Augmentin^® (Tablets, Powder) Instructions for Use

ATC Code

J01CR02 (Amoxicillin and beta-lactamase inhibitor)

Active Substances

Amoxicillin (Rec.INN registered by WHO)

Clavulanic acid (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Broad-spectrum penicillin antibiotic with a beta-lactamase inhibitor

Pharmacotherapeutic Group

Systemic antibacterial agents; beta-lactam antibacterial agents, penicillins; combinations of penicillins, including combinations with beta-lactamase inhibitors

Pharmacological Action

Mechanism of action

Amoxicillin is a broad-spectrum semisynthetic antibiotic active against many gram-positive and gram-negative microorganisms. However, Amoxicillin is susceptible to degradation by beta-lactamases, and therefore the spectrum of activity of amoxicillin does not extend to microorganisms that produce this enzyme.

Clavulanic acid is a beta-lactamase inhibitor structurally related to penicillins, which has the ability to inactivate a wide range of beta-lactamases found in microorganisms resistant to penicillins and cephalosporins. Clavulanic acid is sufficiently effective against plasmid beta-lactamases, which most often cause bacterial resistance, and is less effective against type 1 chromosomal beta-lactamases, which are not inhibited by clavulanic acid.

The presence of clavulanic acid in Augmentin^® EC protects Amoxicillin from degradation by beta-lactamase enzymes, thereby extending the antibacterial spectrum of amoxicillin.

The in vitro activity of the amoxicillin/clavulanic acid combination is given below.

Bacteria usually susceptible to the amoxicillin/clavulanic acid combination

Gram-positive aerobes: Bacillus anthracis, Enterococcus faecalis, Listeria monocytogenes, Nocardia asteroides, Streptococcus pneumoniae^1,2, Streptococcus pyogenes^1,2, Streptococcus agalactiae^1,2, Viridans group Streptococcus², Streptococcus spp. (other beta-hemolytic streptococci)^1,2, Staphylococcus aureus (methicillin-susceptible)¹, Staphylococcus saprophyticus (methicillin-susceptible), Staphylococcus spp. (coagulase-negative, methicillin-susceptible).

Gram-negative aerobes: Bordetella pertussis, Haemophilus influenzae¹, Helicobacter pylori, Moraxella catarrhalis¹, Neisseria gonorrhoeae, Pasteurella multocida, Vibrio cholerae.

Gram-positive anaerobes: Clostridium spp., Peptococcus niger, Peptostreptococcus magnus, Peptostreptococcus micros, Peptostreptococcus spp.

Gram-negative anaerobes: Bacteroides fragilis, Bacteroides spp., Capnocytophaga spp., Eikenella corrodens, Fusobacterium nucleatum, Fusobacterium spp., Porphyromonas spp., Prevotella spp.

Others: Borrelia burgdorferi, Leptospira icterohaemorrhagiae, Treponema pallidum.

Bacteria for which acquired resistance to the amoxicillin/clavulanic acid combination is likely

Gram-negative aerobes: Escherichia coli¹, Klebsiella oxytoca, Klebsiella pneumoniae¹, Klebsiella spp., Proteus mirabilis, Proteus vulgaris, Proteus spp., Salmonella spp., Shigella spp.

Gram-positive aerobes: Corynebacterium spp., Enterococcus faecium.

Bacteria with inherent resistance to the amoxicillin/clavulanic acid combination

Gram-negative aerobes: Acinetobacter spp., Citrobacter freundii, Enterobacter spp., Hafnia alvei, Legionella pneumophila, Morganella morganii, Providencia spp., Pseudomonas spp., Serratia spp., Stenotrophomonas maltophilia, Yersinia enterocolitica.

Others: Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia spp., Coxiella burnetii, Mycoplasma spp.

¹ For these microorganisms, the clinical efficacy of the amoxicillin/clavulanic acid combination has been demonstrated in clinical studies.

² Strains of these bacterial species do not produce beta-lactamases. Susceptibility to amoxicillin monotherapy suggests similar susceptibility to the amoxicillin/clavulanic acid combination.

