Amoxicillin

Uses and Indications

Amoxicillin is indicated for the treatment of infections due to susceptible strains of designated microorganisms. The following conditions are specifically noted for its use:

Infections

• Upper Respiratory Tract Infections: Including infections of the ear, nose, and throat caused by Streptococcus spp. (α- and β-hemolytic strains only), S. pneumoniae, Staphylococcus spp., or H. influenzae.

• Lower Respiratory Tract Infections: Caused by Streptococcus spp. (α- and β-hemolytic strains only), S. pneumoniae, Staphylococcus spp., or H. influenzae.

• Skin and Skin Structure Infections: Due to Streptococcus spp. (α- and β-hemolytic strains only), Staphylococcus spp., or E. coli.

• Genitourinary Tract Infections: Caused by E. coli, P. mirabilis, or E. faecalis.

• Gonorrhea: Acute uncomplicated ano-genital and urethral infections due to N. gonorrhoeae (males and females).

Helicobacter pylori Eradication

• Amoxicillin is indicated for the eradication of H. pylori to reduce the risk of duodenal ulcer recurrence. It can be used in:

  • Triple Therapy: In combination with clarithromycin and lansoprazole for patients with H. pylori infection and duodenal ulcer disease (active or 1-year history).

  • Dual Therapy: In combination with lansoprazole for patients who are allergic or intolerant to clarithromycin or in whom resistance to clarithromycin is known or suspected.

Usage Notes

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

Limitations of Use

Amoxicillin is not recommended for the empiric treatment of gonorrhea due to high rates of resistance.

Teratogenic and Nonteratogenic Effects

No teratogenic or nonteratogenic effects have been specifically mentioned in the provided information.

Dosage and Administration

The recommended dosage of Amoxicillin varies based on the patient's age, weight, and specific condition being treated.

For neonates and infants aged ≤ 12 weeks (≤ 3 months), the upper dose is 30 mg/kg/day, divided every 12 hours.

For adults and pediatric patients over 3 months of age, the following dosing regimens are recommended:

• General Dosage:

  • Adults: 750 to 1750 mg/day in divided doses every 8 to 12 hours.

  • Pediatric Patients: 20 to 45 mg/kg/day in divided doses every 8 to 12 hours. Specific dosing regimens should be referred to in the full prescribing information.

• Infection Specific Dosages:

  • Ear/Nose/Throat:

    • Mild/Moderate:

      • Adults: 500 mg every 12 hours or 250 mg every 8 hours.

      • Children: 25 mg/kg/day in divided doses every 12 hours or 20 mg/kg/day in divided doses every 8 hours.

    • Severe:

      • Adults: 875 mg every 12 hours or 500 mg every 8 hours.

      • Children: 45 mg/kg/day in divided doses every 12 hours or 40 mg/kg/day in divided doses every 8 hours.

  • Lower Respiratory Tract:

    • Mild/Moderate or Severe:

      • Adults: 875 mg every 12 hours or 500 mg every 8 hours.

      • Children: 45 mg/kg/day in divided doses every 12 hours or 40 mg/kg/day in divided doses every 8 hours.

  • Skin/Skin Structure:

    • Mild/Moderate:

      • Adults: 500 mg every 12 hours or 250 mg every 8 hours.

      • Children: 25 mg/kg/day in divided doses every 12 hours or 20 mg/kg/day in divided doses every 8 hours.

    • Severe:

      • Adults: 875 mg every 12 hours or 500 mg every 8 hours.

      • Children: 45 mg/kg/day in divided doses every 12 hours or 40 mg/kg/day in divided doses every 8 hours.

  • Genitourinary Tract:

    • Mild/Moderate:

      • Adults: 500 mg every 12 hours or 250 mg every 8 hours.

      • Children: 25 mg/kg/day in divided doses every 12 hours or 20 mg/kg/day in divided doses every 8 hours.

    • Severe:

      • Adults: 875 mg every 12 hours or 500 mg every 8 hours.

      • Children: 45 mg/kg/day in divided doses every 12 hours or 40 mg/kg/day in divided doses every 8 hours.

  • Gonorrhea:

    • Adults: 3 grams as a single oral dose.

    • Prepubertal children: 50 mg/kg Amoxicillin combined with 25 mg/kg probenecid as a single dose (not to be used in children under 2 years).

• H. pylori Eradication:

  • Triple Therapy: 1 gram amoxicillin, 500 mg clarithromycin, and 30 mg lansoprazole, all given twice daily (every 12 hours) for 14 days.

