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 comprising the semisynthetic antibiotic amoxicillin, USP, and the β-lactamase inhibitor clavulanate potassium, which is 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. 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 β-lactam that is structurally related to penicillins. It effectively inactivates a variety of β-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, 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 the reconstituted suspension contains 600 mg of amoxicillin, USP, as the trihydrate, and 42.9 mg of clavulanic acid as clavulanate potassium, with a potassium content of 0.25 mEq. Inactive ingredients include aspartame, colloidal silicon dioxide, monosodium citrate, silicon dioxide, sodium citrate (as dihydrate), strawberry flavor, strawberry guarana flavor, and xanthan gum.

Uses and Indications

Amoxicillin and clavulanate potassium for oral suspension, USP, 600 mg/42.9 mg per 5 mL is indicated for the treatment of pediatric patients with recurrent or persistent acute otitis media caused by specific pathogens. This includes infections due to Streptococcus pneumoniae (penicillin minimum inhibitory concentrations MICs ≤ 2 mcg/mL), Haemophilus influenzae (including β-lactamase-producing strains), and Moraxella catarrhalis (including β-lactamase-producing strains).

This medication is particularly indicated for patients exhibiting risk factors such as antibiotic exposure for acute otitis media within the preceding 3 months, along with either of the following conditions: age ≤ 2 years or daycare attendance. It is important to note that acute otitis media solely due to S. pneumoniae can be treated with amoxicillin alone.

Amoxicillin and clavulanate potassium for oral suspension is not indicated for the treatment of acute otitis media caused by S. pneumoniae with penicillin MIC ≥ 4 mcg/mL. Therapy may be initiated prior to obtaining results from bacteriological studies if there is a clinical suspicion that the infection may involve both S. pneumoniae (penicillin MIC ≤ 2 mcg/mL) and the aforementioned β-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 caused by susceptible bacteria.

Dosage and Administration

Pediatric patients aged 3 months and older are recommended to receive amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL, at a dosage of 90 mg/kg/day, divided into two doses every 12 hours, for a duration of 10 days.

To minimize gastrointestinal intolerance, it is advised that the oral suspension be administered at the start of a meal. This timing may enhance the absorption of clavulanate potassium.

The volume of amoxicillin and clavulanate potassium for oral suspension to be administered is based on the patient's body weight, as follows:

• For a body weight of 8 kg: 3 mL twice daily

• For a body weight of 12 kg: 4.5 mL twice daily

• For a body weight of 16 kg: 6 mL twice daily

• For a body weight of 20 kg: 7.5 mL twice daily

• For a body weight of 24 kg: 9 mL twice daily

• For a body weight of 28 kg: 10.5 mL twice daily

• For a body weight of 32 kg: 12 mL twice daily

• For a body weight of 36 kg: 13.5 mL twice daily

For preparation of the oral suspension, the following steps should be followed: Tap the bottle until all the powder flows freely. Add approximately two-thirds of the total amount of water required for reconstitution and shake vigorously to ensure the powder is suspended. Then, add the remaining water and shake vigorously again.

It is essential to shake the oral suspension well before each use to ensure proper mixing.

Contraindications

Amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL is contraindicated in patients with a history of allergic reactions to any penicillin. Additionally, use is contraindicated in individuals with a previous history of cholestatic jaundice or hepatic dysfunction associated with the use of amoxicillin and clavulanate potassium.

Warnings and Precautions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients undergoing penicillin therapy. These reactions are particularly likely to occur in individuals with a history of penicillin hypersensitivity and/or sensitivity to multiple allergens. Notably, there have been instances of individuals with a history of penicillin hypersensitivity experiencing severe reactions when treated with cephalosporins. Prior to initiating therapy with amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL, a thorough inquiry regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens is essential. Should an allergic reaction occur, the administration of amoxicillin and clavulanate potassium should be discontinued immediately, and appropriate therapeutic measures should be instituted.

In cases of serious anaphylactic reactions, immediate emergency treatment with epinephrine is required. Additional interventions may include the administration of oxygen, intravenous steroids, and airway management, including intubation, as clinically indicated.