Pharmacokinetics

Absorption

The active substances of Augmentin^® EC, Amoxicillin and Clavulanic acid, are rapidly and completely absorbed from the gastrointestinal tract after oral administration. Absorption of the active substances is optimal when Augmentin^® EC is taken with food.

The pharmacokinetic parameters of amoxicillin and clavulanic acid after administration of a dose of 45 mg/kg every 12 hours to patients under 12 years of age are given below.

Mean pharmacokinetic parameters

Distribution

As with intravenous administration of the amoxicillin/clavulanic acid combination, therapeutic concentrations of amoxicillin and clavulanic acid are found in various organs and tissues, and interstitial fluid (abdominal organs, adipose, bone and muscle tissues, synovial and peritoneal fluids, skin, bile, purulent discharge).

Amoxicillin and Clavulanic acid have a low degree of binding to plasma proteins. Studies have shown that approximately 25% of the total amount of clavulanic acid and 18% of amoxicillin bind to plasma proteins.

Animal studies have not revealed accumulation of the components of Augmentin^® EC in any organ.

Amoxicillin, like most penicillins, passes into breast milk. Trace amounts of clavulanic acid have also been found in breast milk. Apart from the possibility of sensitization, diarrhea, and candidiasis of the oral mucosa, no other negative effects of amoxicillin and clavulanic acid on the health of breastfed infants are known.

Reproductive studies in animals have shown that Amoxicillin and Clavulanic acid cross the placental barrier. However, no negative effects on the fetus were identified.

Metabolism

10-25% of the initial dose of amoxicillin is excreted by the kidneys as an inactive metabolite (penicilloic acid). Clavulanic acid undergoes extensive metabolism to 2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid and 1-amino-4-hydroxy-butan-2-one and is excreted by the kidneys, through the gastrointestinal tract, and in exhaled air as carbon dioxide.

Excretion

Like other penicillins, Amoxicillin is excreted mainly by the kidneys, whereas Clavulanic acid is excreted by both renal and extrarenal mechanisms. Approximately 60-70% of amoxicillin and about 40-65% of clavulanic acid are excreted unchanged by the kidneys within the first 6 hours after taking 1 tablet of Augmentin^®, film-coated tablets 250 mg/125 mg or 500 mg/125 mg.

Indications

Treatment of infections caused by susceptible microorganisms in children

• ENT infections (recurrent or persistent acute otitis media caused by Streptococcus pneumoniae (MIC ≤4 µg/mL), Haemophilus influenzae* and Moraxella catarrhalis*);
• Tonsillopharyngitis and sinusitis, usually caused by Streptococcus pneumoniae, Haemophilus influenzae*, Moraxella catarrhalis* and Streptococcus pyogenes;
• Lower respiratory tract infections (lobar pneumonia and bronchopneumonia) caused by Streptococcus pneumoniae, Haemophilus influenzae*, Moraxella catarrhalis*;
• Skin and soft tissue infections, usually caused by Staphylococcus aureus* and Streptococcus pyogenes.

* Some strains of these bacterial species produce beta-lactamases, making them insensitive to amoxicillin monotherapy.

Infections caused by amoxicillin-susceptible microorganisms can be treated with Augmentin^® EC, since Amoxicillin is one of its active substances.

Augmentin^® EC is also indicated for the treatment of mixed infections caused by amoxicillin-susceptible microorganisms and beta-lactamase-producing microorganisms susceptible to the amoxicillin/clavulanic acid combination.

Bacterial susceptibility to the amoxicillin/clavulanic acid combination varies by region and over time. Where possible, local susceptibility data should be taken into account. If necessary, microbiological samples should be collected and tested for bacteriological susceptibility.

ICD codes

Dosage Regimen

Powder

Dosing of Augmentin^® EC is based on the child’s age, with the dose calculated in mg per kg per day or in ml of the prepared suspension. The dose is calculated based on amoxicillin and clavulanic acid, except when dosing is based on each component separately.

To minimize potential gastrointestinal adverse events and optimize absorption, the drug should be taken orally at the start of a meal.

Treatment should not be continued for more than 14 days without review of the clinical situation.

