Amoxicillin/Clavulanate potassium

Uses and Indications

This drug is indicated for the treatment of the following infections in adults and pediatric patients:

Infections

• Lower Respiratory Tract Infections

• Acute Bacterial Otitis Media

• Sinusitis

• Skin and Skin Structure Infections

• Urinary Tract Infections

Pediatric-Specific Indications

Amoxicillin and clavulanate potassium for oral suspension (600 mg/42.9 mg per 5 mL) is specifically indicated for pediatric patients aged 3 months to 12 years weighing less than or equal to 40 kg with recurrent or persistent acute otitis media due to:

• S. pneumoniae (penicillin MICs ≤ 2 mcg/mL)

• H. influenzae (including β-lactamase-producing strains)

• M. catarrhalis (including β-lactamase-producing strains)

Risk factors for this indication include:

• Antibiotic exposure for acute otitis media within the preceding 3 months

• Age 2 years or younger

• Daycare attendance

Limitations of Use

• Amoxicillin and clavulanate potassium should not be used when susceptibility test results show susceptibility to amoxicillin, indicating no beta-lactamase production.

• The oral suspension is not indicated for the treatment of acute otitis media due to S. pneumoniae with penicillin MIC ≥ 4 mcg/mL.

• Acute otitis media due to S. pneumoniae alone can be treated with amoxicillin.

Usage Notes

To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium and other antibacterial drugs, it should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Dosage and Administration

For adults and pediatric patients weighing greater than 40 kg, the recommended dosage of Amoxicillin and Clavulanate Potassium is 500 mg/125 mg or 875 mg/125 mg every 12 hours, or 250 mg/125 mg or 500 mg/125 mg every 8 hours, depending on the severity of the infection.

For pediatric patients aged 12 weeks (3 months) and older, the dosage is based on body weight, with a recommended range of 25 to 45 mg/kg/day divided every 12 hours, or 20 to 40 mg/kg/day divided every 8 hours, not exceeding the adult dose. For pediatric patients weighing less than or equal to 40 kg, a specific dosage of 90 mg/kg/day divided every 12 hours is recommended for a duration of 10 days.

Neonates and infants less than 12 weeks of age should receive 30 mg/kg/day divided every 12 hours, based on the amoxicillin component. The use of the 125 mg/5 mL oral suspension is recommended for this age group.

For the 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 for reconstitution and shake vigorously to suspend the powder. Add the remainder of the water and shake vigorously again. It is essential to shake the oral suspension well before each use.

To minimize gastrointestinal intolerance, Amoxicillin and Clavulanate Potassium should be taken at the start of a meal, as absorption of clavulanate potassium may be enhanced when administered in this manner.

For patients with impaired renal function, specific dosing adjustments are necessary. Patients with a glomerular filtration rate (GFR) less than 30 mL/min should not receive the 875 mg tablet. For those with a GFR of 10 to 30 mL/min, the dosage should be adjusted to 500 mg/125 mg or 250 mg/125 mg every 12 hours, depending on the severity of the infection. Patients with a GFR less than 10 mL/min should receive 500 mg/125 mg or 250 mg/125 mg every 24 hours, also depending on the severity of the infection. Hemodialysis patients should receive 500 mg/125 mg or 250 mg/125 mg every 24 hours, with an additional dose during and at the end of dialysis.

Hepatically impaired patients should be dosed with caution, and hepatic function should be monitored at regular intervals.

Contraindications

History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin and clavulanate potassium or to other beta-lactams (e.g., penicillins or cephalosporins) is a contraindication for use. Additionally, a history of cholestatic jaundice or hepatic dysfunction associated with amoxicillin and clavulanate potassium is also contraindicated.

Amoxicillin and clavulanate potassium is contraindicated in patients with a history of allergic reactions to any penicillin. Furthermore, it should not be administered to patients with mononucleosis due to the risk of serious adverse reactions.

Warnings and Precautions

Serious hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity or sensitivity to multiple allergens. Prior to initiating therapy with Amoxicillin and Clavulanate Potassium, careful inquiry regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens should be conducted. If an allergic reaction occurs, the medication should be discontinued immediately, and appropriate therapy instituted. Serious anaphylactic reactions require immediate emergency treatment with epinephrine, oxygen, intravenous steroids, and airway management, including intubation, as indicated.

Clostridioides difficile-Associated Diarrhea (CDAD)

CDAD has been reported with nearly all antibacterial agents, including Amoxicillin and Clavulanate Potassium, and can range from mild diarrhea to fatal colitis. It is essential to consider this diagnosis in patients who present with diarrhea following antibiotic use. Careful medical history is necessary, as CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued, and appropriate management should be instituted.