Pseudomembranous colitis has been associated with nearly all antibacterial agents, including amoxicillin/clavulanate potassium, and can range in severity from mild to life-threatening. Therefore, it is crucial to consider this diagnosis in patients who present with diarrhea following the administration of antibacterial agents.

Amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL, should be used with caution in patients exhibiting evidence of hepatic dysfunction. While hepatic toxicity related to the use of amoxicillin/clavulanate potassium is typically reversible, there have been rare reports of fatalities (less than one death per estimated four million prescriptions worldwide). These cases have generally involved patients with serious underlying conditions or those receiving concomitant medications. Regular monitoring of liver function may be warranted in these patients to ensure safety during treatment.

Side Effects

Common adverse reactions observed in patients include contact dermatitis (diaper rash) at a rate of 3.5%, diarrhea (2.9%), vomiting (2.2%), moniliasis (1.4%), and rash (1.1%). Notably, diarrhea and vomiting were also among the adverse reactions leading to withdrawal from treatment, occurring in 2.5% and 1.4% of participants, respectively.

Gastrointestinal adverse reactions encompass a range of symptoms, including diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic or pseudomembranous colitis, with the onset of symptoms potentially occurring during or after antibiotic treatment.

Hypersensitivity reactions may manifest as skin rashes, pruritus, urticaria, angioedema, and serum sickness-like reactions, which can include urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever. Rare but serious hypersensitivity reactions, such as erythema multiforme (and rarely Stevens-Johnson syndrome), acute generalized exanthematous pustulosis, and exfoliative dermatitis (including toxic epidermal necrolysis), have been reported. There are also instances of serious and occasionally fatal anaphylactic reactions.

Liver-related adverse reactions include moderate rises in AST (SGOT) and/or ALT (SGPT), hepatic dysfunction (which may include hepatitis and cholestatic jaundice), and increases in serum transaminases, serum bilirubin, and/or alkaline phosphatase. Severe hepatic dysfunction, typically reversible, has been noted, along with rare reports of death associated with serious underlying diseases or concomitant medications.

Renal adverse reactions are rare and include interstitial nephritis, hematuria, and crystalluria.

In the hemic and lymphatic systems, adverse reactions may present as anemia (including hemolytic anemia), thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, agranulocytosis, slight thrombocytosis (less than 1%), and increased prothrombin time in patients receiving anticoagulant therapy concomitantly.

Central nervous system effects are rare and may include agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity.

Miscellaneous adverse reactions include tooth discoloration, which may present as brown, yellow, or gray staining, and is considered rare.

Drug Interactions

Probenecid is known to decrease the renal tubular secretion of amoxicillin. When amoxicillin and clavulanate potassium for oral suspension (600 mg/42.9 mg per 5 mL) is administered concurrently with probenecid, there may be an increase in blood levels of amoxicillin, leading to prolonged effects. Therefore, co-administration of probenecid with this formulation is not recommended.

The concurrent use of allopurinol with ampicillin has been associated with a significantly higher incidence of rashes compared to patients receiving ampicillin alone. It remains unclear whether this increased incidence is attributable to allopurinol or the hyperuricemia present in these patients. There is no available data regarding the concurrent administration of allopurinol with amoxicillin and clavulanate potassium for oral suspension (600 mg/42.9 mg per 5 mL).

Amoxicillin/clavulanate, like other broad-spectrum antibiotics, may diminish the effectiveness of oral contraceptives. Patients using both medications should be advised to consider alternative or additional contraceptive methods.

Oral administration of amoxicillin and clavulanate potassium results in high concentrations of amoxicillin in urine. This can lead to false-positive results for glucose when using tests such as CLINITEST®, Benedict’s Solution, or Fehling’s Solution. It is recommended that glucose testing utilize enzymatic glucose oxidase reactions (e.g., CLINISTIX®) to avoid this issue.

In pregnant women, administration of ampicillin has been observed to cause a transient decrease in plasma concentrations of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol. This effect may also be applicable to amoxicillin and, consequently, to amoxicillin and clavulanate potassium for oral suspension (600 mg/42.9 mg per 5 mL). Monitoring of hormone levels may be warranted in pregnant patients receiving these medications.