  • Dual Therapy: 1 gram amoxicillin and 30 mg lansoprazole, each given three times daily (every 8 hours) for 14 days.

Renal Impairment Dosing:

• Patients with a glomerular filtration rate (GFR) of < 30 mL/min should not receive the 875 mg tablet.

• For patients with a GFR of 10 to 30 mL/min, administer 500 mg or 250 mg every 12 hours, depending on the severity of the infection.

• For patients with a GFR of < 10 mL/min, administer 500 mg or 250 mg every 24 hours, depending on severity.

• Hemodialysis patients should receive 500 mg or 250 mg every 24 hours, with an additional dose during and at the end of dialysis.

Administration Notes:Amoxicillin capsules, chewable tablets, and oral suspensions may be given without regard to meals. The 875 mg tablet has been studied only when administered at the start of a light meal. After reconstitution, the required amount of suspension should be placed directly on the child's tongue for swallowing or added to formula, milk, fruit juice, water, ginger ale, or cold drinks, and taken immediately. Shake the oral suspension well before use, and discard any unused portion after 14 days. Refrigeration is preferable but not required.

Treatment should be continued for a minimum of 48 to 72 hours beyond the time that the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. For infections caused by Streptococcus pyogenes, at least 10 days of treatment is recommended to prevent the occurrence of acute rheumatic fever.

Contraindications

A history of allergic reactions to any of the penicillins is a contraindication for the use of amoxicillin. Additionally, a history of serious hypersensitivity reactions, such as anaphylaxis or Stevens-Johnson syndrome, to amoxicillin or to other beta-lactams (including penicillins and cephalosporins) is also a contraindication.

Amoxicillin should not be administered to patients with mononucleosis due to the risk of serious adverse reactions.

Warnings and Precautions

Serious Warnings

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy, including amoxicillin. Anaphylaxis is more frequent following parenteral therapy but has occurred in patients on oral penicillins. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens before initiating therapy with amoxicillin. If an allergic reaction occurs, amoxicillin should be discontinued and appropriate therapy instituted. Serious anaphylactic reactions require immediate emergency treatment with epinephrine, oxygen, intravenous steroids, and airway management, including intubation, as indicated.

Clostridium Difficile-Associated Diarrhea (CDAD)

Clostridium difficile associated diarrhea (CDAD) has been reported with the use of nearly all antibacterial agents, including amoxicillin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since 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. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

General Precautions

The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur, amoxicillin should be discontinued and appropriate therapy instituted. A high percentage of patients with mononucleosis who receive ampicillin develop an erythematous skin rash; thus, ampicillin-class antibiotics should not be administered to patients with mononucleosis. Prescribing amoxicillin in the absence of 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.

Laboratory Tests

As with any potent drug, periodic assessment of renal, hepatic, and hematopoietic function should be made during prolonged therapy. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with amoxicillin should have a follow-up serologic test for syphilis after 3 months.

Get Emergency Medical Help Instructions

Serious anaphylactic reactions require immediate emergency treatment with epinephrine, oxygen, intravenous steroids, and airway management, including intubation, as indicated.

Stop Taking and Call Your Doctor Instructions

If an allergic reaction occurs, amoxicillin should be discontinued and appropriate therapy instituted. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.

Side Effects

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy, including amoxicillin. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. If an allergic reaction occurs, amoxicillin should be discontinued and appropriate therapy instituted. Serious anaphylactic reactions require immediate emergency treatment with epinephrine, oxygen, intravenous steroids, and airway management, including intubation, as indicated.

Common Adverse Reactions

• Diarrhea

• Rash

• Vomiting

• Nausea

Serious Adverse Reactions

• Anaphylactic reactions: Serious and occasionally fatal anaphylactic reactions have been reported in patients on penicillin therapy, including amoxicillin. Discontinue amoxicillin if a reaction occurs.

• Severe cutaneous adverse reactions (SCAR): Monitor closely. Discontinue if rash progresses.

• Drug-induced enterocolitis syndrome (DIES): Has been reported with amoxicillin use. If this occurs, discontinue amoxicillin and institute appropriate therapy.

• Clostridioides difficile-associated diarrhea (CDAD): Ranging from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs.

Infections and Infestations

• Mucocutaneous candidiasis.

Gastrointestinal

• Nausea

• Vomiting

• Diarrhea

• Black hairy tongue

• Hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment.