Drug-Induced Enterocolitis Syndrome (DIES)

DIES has been reported with the use of amoxicillin, a component of Amoxicillin and Clavulanate Potassium. If this occurs, the medication should be discontinued, and appropriate therapy instituted.

Hepatic Dysfunction

Amoxicillin and Clavulanate Potassium should be used with caution in patients with evidence of hepatic dysfunction. Hepatic toxicity associated with the use of this medication is usually reversible, but on rare occasions, deaths have been reported, typically in patients with serious underlying diseases or concomitant medications. Discontinue the medication if signs or symptoms of hepatitis occur, and monitor liver function tests in patients with hepatic impairment.

Severe Cutaneous Adverse Reactions (SCAR)

Patients should be monitored closely for severe cutaneous adverse reactions. If a rash progresses, the medication should be discontinued.

Mononucleosis

Patients with mononucleosis who receive Amoxicillin and Clavulanate Potassium may develop a skin rash. Therefore, the use of this medication should be avoided in these patients.

Overgrowth

The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfections occur, the drug should be discontinued, and appropriate therapy instituted.

Laboratory Monitoring

Periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable during prolonged therapy. High urine concentrations of amoxicillin may result in false-positive reactions when testing for glucose in urine using certain methods; it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

Pregnancy Considerations

Following administration of amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted.

Prescribing Amoxicillin and Clavulanate Potassium in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Side Effects

The most frequently reported adverse reactions associated with Amoxicillin and Clavulanate Potassium (including Augmentin) are as follows:

Common Adverse Reactions

• Diarrhea/loose stools: 9%

• Nausea: 3%

• Skin rashes and urticaria: 3%

• Vomiting: 1%

• Vaginitis: 1%

• Contact dermatitis (diaper rash): 3.5% (specific to oral suspension)

• Moniliasis: 1.4% (specific to oral suspension)

Less Common Adverse Reactions

• Abdominal discomfort

• Flatulence

• Headache

• Indigestion

• Gastritis

• Stomatitis

• Glossitis

• Black “hairy” tongue

• Mucocutaneous candidiasis

• Enterocolitis

• Hemorrhagic/pseudomembranous colitis: Symptoms may occur during or after antibiotic treatment.

Serious Adverse Reactions

• Serious hypersensitivity reactions: Discontinue Amoxicillin and Clavulanate Potassium if a reaction occurs. This includes anaphylactic reactions, which can be fatal.

• Severe Cutaneous Adverse Reactions (SCAR): Monitor closely and discontinue if rash progresses.

• Drug-induced enterocolitis syndrome (DIES): If this occurs, discontinue the medication and institute appropriate therapy.

• Hepatic dysfunction and cholestatic jaundice: Discontinue if signs/symptoms of hepatitis occur. Monitor liver function tests in patients with hepatic impairment.

• Clostridioides difficile-associated diarrhea (CDAD): Evaluate patients if diarrhea occurs; this can range from mild diarrhea to fatal colitis.

• Patients with mononucleosis: Those receiving Amoxicillin and Clavulanate Potassium may develop skin rash; avoid use in these patients.

• Overgrowth: The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy.

Additional Adverse Reactions or Important Notes

• Interstitial nephritis: Resulting in oliguric renal failure has been reported in patients after overdosage.

• Crystalluria: In some cases leading to renal failure, has also been reported after overdosage in adult and pediatric patients.

• History of hypersensitivity: A serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to Amoxicillin and Clavulanate Potassium or to other beta-lactams (e.g., penicillins or cephalosporins) should be noted.

• History of cholestatic jaundice/hepatic dysfunction: Associated with Amoxicillin and Clavulanate Potassium should be considered.

Patients should be monitored for these adverse reactions, and appropriate measures should be taken if they occur.

Drug Interactions

Co-administration of amoxicillin and clavulanate potassium (including formulations such as Augmentin) with probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin, which may lead to increased and prolonged blood levels of amoxicillin.

The concurrent use of amoxicillin and clavulanate potassium with oral anticoagulants may result in an increased prolongation of prothrombin time, necessitating appropriate monitoring and potential adjustments in the dosage of anticoagulants to maintain the desired level of anticoagulation.

Additionally, co-administration with allopurinol has been associated with an increased risk of rash. This interaction has been noted with both ampicillin and amoxicillin, although specific data regarding amoxicillin and clavulanate potassium in conjunction with allopurinol are limited.

In common with other broad-spectrum antibiotics, amoxicillin and clavulanate potassium may reduce the efficacy of oral contraceptives. Therefore, alternative or additional contraceptive measures should be considered during treatment.

Oral administration of amoxicillin and clavulanate potassium can lead to high urine concentrations of amoxicillin, which may cause false-positive results in urine glucose tests using CLINITEST®, Benedict’s Solution, or Fehling’s Solution. It is recommended to use glucose tests based on enzymatic glucose oxidase reactions, such as CLINISTIX®.