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 efficacy of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL, have not been established in infants younger than 3 months. However, this formulation has demonstrated safety and efficacy for the treatment of acute otitis media in pediatric patients aged 3 months to 12 years. Additionally, it has been shown to be effective for the treatment of acute bacterial sinusitis in the same age group. Caution is advised when prescribing this medication to infants under 3 months of age, as data supporting its use in this population is lacking.

Geriatric Use

Elderly patients should use amoxicillin and clavulanate potassium for oral suspension with caution, particularly those with evidence of hepatic dysfunction, which is more prevalent in this population. Hepatic dysfunction, including conditions such as hepatitis and cholestatic jaundice, has been reported more frequently among elderly patients, especially in males or those undergoing prolonged treatment. Histologic findings from liver biopsies in geriatric patients have typically shown predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes.

It is important to note that the onset of signs and symptoms indicative of hepatic dysfunction may occur during treatment or several weeks after discontinuation of therapy. Therefore, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable for elderly patients receiving therapy beyond the approved duration.

Renal impairment in elderly patients appears to be reversible upon cessation of drug administration; however, these patients may experience higher blood levels of the drug due to decreased renal clearance of both amoxicillin and clavulanate. Additionally, elderly patients may exhibit increased sensitivity to side effects, including gastrointestinal intolerance, necessitating close monitoring for adverse reactions.

Pregnancy

The use of amoxicillin and clavulanate potassium during pregnancy has not been well studied, and it is not known whether its administration in humans during labor or delivery has immediate or delayed adverse effects on the fetus. There is insufficient data to determine if this medication prolongs the duration of labor or increases the likelihood of requiring obstetrical interventions, such as forceps delivery or resuscitation of the newborn.

In a single study involving women with premature rupture of fetal membranes, prophylactic treatment with amoxicillin and clavulanate potassium was associated with an increased risk of necrotizing enterocolitis in neonates. Given these considerations, healthcare professionals should weigh the potential benefits against the risks when prescribing this medication to pregnant patients. Caution is advised, particularly in the context of labor and delivery.

Lactation

Ampicillin-class antibiotics, 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 use of this antibiotic in nursing women.

Renal Impairment

Patients with renal impairment should use amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL with caution. While specific dosing adjustments for patients with reduced kidney function are not detailed, it is important to monitor these patients closely due to the potential for altered pharmacokinetics. Additionally, patients with evidence of hepatic dysfunction may require further evaluation before initiating treatment.

Hepatic Impairment

Amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL should be used with caution in patients with evidence of hepatic dysfunction. While hepatic toxicity associated with the use of amoxicillin/clavulanate potassium is usually reversible, it is important for healthcare providers to monitor liver function in these patients.

Although rare, there have been reports of fatalities associated with the use of this medication, with less than one death reported per estimated 4 million prescriptions worldwide. These cases have generally involved patients with serious underlying diseases or those taking concomitant medications that may contribute to hepatic impairment. Therefore, careful consideration and monitoring are advised when prescribing this medication to patients with compromised liver function.

Overdosage

Following 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 the medication and to treat the patient symptomatically while instituting supportive measures as necessary. If the overdosage has occurred very 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 overdosages of less than 250 mg/kg of amoxicillin are generally not associated with significant clinical symptoms and do not necessitate gastric emptying.

It is important to note that interstitial nephritis resulting in oliguric renal failure has been reported in a small number of cases following overdosage with amoxicillin. Furthermore, crystalluria, which in some instances has led to renal failure, has also 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 drug administration. It is crucial to recognize 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 the circulation through hemodialysis, which may be necessary in cases of significant overdosage.

Nonclinical Toxicology

Reproduction studies conducted in pregnant rats and mice administered amoxicillin and clavulanate potassium at oral dosages up to 1,200 mg/kg/day (4.9 and 2.8 times the maximum adult human oral dose based on body surface area, respectively) demonstrated no evidence of teratogenic effects on the fetus. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human response, the use of this drug during pregnancy should be considered only when clearly necessary.

In terms of non-teratogenic effects, amoxicillin and clavulanate potassium, when given at oral doses of up to 1,200 mg/kg/day (5.7 times the maximum adult human dose based on body surface area), did not adversely affect fertility or reproductive performance in rats treated with a 2:1 ratio formulation of amoxicillin to clavulanate.