If necessary, step-down therapy may be administered (starting with intravenous administration of Augmentin^® in the form of powder for solution for intravenous injection followed by a switch to Augmentin^® in oral dosage forms).

Children

Augmentin^® EC is recommended for children aged 3 months and older. There is no experience with the use of Augmentin^® EC in children under 3 months.

The recommended daily dose is 90 mg of amoxicillin and 6.4 mg of clavulanic acid per 1 kg of body weight, divided into 2 doses every 12 hours, for 10 days.

For patients weighing more than 40 kg, other dosage forms of Augmentin^® are recommended.

In terms of clavulanic acid content, Augmentin^® EC differs from other suspensions containing Amoxicillin and clavulanic acid. Augmentin^® EC contains 600 mg of amoxicillin and 42.9 mg of clavulanic acid in 5 ml of the reconstituted suspension, whereas preparations containing 200 mg and 400 mg of amoxicillin in 5 ml of suspension contain 28.5 mg and 57 mg of clavulanic acid in 5 ml of suspension, respectively. Suspension formulations with dosages of 200 mg amoxicillin in 5 ml, 400 mg amoxicillin in 5 ml, and Augmentin^® EC are not interchangeable.

Special patient groups

No dosage adjustment is required for CrCl ≥30 ml/min. The drug is contraindicated for use in CrCl <30 ml/min.

In patients with impaired liver function, treatment should be carried out with caution; liver function should be monitored regularly. There is insufficient data to recommend dosage regimen changes in such patients.

Method of suspension preparation

The suspension is prepared immediately before first use.

Add approximately 2/3 of the volume of boiled water cooled to room temperature indicated in the table below to the bottle with the powder, then close the bottle with the cap and shake until the powder is completely dissolved, let the bottle stand for 5 minutes to ensure complete dissolution. Then add water up to the mark on the bottle and shake the bottle again.

The bottle should be shaken well before each use. For accurate dosing of the drug, a measuring spoon should be used, which must be rinsed well with water after each use. After reconstitution, the suspension should be stored for no more than 10 days in a refrigerator, but not frozen.

Approximate volume of water for suspension preparation

Tablets

The drug is taken orally.

To optimize absorption, the drug should be taken at the start of a meal.

Treatment should not last more than 14 days without review of the clinical situation.

The tablets have a score line allowing them to be broken in half for ease of swallowing, but not for dose reduction: both halves must be taken simultaneously.

The recommended dose is 2 tablets twice daily.

Adults (16 years and older)

Respiratory tract infections 2 tablets twice daily for 7-10 days, including

Prevention of local infections after surgical dental interventions 2 tablets twice daily for 5 days starting 3 hours after the intervention.

The drug is not used in children under 16 years of age.

No dosage adjustment is required for elderly patients.

No dosage adjustment is required for CrCl ≥30 ml/min. The drug is contraindicated in patients with CrCl <30 ml/min. Not recommended during hemodialysis.

In impaired liver function, there is insufficient data to recommend a dosage regimen for this group of patients, therefore the drug is prescribed with caution with regular monitoring of liver function.

Adverse Reactions

The adverse reactions listed below are presented according to system organ class and frequency of occurrence. Frequency is defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000, including isolated reports).

Frequency categories were formed based on clinical studies of the drug and post-marketing surveillance.

Infections and infestations common – candidiasis of the skin and mucous membranes.

Blood and lymphatic system disorders: rare – reversible leukopenia (including neutropenia) and reversible thrombocytopenia; very rare – reversible agranulocytosis and reversible hemolytic anemia, prolongation of prothrombin time and bleeding time, anemia, eosinophilia, thrombocytosis.

Immune system disorders: very rare – angioedema, anaphylactic reactions, serum sickness-like syndrome, allergic vasculitis.

Nervous system disorders: uncommon – dizziness, headache; very rare – reversible hyperactivity, convulsions (convulsions may occur in patients with impaired renal function and in those receiving high doses of the drug), insomnia, agitation, anxiety, behavior change.