Furthermore, following administration of ampicillin to pregnant women, a transient decrease in plasma concentrations of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been observed. This effect may also occur with amoxicillin and clavulanate potassium.

Pediatric Use

The safety and effectiveness of amoxicillin and clavulanate potassium, as well as AUGMENTIN, have been established in pediatric patients aged 3 months to 12 years for the treatment of acute otitis media and acute bacterial sinusitis.

Efficacy

• Amoxicillin and Clavulanate Potassium:

  • Demonstrated efficacy for oral suspension (600 mg/42.9 mg per 5 mL) in pediatric patients aged 3 months to 12 years weighing less than or equal to 40 kg.

  • Safety and efficacy have not been established in patients younger than 3 months or those aged 3 months to 12 years weighing more than 40 kg.

• AUGMENTIN:

  • Established efficacy for oral suspension and chewable tablets in pediatric patients aged 3 months to 12 years for the treatment of acute otitis media and acute bacterial sinusitis.

Safety

• The safety and efficacy of amoxicillin and clavulanate potassium for oral suspension in infants younger than 3 months have not been established.

• In pediatric patients aged less than 12 weeks (less than 3 months), dosing should be modified due to incompletely developed renal function, which may delay the elimination of amoxicillin; clavulanate elimination is unaltered in this age group.

Dosing

• Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations.

• Dosing of amoxicillin and clavulanate potassium should be modified in pediatric patients aged less than 12 weeks (less than 3 months) due to renal function considerations.

The use of amoxicillin and clavulanate potassium in pediatric patients is supported by evidence from studies involving both adults and pediatric patients aged 2 months to 12 years with acute otitis media.

Geriatric Use

In clinical studies of amoxicillin and clavulanate potassium, 32% of the 3,119 patients analyzed were aged 65 years or older, with 14% aged 75 years or older. No significant differences in safety or effectiveness were observed between elderly patients and younger subjects. However, greater sensitivity in some older individuals cannot be ruled out.

Amoxicillin and clavulanate potassium is primarily excreted by the kidneys, which raises the risk of adverse reactions in patients with impaired renal function. Given that elderly patients are more likely to have decreased renal function, careful consideration should be given to dose selection. Monitoring of renal function is recommended to mitigate potential risks.

Additionally, hepatic dysfunction has been reported more frequently in elderly patients, particularly in those undergoing prolonged treatment. This may manifest as increases in serum transaminases, bilirubin, and alkaline phosphatase levels. The onset of hepatic dysfunction can occur during or after therapy, and while it is usually reversible, severe cases have been documented, including fatalities. Therefore, regular monitoring of hepatic function is advised in geriatric patients receiving this medication.

Pregnancy

Reproduction studies conducted in pregnant rats and mice given amoxicillin and clavulanate potassium (2:1 ratio formulation) at oral doses up to 1200 mg/kg/day have shown 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 (875 mg every 12 hours), while the clavulanate doses were approximately 9 and 4 times the maximum recommended adult human oral dose (125 mg every 8 hours). Despite these findings, there are no adequate and well-controlled studies in pregnant women, and animal reproduction studies are not always predictive of human response. Therefore, amoxicillin and clavulanate potassium should be used during pregnancy only if clearly needed.

Amoxicillin and clavulanate potassium is classified as Pregnancy Category B. Available data from published epidemiologic studies and pharmacovigilance case reports over several decades of use during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal outcomes. However, a study involving women with premature rupture of fetal membranes (PPROM) indicated that prophylactic treatment with amoxicillin and clavulanate may be associated with an increased risk of necrotizing enterocolitis in neonates, with a reported incidence of 1.9% in the treatment group compared to 0.5% in the placebo group (p = 0.001).

It is not known whether the use of amoxicillin and clavulanate potassium during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood of obstetrical interventions or resuscitation of the newborn. Given the background risk of major birth defects and miscarriage in the U.S. general population, estimated at 2 to 4% and 15 to 20%, respectively, healthcare providers should weigh the potential benefits against the risks when considering the use of this medication in pregnant patients.

Lactation

Amoxicillin and clavulanate potassium are excreted in human milk, and their use by lactating mothers may lead to sensitization in breastfed infants. Caution is advised when administering these medications to nursing women due to the potential for adverse effects on the infant.

Clinical data indicate that infants exposed to amoxicillin and clavulanate potassium through breast milk may experience symptoms such as diarrhea, irritability, and rash. Therefore, monitoring of breastfed infants for these symptoms is recommended. There is currently no available data on the effects of amoxicillin and clavulanate potassium on milk production.

The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for amoxicillin and clavulanate potassium, as well as any potential adverse effects on the breastfed child stemming from the medication or the underlying maternal condition.