Long-term studies in animals have not been conducted to assess the carcinogenic potential of amoxicillin and clavulanate potassium. The mutagenic potential of this drug was evaluated through various in vitro assays, including the Ames test, a human lymphocyte cytogenetic assay, a yeast test, and a mouse lymphoma forward mutation assay, as well as in vivo assessments using mouse micronucleus tests and a dominant lethal test. All tests returned negative results, except for the in vitro mouse lymphoma assay, which indicated weak activity at very high, cytotoxic concentrations.

Postmarketing Experience

Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving penicillin therapy. These reactions are more prevalent in individuals with a history of penicillin hypersensitivity or sensitivity to multiple allergens.

Pseudomembranous colitis has been documented with nearly all antibacterial agents, including amoxicillin/clavulanate potassium, with severity ranging from mild to life-threatening.

Hepatic dysfunction, encompassing hepatitis and cholestatic jaundice, has been infrequently reported in association with amoxicillin and clavulanate potassium, occurring more commonly in elderly patients, males, or those undergoing prolonged treatment. The onset of hepatic dysfunction may manifest during therapy or several weeks after discontinuation, and while it can be severe, it is typically reversible.

On rare occasions, deaths have been reported, with an estimated incidence of less than one death per four million prescriptions worldwide. These cases have generally involved patients with serious underlying conditions or those taking concomitant medications.

Adverse reactions associated with ampicillin-class antibiotics include gastrointestinal effects (such as diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis), hypersensitivity reactions (including skin rashes, pruritus, urticaria, angioedema, serum sickness-like reactions, erythema multiforme, acute generalized exanthematous pustulosis, and exfoliative dermatitis), renal effects (such as interstitial nephritis and hematuria), and central nervous system effects (including agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity).

A moderate increase in AST (SGOT) and/or ALT (SGPT) levels has been observed in patients treated with ampicillin-class antibiotics; however, the clinical significance of these findings remains unclear.

Patient Counseling

Healthcare providers should advise patients 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. Patients should be informed that if they experience severe diarrhea or if diarrhea persists for more than 2 or 3 days, they should contact their doctor.

It is important to instruct patients to keep the suspension refrigerated and to shake the bottle well before each use. When dosing children with the liquid suspension, healthcare providers should recommend the use of a dosing spoon or medicine dropper, emphasizing the need to rinse the spoon or dropper after each use to ensure accurate dosing.

Patients should be made aware that bottles of amoxicillin and clavulanate potassium for oral suspension may contain more liquid than is necessary for their treatment. They should follow their doctor’s instructions regarding the appropriate amount to use and the duration of treatment, and any unused medicine should be discarded.

Counsel patients 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. When prescribed for a bacterial infection, patients should be reminded that it is common to feel better early in the treatment course; however, it is crucial 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.

Lastly, healthcare providers should inform patients that each 5 mL dose of the suspension contains 5.6 mg of phenylalanine, which may be relevant for individuals with phenylketonuria (PKU) or other conditions requiring dietary restrictions.

Storage and Handling

The dry powder for oral suspension is supplied in its original container and should be stored at a temperature range of 20 – 25° C (68 – 77° F), in accordance with USP Controlled Room Temperature guidelines.

Once reconstituted, the suspension must be stored under refrigeration. Any unused suspension should be discarded after 10 days to ensure safety and efficacy.

Additional Clinical Information

High urine concentrations of amoxicillin may lead to false-positive results in glucose testing when using CLINITEST, Benedict’s Solution, or Fehling’s Solution. Clinicians are advised to utilize glucose tests based on enzymatic glucose oxidase reactions, such as CLINISTIX, for accurate results.

Amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL, should be administered every 12 hours with a meal or snack to minimize gastrointestinal upset. Patients should be counseled that this antibacterial medication is effective only against bacterial infections and not viral infections, such as the common cold. It is important for patients to adhere to the prescribed regimen, as skipping doses or failing to complete the full course may reduce treatment effectiveness and increase the risk of bacterial resistance.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Amoxicillin and Clavulanate Potassium as submitted by Ranbaxy Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)