Gastrointestinal disorders: common – diarrhea, nausea, vomiting (nausea is more common when taking high oral doses. If gastrointestinal disturbances are confirmed, they may be alleviated by taking the drug at the start of a meal); uncommon – indigestion; very rare – antibiotic-associated colitis induced by antibiotic use (including pseudomembranous colitis and hemorrhagic colitis), black "hairy" tongue. In children, discoloration of the superficial layer of tooth enamel has been very rarely reported.

Hepatobiliary disorders: uncommon – moderate increase in AST and/or ALT activity (observed in patients receiving beta-lactam antibiotic therapy, but its clinical significance is unknown); very rare – hepatitis and cholestatic jaundice (these reactions have been reported with therapy with other penicillins and cephalosporins), increased bilirubin and alkaline phosphatase concentrations. Hepatic adverse reactions were observed mainly in men and elderly patients and may be associated with long-term therapy. These adverse reactions are very rarely observed in children.

The listed signs and symptoms usually occur during or immediately after therapy, but in some cases may not appear for several weeks after completion of therapy. Adverse reactions are generally reversible. Adverse reactions from the liver may be severe; in exceptionally rare cases, fatalities have been reported. In almost all cases, these were individuals with serious concomitant pathology or individuals receiving potentially hepatotoxic drugs simultaneously.

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus, urticaria; rare – erythema multiforme; very rare – Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis.

In case of skin allergic reactions, treatment with Augmentin^® EC must be discontinued.

Urinary system disorders: very rare – interstitial nephritis, crystalluria, hematuria.

Contraindications

• Hypersensitivity to amoxicillin, clavulanic acid, other components of the drug, beta-lactam antibiotics (e.g., penicillins, cephalosporins) in the medical history;
• Previous episodes of jaundice or impaired liver function associated with the use of the amoxicillin/clavulanic acid combination in the medical history;
• Children under 3 months of age;
• Renal impairment (CrCl less than 30 ml/min);
• Phenylketonuria.

With caution: hepatic impairment.

Use in Pregnancy and Lactation

In studies of reproductive function in animals, oral and parenteral administration of Augmentin^® did not cause teratogenic effects.

In a single study in women with premature rupture of membranes, it was found that prophylactic therapy with the drug may be associated with an increased risk of necrotizing enterocolitis in newborns. Like all medicines, Augmentin^® EC is not recommended during pregnancy, except in cases where the expected benefit of use for the mother outweighs the potential risk to the fetus.

Augmentin^® EC can be used during breastfeeding. Except for the possibility of sensitization, diarrhea, or candidiasis of the oral mucosa associated with the penetration of trace amounts of the active substances of this drug into breast milk, no other adverse effects have been observed in breastfed infants. If adverse effects occur in breastfed infants, breastfeeding should be discontinued.

Use in Hepatic Impairment

Administer with caution in hepatic impairment (with monitoring of liver function).

Contraindicated in previous episodes of jaundice or impaired liver function associated with the use of the amoxicillin/clavulanic acid combination in the medical history.

Use in Renal Impairment

No dosage adjustment is required for CrCl ≥30 ml/min, use is not recommended for CrCl <30 ml/min.

Pediatric Use

Use of the drug is contraindicated in children under 3 months of age.

Special Precautions

Before starting treatment with Augmentin^® EC, a detailed history should be taken concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other substances causing an allergic reaction in the patient.

Serious, and sometimes fatal, hypersensitivity reactions (including anaphylactic reactions) to penicillins have been reported. The risk of such reactions is highest in patients with a history of hypersensitivity reactions to penicillins. If an allergic reaction occurs, treatment with Augmentin^® EC must be discontinued. In case of serious hypersensitivity reactions, epinephrine should be administered immediately. Oxygen therapy, intravenous corticosteroids, and ensuring airway patency, including intubation, may also be required.

Prescription of Augmentin^® EC is not recommended if infectious mononucleosis is suspected, since in patients with this disease, Amoxicillin can cause a measles-like rash, which complicates the diagnosis of the disease.

Long-term treatment with Augmentin^® EC sometimes leads to overgrowth of non-susceptible microorganisms.

In general, Augmentin^® EC is well tolerated and has the low toxicity characteristic of all penicillins. During long-term therapy with Augmentin^® EC, it is recommended to periodically evaluate renal, hepatic, and hematopoietic function.