Renal Impairment

Amoxicillin is primarily eliminated by the kidneys, necessitating dosage adjustments in patients with severe renal impairment, specifically those with a glomerular filtration rate (GFR) of less than 30 mL/min. In such cases, careful monitoring and specific recommendations should be followed to ensure safe and effective use.

For formulations of Amoxicillin and Clavulanate Potassium, there is no specific information provided regarding dosage adjustments, monitoring, or safety considerations for patients with renal impairment across various forms, including tablets and suspensions. However, caution is advised when using these medications in patients with evidence of hepatic dysfunction, indicating the need for careful assessment of overall patient health.

In summary, while Amoxicillin requires dosage adjustments in severe renal impairment, the available data for Amoxicillin and Clavulanate Potassium does not specify similar requirements, highlighting a gap in guidance for these formulations in patients with reduced kidney function.

Hepatic Impairment

Patients with hepatic impairment should use amoxicillin and clavulanate potassium with caution, particularly in the forms of tablets, film-coated tablets, and oral suspensions. Hepatic dysfunction and cholestatic jaundice may occur; therefore, it is essential to discontinue treatment if any signs or symptoms of hepatitis arise.

Monitoring of liver function tests is recommended for patients with hepatic impairment to assess liver health and detect any potential adverse effects. Hepatic toxicity associated with amoxicillin and clavulanate potassium is generally reversible, but on rare occasions, fatalities have been reported, typically in patients with serious underlying conditions or those taking concomitant medications.

For the oral suspension formulation of amoxicillin and clavulanate potassium (600 mg/42.9 mg per 5 mL), caution is advised in patients with evidence of hepatic dysfunction.

Overdosage

In cases of overdosage with amoxicillin and clavulanate potassium, it is essential 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 less than 250 mg/kg of amoxicillin are generally not associated with significant clinical symptoms and do not typically require gastric emptying.

Patients may experience primarily gastrointestinal symptoms, including stomach and abdominal pain, vomiting, and diarrhea. Additionally, some patients have reported rash, hyperactivity, or drowsiness. 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.

Interstitial nephritis resulting in oliguric renal failure has been documented in patients following overdosage with amoxicillin and clavulanate potassium. Crystalluria, which can lead to renal failure, has also been reported in both adult and pediatric patients after overdosage. To mitigate the risk of crystalluria, it is crucial 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 high blood levels of amoxicillin and clavulanate potassium may occur more readily in patients with impaired renal function due to decreased renal clearance. Both amoxicillin and clavulanate potassium can be removed from circulation through hemodialysis.

Nonclinical Toxicology

Teratogenic Effects

Amoxicillin and clavulanate potassium is classified as Pregnancy Category B. Reproduction studies conducted in pregnant rats and mice administered oral doses of up to 1,200 mg/kg/day (approximately 4.9 and 2.8 times the maximum recommended adult human oral dose based on body surface area) revealed no evidence of harm to the fetus. However, there are no adequate and well-controlled studies in pregnant women. Therefore, this drug should be used during pregnancy only if clearly needed, as animal reproduction studies are not always predictive of human response.

Nonclinical Toxicology

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of amoxicillin and clavulanate potassium. The mutagenic potential was assessed through various assays, including the Ames bacterial mutation assay, yeast gene conversion assay, and mouse lymphoma forward mutation assay, both in vitro and in vivo. Results indicated that amoxicillin and clavulanate potassium was non-mutagenic in the Ames and yeast assays. It was weakly positive in the mouse lymphoma assay, but this trend toward increased mutation frequencies occurred at doses associated with decreased cell survival. Additionally, amoxicillin and clavulanate potassium was negative in the mouse micronucleus test and the dominant lethal assay in mice. Potassium clavulanate alone was also tested in the Ames and micronucleus assays, yielding negative results in both.

Impairment of Fertility

Amoxicillin and clavulanate potassium, at oral doses of up to 1,200 mg/kg/day (approximately 4 times the maximum recommended adult human oral dose for amoxicillin and 9 times for clavulanate based on body surface area), was found to have no effect on fertility and reproductive performance in rats.

Storage and Handling

Augmentin and Amoxicillin and Clavulanate Potassium are supplied in various forms, including tablets, film-coated tablets, and powders for suspension.

Storage Conditions:

• Dry Powder:

  • Store at or below 25°C (77°F) for Augmentin and at 20° to 25°C (68° to 77°F) for Amoxicillin and Clavulanate Potassium.

• Reconstituted Suspension:

  • Store under refrigeration. Discard any unused suspension after 10 days.

Handling Requirements:

• All products should be dispensed in their original containers.

• Tablets and powders should be kept tightly closed and stored in a moisture-proof container.

• It is advised to keep all medications out of the reach of children.

• For tablets, ensure that the inner seal is intact before use.