Hypersensitivity Reactions

• Serum sickness-like reactions

• Erythematous maculopapular rashes

• Erythema multiforme

• Stevens-Johnson syndrome

• Exfoliative dermatitis

• Toxic epidermal necrolysis

• Acute generalized exanthematous pustulosis

• Hypersensitivity vasculitis

• Urticaria These hypersensitivity reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, amoxicillin should be discontinued unless, in the opinion of the physician, the condition being treated is life-threatening and amenable only to amoxicillin therapy.

Liver

• Moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted, but the significance of this finding is unknown.

• Hepatic dysfunction, including cholestatic jaundice, hepatic cholestasis, and acute cytolytic hepatitis, has been reported.

Renal

• Crystalluria has also been reported, in some cases leading to renal failure, particularly after overdosage with amoxicillin.

Hemic and Lymphatic Systems

• Anemia, including hemolytic anemia

• Thrombocytopenia

• Thrombocytopenic purpura

• Eosinophilia

• Leukopenia

• Agranulocytosis These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena.

Central Nervous System

• Reversible hyperactivity

• Agitation

• Anxiety

• Insomnia

• Confusion

• Convulsions

• Behavioral changes

• Dizziness These have been reported rarely.

Miscellaneous

• Tooth discoloration (brown, yellow, or gray staining) has been rarely reported, mostly in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases.

Warnings

• Clostridium difficile associated diarrhea (CDAD) has been reported with the use of nearly all antibacterial agents, including amoxicillin, and may range in severity from mild diarrhea to fatal colitis. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since 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. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Drug Interactions

Concurrent use of amoxicillin with certain medications can lead to significant interactions that may affect therapeutic outcomes and safety.

Pharmacokinetic Interactions

• Probenecid: The renal tubular secretion of amoxicillin is decreased by probenecid, which may result in increased and prolonged blood levels of amoxicillin. Therefore, co-administration with probenecid is not recommended.

Pharmacodynamic Interactions

• Oral Anticoagulants: The concomitant use of amoxicillin and oral anticoagulants may lead to an increased prolongation of prothrombin time, necessitating careful monitoring and potential dose adjustments of the anticoagulant to maintain the desired level of anticoagulation.

• Allopurinol: Co-administration of amoxicillin with allopurinol has been associated with an increased risk of rash. The exact mechanism of this interaction is not fully understood.

• Oral Contraceptives: Amoxicillin may reduce the efficacy of combined oral estrogen/progesterone contraceptives by affecting gut flora, which can lead to lower estrogen reabsorption.

Other Interactions

• Antibacterial Agents: Chloramphenicol, macrolides, sulfonamides, and tetracyclines may interfere with the bactericidal effects of penicillin, including amoxicillin. While this interaction has been demonstrated in vitro, its clinical significance remains uncertain.

Drug/Laboratory Test Interactions

• High urine concentrations of ampicillin, which may also occur with amoxicillin, can result in false-positive reactions when testing for glucose in urine 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®) for accurate results.

• Following administration of ampicillin or amoxicillin to pregnant women, a transient decrease in plasma concentrations of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted, which may also occur with amoxicillin.

These interactions highlight the importance of monitoring and adjusting therapy as necessary when amoxicillin is prescribed alongside other medications.

Pediatric Use

The safety and effectiveness of amoxicillin for the treatment of upper respiratory tract infections, infections of the genitourinary tract, skin and skin structure, and lower respiratory tract have been established in pediatric patients. However, the safety and effectiveness of amoxicillin for the treatment of H. Pylori infection have not been established in this population.

Due to incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed. Therefore, dosing of amoxicillin should be modified in pediatric patients 12 weeks or younger (≤ 3 months).

Geriatric Use

An analysis of clinical studies of amoxicillin has been conducted to evaluate the response of subjects aged 65 and over compared to younger patients. These analyses have not identified significant differences in responses between elderly and younger patients; however, a greater sensitivity of some older individuals cannot be ruled out.

Amoxicillin is substantially excreted by the kidneys, and the risk of toxic reactions may be increased 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. It is advisable to monitor renal function in this population to mitigate potential risks associated with renal impairment.

Pregnancy

Amoxicillin is classified as Pregnancy Category B. Reproduction studies conducted in mice and rats at doses up to 2000 mg/kg (3 and 6 times the 3 g human dose, based on body surface area) have shown no evidence of impaired fertility or harm to 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, amoxicillin should be used during pregnancy only if clearly needed. Careful consideration should be given to the potential risks to the fetus associated with the use of amoxicillin, as safety and efficacy in pregnant patients have not been established.