Cases of pseudomembranous colitis have been reported with antibiotic use, the severity of which can range from mild to life-threatening. Therefore, it is important to consider the possibility of pseudomembranous colitis in patients with diarrhea during or after antibiotic use. If diarrhea is prolonged or severe, or the patient experiences abdominal cramps, treatment should be discontinued immediately and the patient should be examined.

In patients receiving the amoxicillin/clavulanic acid combination concomitantly with indirect (oral) anticoagulants, cases of increased prothrombin time (increased INR) have been rarely reported. When prescribing indirect (oral) anticoagulants concomitantly with the amoxicillin/clavulanic acid combination, appropriate parameters should be monitored. Adjustment of the dose of oral anticoagulants may be required to maintain the desired effect.

In patients with reduced diuresis, very rare cases of crystalluria have been reported, mainly with parenteral use of the drug. During administration of high doses of amoxicillin, it is recommended to take sufficient fluids and maintain adequate diuresis to reduce the likelihood of amoxicillin crystal formation.

Oral intake of Augmentin^® EC leads to high concentrations of amoxicillin in the urine, which may lead to false-positive results when testing for glucose in urine (e.g., Benedict’s test, Fehling’s test). In this case, it is recommended to use the glucose oxidase method for determining urine glucose concentration.

Oral care helps prevent tooth discoloration, as brushing teeth is sufficient for this.

Drug abuse and dependence

No drug dependence, habituation, or euphoric reactions associated with the use of Augmentin^® EC have been observed.

Effect on ability to drive and operate machinery

Since the drug may cause dizziness, patients should be cautioned about precautions when driving a vehicle or operating machinery.

Overdose

Symptoms may include gastrointestinal symptoms and disturbances of water and electrolyte balance. Amoxicillin crystalluria has been described, in some cases leading to renal failure. Seizures may occur in patients with renal impairment and in those receiving high doses of the drug.

Treatment for gastrointestinal symptoms is symptomatic therapy, with particular attention to normalization of water and electrolyte balance. In case of overdose, Amoxicillin and Clavulanic acid can be removed from the bloodstream by hemodialysis.

Results of a prospective study involving 51 children in a poison control center showed that administration of amoxicillin at a dose of less than 250 mg/kg did not lead to significant clinical symptoms and did not require gastric lavage.

Drug Interactions

Concomitant use of Augmentin^® EC and probenecid is not recommended. Probenecid reduces the tubular secretion of amoxicillin, and therefore concomitant use of Augmentin^® EC and probenecid may lead to increased and persistent blood concentrations of amoxicillin, but not clavulanic acid.

Concomitant use of allopurinol and amoxicillin may increase the risk of skin allergic reactions. Currently, there are no data in the literature on the concomitant use of the amoxicillin/clavulanic acid combination and allopurinol.

Penicillins can slow the elimination of methotrexate from the body by inhibiting its tubular secretion; therefore, concomitant use of Augmentin^® EC and methotrexate may increase the toxicity of methotrexate.

Like other antibacterial drugs, Augmentin^® EC may affect the intestinal microflora, leading to reduced absorption of estrogens from the gastrointestinal tract and reduced effectiveness of combined oral contraceptives.

The literature describes rare cases of increased INR in patients with concomitant use of acenocoumarol or warfarin and amoxicillin. If concomitant administration of Augmentin^® EC with anticoagulants is necessary, prothrombin time or INR should be carefully monitored when initiating or discontinuing Augmentin^® EC; adjustment of the dose of oral anticoagulants may be required.

In patients receiving mycophenolate mofetil, after starting the amoxicillin/clavulanic acid combination, a decrease in the concentration of the active metabolite, mycophenolic acid, before the next dose of the drug by approximately 50% was observed. Changes in this concentration may not accurately reflect overall changes in mycophenolic acid exposure.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F); shelf life – 2 years. Do not take the drug after the expiration date stated on the packaging.

The prepared suspension should be stored in the refrigerator at a temperature of 2-8°C (17.6°F) in a tightly closed bottle; shelf life of the prepared suspension is 10 days.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.