Augmentin EC, 600 mg+42, 9 mg/5 ml 23.13g

Pharmacological action – broad spectrum antibacterial (bactericidal).
Pharmacodynamics

Mechanism of action

Amoxicillin is a semi-synthetic broad spectrum antibiotic with activity against many Gram-positive and Gram-negative microorganisms. At the same time, 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 and has the ability to inactivate a wide range of beta-lactamases found in microorganisms that are resistant to penicillins and cephalosporins. Clavulanic acid is sufficiently effective against plasmid beta-lactamases, which most often cause bacterial resistance, and less effective against type 1 chromosomal beta-lactamases that are not inhibited by clavulanic acid. The presence of clavulanic acid in Augmentin® EC protects amoxicillin from degradation by beta-lactamase enzymes, which allows to expand the antibacterial spectrum of amoxicillin.

The in vitro activity of the combination of amoxicillin with clavulanic acid is shown below.

Bacteria commonly susceptible to the combination of amoxicillin with clavulanic acid

Gram-positive aerobes – Bacillus anthracis; Enterococcus faecalis; Listeria monocytogenes; Nocardia asteroides; Streptococcus pneumoniae1,2; Streptococcus pyogenes1,2; Streptococcus agalactiae1,2; Streptococcus viridans Streptococcus spp. (other beta-haemolytic streptococci)1,2; Staphylococcus aureus (methicillin-sensitive)1; Staphylococcus saprophyticus (methicillin-sensitive); coagulazonegative staphylococci (methicillin-sensitive).

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

Others – Borrelia burgdorferi; Leptospira icterohaemorrhagiae; Treponema pallidum.

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.

Bacteria for which acquired resistance to the combination of amoxicillin with clavulanic acid 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 natural resistance to the combination of amoxicillin with clavulanic acid

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.

Other – Chlamydia pneumoniae; Chlamydia psittaci; Chlamydia spp.; Coxiella burnetii; Mycoplasma spp.

1 for these bacteria, the clinical efficacy of the combination of amoxicillin with clavulanic acid has been demonstrated in clinical trials;

2 strains of these bacterial species do not produce beta-lactamase. Sensitivity with amoxicillin monotherapy suggests similar sensitivity to a combination of amoxicillin and clavulanic acid.

Pharmacokinetics

Intake

The active substances of the drug Augmentin® EC – amoxicillin and clavulanic acid are rapidly and completely absorbed from the gastrointestinal tract after oral administration. Absorption of active ingredients is optimal when Augmentin® EC is taken together with meals.

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

Table 2

Average values of pharmacokinetic parameters

Distribution

As with IV administration of the combination of amoxicillin and clavulanic acid, therapeutic concentrations of amoxicillin and clavulanic acid are found in various tissues and interstitial fluid (gallbladder, abdominal tissues, skin, fatty and muscular tissues, synovial and peritoneal fluids, bile, pus discharge).

Amoxicillin and clavulanic acid have weak binding to blood plasma proteins. Studies have shown that about 25% of total clavulanic acid and 18% of amoxicillin in blood plasma bind to plasma proteins. In animal studies no cumulation of components of the drug Augmentin® EC in any organ was found.

Amoxicillin, like most penicillins, penetrates into breast milk. Trace amounts of clavulanic acid may also be found in breast milk. Except for the possibility of diarrhea and oral candidiasis, there are no known adverse effects of amoxicillin and clavulanic acid on the health of breastfed infants. Studies of reproductive function in animals have shown that amoxicillin and clavulanic acid penetrate the placental barrier. However, no adverse effects on the fetus have been found.

Metabolism

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

Like other penicillins, amoxicillin is excreted mainly by the kidneys, while clavulanic acid is excreted through both renal and extrarenal mechanisms. Approximately 60-70% of amoxicillin and about 40-65% of clavulanic acid are excreted unchanged by the kidneys in the first 6 hours after the administration of 1 tablet 250/125 mg or 1 tablet 500/125 mg. Concomitant administration of probenecid slows excretion of amoxicillin but not clavulanic acid (see “Interaction”).

Indications

The drug Augmentin® EC is used for short-term treatment of infections caused by sensitive microorganisms in children.

1 Some strains of these bacterial species produce beta-lactamases, making them insensitive to amoxicillin monotherapy (see also Pharmacodynamics).

Infections caused by amoxicillin-sensitive microorganisms can be treated with Augmentin® EC because amoxicillin is one of its active substances. Augmentin® EC is also indicated for treatment of mixed infections caused by amoxicillin-sensitive and beta-lactamase-producing microorganisms that are sensitive to the combination of amoxicillin and clavulanic acid. The sensitivity of bacteria to the combination of amoxicillin and clavulanic acid varies by region and over time.