In summary, while animal studies indicate no significant fetal harm, the absence of human data necessitates a cautious approach when prescribing amoxicillin to pregnant patients.

Lactation

Amoxicillin, a penicillin antibiotic, is known to be excreted in human milk. Lactating mothers should be aware of this potential excretion, as it may lead to sensitization in breastfed infants. The use of amoxicillin during lactation requires caution due to the risk of adverse effects in nursing infants.

Healthcare professionals are advised to exercise caution when prescribing amoxicillin to nursing mothers, considering the potential for infant exposure through breast milk. Monitoring for any signs of sensitization or adverse reactions in breastfed infants is recommended.

Renal Impairment

Patients with renal impairment may not have specific dosage adjustments, monitoring requirements, or safety considerations outlined for the use of Amoxicillin across its various formulations, including tablets, capsules, and powders for suspension. The available data from multiple labels consistently indicate a lack of information regarding the management of Amoxicillin in individuals with reduced kidney function.

As such, healthcare professionals should exercise caution when prescribing Amoxicillin to patients with renal impairment, given the absence of guidance on how to adjust dosing or monitor these patients effectively. It is advisable to consider individual patient factors and clinical judgment when determining the appropriateness of Amoxicillin therapy in this population.

Hepatic Impairment

Patients with hepatic impairment do not require specific dosage adjustments, special monitoring, or precautions when using Amoxicillin in any of its available forms, including tablets, capsules, and powders for suspension. The available data does not indicate any need for alterations in dosing or additional monitoring parameters for this patient population. Therefore, standard dosing regimens may be followed without modification for patients with liver problems.

Overdosage

In the event of an overdosage of amoxicillin, it is essential to discontinue the medication immediately and provide symptomatic treatment along with 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 typically require gastric emptying. However, interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients following an overdosage of amoxicillin. Additionally, crystalluria, which can lead to renal failure, has been observed in both adult and pediatric patients after amoxicillin overdosage.

To mitigate the risk of crystalluria, it is recommended to maintain adequate fluid intake and diuresis. Renal impairment resulting from overdosage appears to be reversible upon cessation of amoxicillin administration. It is important to note that high blood levels of amoxicillin may occur more readily in patients with impaired renal function due to decreased renal clearance.

In cases of severe overdosage, amoxicillin may be removed from circulation through hemodialysis. Continuous monitoring of renal function and other relevant parameters is advised to ensure patient safety and effective management of any complications arising from the overdosage.

Nonclinical Toxicology

Teratogenic Effects

Amoxicillin is classified as Pregnancy Category B. Reproduction studies conducted in mice and rats at doses up to ten times the human dose have shown no evidence of impaired fertility or harm to the fetus. However, there are no adequate and well-controlled studies in pregnant women. Due to the variability of animal reproduction studies in predicting human response, this drug should be used during pregnancy only if clearly needed.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of amoxicillin. Studies specifically designed to detect the mutagenic potential of amoxicillin alone have not been conducted. However, data from tests on a 4:1 mixture of amoxicillin and potassium clavulanate indicate the following:

• The mixture was non-mutagenic in the Ames bacterial mutation assay and the yeast gene conversion assay.

• It was weakly positive in the mouse lymphoma assay, although the observed trend toward increased mutation frequencies occurred at doses associated with decreased cell survival.

• The mixture was negative in the mouse micronucleus test and in the dominant lethal assay in mice.

• Potassium clavulanate alone was also tested in the Ames bacterial mutation assay and the mouse micronucleus test, yielding negative results in both assays.

In a multi-generation reproduction study in rats, no impairment of fertility or other adverse reproductive effects were observed at doses up to 500 mg/kg, which is approximately two to three times the human dose based on body surface area.

Storage and Handling

Amoxicillin is supplied in various forms, including tablets (coated, film-coated, chewable), capsules, and powders for suspension. All formulations should be dispensed in a tight container to ensure product integrity.

Storage Conditions:

• Amoxicillin should be stored at 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as defined by USP Controlled Room Temperature.

• The dry powder for suspension should be kept in a tightly closed container and can be refrigerated, although refrigeration is not required. It is important to shake well before use and to discard any unused suspension after 14 days.

• All forms of Amoxicillin should be protected from light and kept tightly closed to maintain efficacy.

Handling Requirements:

• It is essential to keep this and all medications out of the reach of children.

• For specific formulations, such as chewable tablets and certain capsules, a light-resistant container with a child-resistant closure is required to enhance safety.