treatment period.

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 in patients receiving amoxicillin and clavulanate potassium. In the event of such a reaction, it is imperative to discontinue the medication immediately.

Patients with hepatic dysfunction are at an increased risk for cholestatic jaundice. Should any signs or symptoms of hepatitis arise, amoxicillin and clavulanate potassium must be discontinued. It is recommended that liver function tests be monitored in patients with pre-existing hepatic impairment to ensure safety during treatment.

Clostridium difficile-associated diarrhea (CDAD) has been associated with the use of this medication. Healthcare professionals should evaluate patients for CDAD if they present with diarrhea during or following treatment.

Additionally, patients diagnosed with mononucleosis who are treated with amoxicillin and clavulanate potassium may develop a skin rash. Therefore, the use of this medication is contraindicated in patients with mononucleosis to prevent adverse reactions.

Side Effects

Patients receiving amoxicillin and clavulanate potassium may experience a range of adverse reactions. Common adverse reactions observed in clinical trials include diaper rash (4%), diarrhea (3%), vomiting (2%), candidiasis (1%), and rash (1%).

Serious adverse reactions, although less frequent, warrant careful monitoring. These include serious hypersensitivity reactions, which can be fatal; patients should discontinue the medication if such reactions occur. Hepatic dysfunction and cholestatic jaundice have also been reported, necessitating discontinuation of the drug if signs or symptoms of hepatitis arise. Liver function tests should be monitored in patients with pre-existing hepatic impairment. Additionally, Clostridium difficile-associated diarrhea (CDAD) should be evaluated if diarrhea occurs during treatment. It is important to note that patients with mononucleosis who receive amoxicillin and clavulanate potassium may develop skin rashes, and the use of this medication is contraindicated in these individuals.

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 the use of amoxicillin and clavulanate potassium should also be taken into account.

In cases of overdosage, patients have primarily experienced gastrointestinal symptoms, including stomach and abdominal pain, vomiting, and diarrhea. Some patients have also reported rash, hyperactivity, or drowsiness. Rarely, interstitial nephritis resulting in oliguric renal failure has been observed following overdosage. Crystalluria, which in some instances has led to renal failure, has been reported in both adult and pediatric patients. To mitigate the risk of crystalluria, it is advised to maintain adequate fluid intake and diuresis in cases of overdosage.

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 safe 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.

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

Safety and efficacy of amoxicillin and clavulanate potassium have not been established in infants younger than 3 months. For pediatric patients aged 3 months to 12 years, the safety and efficacy of this medication have been demonstrated in the treatment of acute otitis media. Additionally, amoxicillin and clavulanate potassium for oral suspension has been shown to be safe and effective for treating acute bacterial sinusitis in the same age group.

Geriatric Use

Elderly patients may experience unique considerations when prescribed amoxicillin and clavulanate potassium. Experience with this formulation in adults is limited, and it is not recommended for those who have difficulty swallowing, as they should not substitute the oral suspension for the 500-mg or 875-mg tablet forms.

Hepatic dysfunction, including conditions such as hepatitis and cholestatic jaundice, has been reported more frequently in geriatric patients, particularly in males or those undergoing prolonged treatment. Therefore, it is essential to monitor hepatic function at regular intervals in patients with hepatic impairment. While hepatic dysfunction can be severe, it is typically reversible upon discontinuation of the medication.

Additionally, increased prothrombin time has been observed in patients receiving amoxicillin and clavulanate potassium alongside anticoagulant therapy. Consequently, appropriate monitoring is warranted when these medications are prescribed concurrently to mitigate the risk of bleeding complications.

Renal impairment, which may also occur in elderly patients, appears to be reversible with the cessation of the drug. However, it is important to note that high blood levels of the drug may develop more readily in patients with impaired renal function due to decreased renal clearance of both amoxicillin and clavulanate. Therefore, careful consideration of renal function and potential dose adjustments may be necessary in this population.

Pregnancy

Pregnant patients should be informed that amoxicillin and clavulanate potassium is classified as Pregnancy Category B. There are no adequate and well-controlled studies of this medication in pregnant women. Therefore, it should be used during pregnancy only if clearly needed.

Reproductive studies conducted in pregnant rats and mice, which received amoxicillin and clavulanate potassium at a 2:1 ratio formulation at oral doses up to 1200 mg/kg/day, revealed no evidence of harm to the fetus. The doses administered in these studies were approximately twice the recommended clinical dose for amoxicillin in rats and equivalent to the recommended dose in mice, based on body surface area calculations for a 20 kg child. For clavulanate, the doses were approximately 15 times and 7.5 times the recommended daily dose for oral suspension.

Given the lack of human data and the variability in animal studies, healthcare professionals should weigh the potential benefits against the risks when considering the use of amoxicillin and clavulanate potassium in pregnant patients.

Lactation

Ampicillin-class antibacterial drugs, 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 drug's presence in breast milk.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in 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 immediately. Regular assessment of liver function is essential to ensure the safety and efficacy of the therapy in this patient population.

Overdosage

Following 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 for oral suspension. Symptomatic treatment and supportive measures should be instituted as necessary. If the overdosage has occurred 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 an overdosage of less than 250 mg/kg of amoxicillin is generally not associated with significant clinical symptoms and does not necessitate gastric emptying.

There have been reports of interstitial nephritis leading to oliguric renal failure in a small number of patients following overdosage with amoxicillin. Additionally, 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 circulation through hemodialysis.

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 decreased cell survival at the tested concentrations. The formulation was negative in the mouse micronucleus test and in the dominant lethal assay in mice.

Potassium clavulanate, 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 and clavulanate potassium, administered at oral doses of up to 1,200 mg/kg/day, demonstrated no adverse effects on fertility and 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, which is 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 revealed that diarrhea is a frequently reported issue associated with antibacterial drugs, typically resolving upon discontinuation of the medication. Additionally, there have been instances where patients developed watery and bloody stools, with or without accompanying symptoms such as stomach cramps and fever, even two months or more after the last dose of the antibacterial drug. In such cases, it is advised that patients contact their physician promptly.

Patient Counseling

Patients should be advised to take amoxicillin and clavulanate potassium for oral suspension every 12 hours with a meal or snack to minimize the risk of gastrointestinal upset. They should be instructed 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 antibacterial drugs, including amoxicillin and clavulanate potassium for oral suspension, are indicated solely for the treatment of bacterial infections and are ineffective against viral infections, such as the common cold. Patients should be informed that even if they start to feel better early in the treatment course, 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.

Patients should also be made aware that diarrhea is a common side effect associated with antibacterial drugs, which typically resolves upon discontinuation of the medication. However, they should be vigilant for the development of watery and bloody stools, which may occur even weeks after completing the treatment. If such symptoms arise, patients should seek medical attention promptly.

The suspension should be stored in the refrigerator and shaken well before each use. When administering the suspension to a child, patients should use a dosing spoon or medicine dropper and ensure it is rinsed after each use. It is essential to follow the healthcare provider's instructions regarding the appropriate dosage and duration of treatment, and any unused medication should be discarded.

Lastly, patients should be counseled that amoxicillin and clavulanate potassium for oral suspension contains a penicillin-class drug, which may cause allergic reactions in some individuals. They should be advised to report any signs of an allergic reaction to their healthcare provider immediately.

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 a temperature range of 20º to 25°C (68º 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 and stability.

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 Aidarex Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)