Where possible, local sensitivity data should be taken into account. If necessary, microbiological specimen collection and bacteriological sensitivity testing should be performed.

Active ingredient

Composition

5 ml of the ready-made suspension contain:

Active ingredients:

amoxicillin (in the form of trihydrate) – 600 mg;

clavulanic acid (in the form of potassium salt) – 42.9 mg.

Auxiliary substances:

xanthan gum – 3.26 mg,

aspartame – 13.6 mg,

silicon dioxide – 153.29 mg,

p> colloidal silica – 38.08 mg,

sodium carmellose – 32.64 mg,

strawberry flavoring – 28.29 mg.

How to take, the dosage

Ingestion. Dosing of the drug Augmentin® EC is carried out according to the age of the child, the dose is calculated in mg/kg/day or in ml of ready suspension. The dose is calculated for amoxicillin and clavulanic acid, except in cases when dosing is performed for each component separately. The drug should be taken orally at the beginning of the meal in order to minimize the potential adverse effects on the gastrointestinal tract and to optimize absorption.

The treatment should not be continued longer than 14 days without a review of the clinical situation. If necessary, therapy may be staggered (start with intravenous infusion of Augmentin® (powder for preparation of solution for intravenous injection) and then switch to oral therapy).

In children

The EU drug Augmentin® is recommended for children aged 3 months and older. There is no experience with Augmentin® EC in children less than 3 months of age. 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.

Other dosage forms of Augmentin® are recommended for patients with body weight over 40 kg. The content of clavulanic acid in 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 reconstituted suspension, while the preparation containing 200 and 400 mg of amoxicillin in 5 ml of suspension contain respectively 28.5 and 57 mg of clavulanic acid in 5 ml of suspension. The preparations in the form of 200 mg amoxicillin in 5 ml suspension, 400 mg amoxicillin in 5 ml and the drug Augmentin® EC are not interchangeable.

Patient special groups

Patients with impaired renal function. There is no need to correct the dosage regimen in creatinine Cl ?30 ml/min. The drug is not recommended for use in patients with creatinine Cl ?30 ml/min.

Patients with impaired liver function. Treatment should be performed with caution; liver function should be monitored regularly. There is insufficient data to change the dosing recommendation in such patients.

Interaction

The concomitant use of Augmentin® EC and probenecid is not recommended. Probenecid decreases 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.

The concomitant use of allopurinol and amoxicillin may increase the risk of skin allergic reactions. There are currently no data in the literature on the simultaneous use of the combination of amoxicillin with clavulanic acid and allopurinol.

Penicillins can slow down excretion of methotrexate by inhibiting its tubular secretion, therefore concomitant use of Augmentin® EC and methotrexate may increase toxicity of methotrexate.

As with other antibacterials, Augmentin® EC may affect the gut flora resulting in decreased gastrointestinal absorption of estrogens and decreased efficacy of combined oral contraceptives.

The literature describes rare cases of increased INR in patients when coadministering acenocoumarol or warfarin and amoxicillin. If concomitant administration of Augmentin® EC with anticoagulants is necessary, PI or INR should be closely monitored when prescribing or withdrawing Augmentin® EC, oral anticoagulants dose adjustment may be required.

Special Instructions

Before starting treatment with Augmentin® EC, a detailed history of previous hypersensitivity reactions to penicillins, cephalosporins or other allergens should be taken.

Serious and sometimes fatal hypersensitivity reactions (including anaphylactic reactions) to penicillins have been described. The risk of such reactions is highest in patients with a history of hypersensitivity reactions to penicillins. In case of allergic reactions, the treatment with Augmentin® EC should be stopped. In case of serious hypersensitivity reactions, epinephrine should be administered immediately. Oxygen therapy, intravenous GCS and airway management including intubation may also be necessary.

The use of Augmentin® EC is not recommended in patients with suspected infectious mononucleosis because in patients with this disease amoxicillin may cause a skin rash which complicates the diagnosis of the disease.

Long-term treatment with Augmentin® EC sometimes leads to overgrowth of insensitive microorganisms.

In general, Augmentin® EC is well tolerated and of low toxicity which is common to all penicillins. During long-term therapy with Augmentin® EC it is recommended to periodically monitor renal, hepatic and hematopoietic function.

In order to decrease the risk of gastrointestinal side effects, the drug should be taken at the beginning of meals.

In patients who received a combination of amoxicillin with clavulanic acid together with indirect (oral) anticoagulants, in rare cases an increase in PV (increase in INR) has been reported. When co-administration of indirect (oral) anticoagulants with the combination of amoxicillin with clavulanic acid it is necessary to monitor the corresponding indicators. To maintain the desired effect of oral anticoagulants may require adjustment of their dose.

In patients with decreased diuresis in very rare cases crystalluria has been reported, mainly during parenteral administration 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 formation of amoxicillin crystals.

The administration of Augmentin® EC orally causes high amoxicillin content in urine that may lead to false positive results in determining glucose in urine (e.g., Benedict test, Felling test). In this case it is recommended to use glucose-oxidant method of determining glucose concentration in urine.

Monitoring helps prevent discoloration of the teeth, because brushing is sufficient.

Abuse and drug dependence

There have been no drug dependence, addiction, or euphoric reactions associated with the use of EU Augmentin®.

The effect on the ability to drive vehicles, machinery. Because the drug may cause dizziness, patients should be warned about precautions when driving a vehicle or operating moving machinery.

Contraindications

With caution: Augmentin® EC should be used with caution in patients with hepatic impairment.

Side effects

The undesirable phenomena presented below are listed according to anatomico-physiological classification and frequency of occurrence. The frequency is defined as follows: very common, ≥1/10; common, ≥1/100 and < 1/10; not common, ≥1/1000 and < 1/100; rare, ≥1/10000 and < 1/1000; very rare, < 1/10000, including individual cases.

The frequency categories were derived from clinical studies of the drug and post-registration surveillance.

Frequency of adverse events

Infectious and parasitic diseases: often – candidiasis of 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 bleeding time and bleeding time, anemia, eosinophilia, thrombocytosis.

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

Nervous system disorders: infrequent – dizziness, headache; very rare – reversible hyperactivity, seizures (seizures may be observed in patients with renal dysfunction and those who receive high doses of the drug); insomnia, agitation, anxiety, behavior changes.

Gastrointestinal disorders: often – diarrhea, nausea, vomiting. Nausea is more often observed with oral administration of high doses. If gastrointestinal disorders are confirmed, they can be eliminated if the drug is taken at the beginning of a meal; infrequent – digestive disorders; very rare – antibiotic-associated colitis induced by taking antibiotics (including pseudomembranous colitis and hemorrhagic colitis), black “hairy” tongue. Children have very rarely seen discoloration of the surface layer of tooth enamel. Oral care can help prevent discoloration of tooth enamel by simply brushing their teeth.

Liver and biliary tract disorders: infrequent – moderate increase in AST and/or ALT activity. This phenomenon is observed in patients receiving therapy with beta-lactam antibiotics, but its clinical significance is unknown; very rarely – hepatitis and cholestatic jaundice (noted with concomitant therapy with other penicillins and cephalosporins), increased bilirubin and ALT. Undesirable liver phenomena have been observed mostly in men and elderly patients and might be connected with long-term therapy.

These adverse events are very rarely seen 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 therapy ends. The adverse events are usually reversible. Liver adverse events can be severe, and in exceptionally rare cases deaths have been reported. In almost all cases, these were individuals with serious comorbidities or individuals receiving concomitant potentially hepatotoxic medications.

Skin and subcutaneous tissue disorders: infrequent – 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 the treatment with Augmentin® EC should be discontinued.

Renal and urinary tract disorders: very rarely interstitial nephritis, crystalluria (see “Overdose”), hematuria.

Overdose

Gastrointestinal and water-electrolyte balance disorders may occur.

Symptoms: gastrointestinal symptoms and water-electrolyte balance disorders may be observed. Amoxicillin crystalluria has been described, in some cases leading to renal failure (see “Special indications”).

There may be seizures in patients with impaired renal function and in those who receive high doses of the drug.

Treatment: gastrointestinal symptoms – symptomatic therapy, with special attention to normalization of water-electrolyte balance. Amoxicillin and clavulanic acid may be removed from the bloodstream by hemodialysis. Results of a prospective study involving 51 children in a toxicology center showed that administration of amoxicillin at doses less than 250 mg/kg did not result in significant clinical symptoms and did not require gastric lavage.

Pregnancy use

In animal studies of reproductive function, oral and parenteral administration of Augmentin® did not cause teratogenic effects. In a single study in women with premature rupture of fetal membranes, it was found that prophylactic therapy with the drug may be associated with an increased risk of necrotizing enterocolitis in newborns. As all drugs, Augmentin® EC is not recommended for use during pregnancy unless the expected benefit to the mother outweighs the potential risk to the fetus.

The drug Augmentin® EC can be used during breastfeeding. Except for possible diarrhea or oral candidiasis associated with penetration into breast milk of trace amounts of its active principles, no other adverse effects have been observed in breastfed infants. In case of adverse effects in breastfed infants, breastfeeding should be discontinued.

Similarities