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

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

upper respiratory tract infections: recurrent or persistent acute otitis media caused by Streptococcus pneumoniae (minimal inhibitory concentration <4 μg/ml), Haemophilus influenzae1 and Moraxella catarrhalis1; Tonsillo-pharyngitis and sinusitis, usually caused by Streptococcus pneumoniae, Haemophilus influenzae1, Moraxella catarrhalis1 and Streptococcus pyogenes; lower respiratory tract infections: lobar pneumonia and bronchopneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae1, Moraxella catarrhalis1; infections of the skin and soft tissues, usually caused by Staphylococcus aureus1 and Streptococcus pyogenes.

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

Infections caused by microorganisms sensitive to amoxicillin can be treated with Augmentin® EC, since amoxicillin is one of its active ingredients. The drug Augmentin® EC is also indicated for the treatment of mixed infections caused by microorganisms sensitive to amoxicillin, as well as beta-lactamase-producing microorganisms sensitive to the combination of amoxicillin with clavulanic acid. The sensitivity of bacteria to the combination of amoxicillin and clavulanic acid varies regionally and over time.

Where possible, local sensitivity data should be taken into account. If necessary, microbiological samples should be collected and bacteriological susceptibility testing should be carried out.

Pharmacological effect

Pharmacological action – broad spectrum antibacterial (bactericidal).
Pharmacodynamics

Mechanism of action

Amoxicillin is a semisynthetic broad-spectrum antibiotic that is active against many gram-positive and gram-negative microorganisms. At the same time, amoxicillin is susceptible to destruction 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 resistant to penicillins and cephalosporins. Clavulanic acid is quite 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 destruction by enzymes – beta-lactamases, which allows expanding the antibacterial spectrum of amoxicillin.

Below is the activity of the combination of amoxicillin and clavulanic acid in vitro.

Bacteria usually susceptible to the combination of amoxicillin and clavulanic acid

Gram-positive aerobes – Bacillus anthracis; Enterococcus faecalis; Listeria monocytogenes; Nocardia asteroides; Streptococcus pneumoniae1,2; Streptococcus pyogenes1,2; Streptococcus agalactiae1,2; Streptococci of the Viridans group Streptococcus spp. (other beta-hemolytic streptococci)1, 2; Staphylococcus aureus (methicillin sensitive)1; Staphylococcus saprophyticus (sensitive to methicillin); coagulase-negative staphylococci (sensitive to methicillin).

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 and 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 that are naturally resistant to the combination of amoxicillin and 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 effectiveness of the combination of amoxicillin with clavulanic acid has been demonstrated in clinical studies;

2 strains of these types of bacteria do not produce beta-lactamases. Sensitivity during amoxicillin monotherapy suggests similar sensitivity to the combination of amoxicillin and clavulanic acid.

Pharmacokinetics

Suction

The active ingredients of Augmentin® EC – amoxicillin and clavulanic acid – are quickly and completely absorbed from the gastrointestinal tract after oral administration. Absorption of active ingredients is optimal when taking Augmentin® EC with food.

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

Table 2

Average values ​​of pharmacokinetic parameters

Preparation
Cmax, mg/l
Tmax, h
AUC, mg h/ml
T1/2, h
Amoxicillin
Augmentin® EU
15.7
2
59.8
1.4
Clavulanic acid
Augmentin® EU
1.7
1.1
4
1.1

Distribution

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

Amoxicillin and clavulanic acid have a weak degree of binding to plasma proteins. Studies have shown that about 25% of the total amount of clavulanic acid and 18% of amoxicillin in the blood plasma is bound to plasma proteins. In animal studies, no accumulation of the components of Augmentin® EC in any organ was detected.

Amoxicillin, like most penicillins, passes into breast milk. Trace amounts of clavulanic acid may also be found in breast milk. With the exception of the possibility of diarrhea and candidiasis of the oral mucosa, no other negative effects of amoxicillin and clavulanic acid on the health of breastfed infants are known. Animal reproductive studies have shown that amoxicillin and clavulanic acid cross the placental barrier. However, no negative effects on the fetus were detected.

Metabolism

10–25% of the initial dose of amoxicillin is excreted by the kidneys in the form of an inactive metabolite (penicillic acid). Clavulanic acid undergoes intensive 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 also with exhaled air in the form of carbon dioxide.

Removal

Like other penicillins, amoxicillin is eliminated primarily by the kidneys, while clavulanic acid is eliminated 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 administration of 1 tablet. 250/125 mg or 1 tablet. 500/125 mg. Concomitant administration of probenecid slows the elimination of amoxicillin, but not clavulanic acid (see “Interactions”).

Special instructions

Before starting treatment with Augmentin® EC, it is necessary to obtain a detailed history regarding previous hypersensitivity reactions to penicillins, cephalosporins or other allergens.

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. If an allergic reaction occurs, you must stop treatment with Augmentin® EC. For severe hypersensitivity reactions, epinephrine should be administered immediately. Oxygen therapy, intravenous administration of corticosteroids, and airway management, including intubation, may also be required.

It is not recommended to prescribe Augmentin® EC for suspected infectious mononucleosis, since amoxicillin can cause a skin rash in patients with this disease, which makes diagnosing the disease difficult.

Long-term treatment with Augmentin® EC sometimes leads to excessive proliferation of insensitive 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, liver and hematopoietic function.

In order to reduce the risk of developing side effects from the gastrointestinal tract, the drug should be taken at the beginning of a meal.

In patients receiving a combination of amoxicillin and clavulanic acid together with indirect (oral) anticoagulants, an increase in PT (increased INR) has been reported in rare cases. When co-prescribing indirect (oral) anticoagulants with a combination of amoxicillin and clavulanic acid, monitoring of relevant indicators is necessary. Dosage adjustments may be required to maintain the desired effect of oral anticoagulants.

In patients with reduced diuresis, the development of crystalluria has been reported in very rare cases, 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.

Taking Augmentin® EC orally leads to a high level of amoxicillin in the urine, which can lead to false-positive results when determining glucose in the urine (for example, Benedict’s test, Fehling’s test). In this case, it is recommended to use the glucose oxidant method for determining the concentration of glucose in the urine.

Oral care helps prevent tooth discoloration by simply brushing your teeth.

Drug abuse and dependence

There was no drug dependence, addiction, or euphoric reactions associated with the use of Augmentin® EC.

Influence on the ability to drive vehicles and machinery. Since the drug may cause dizziness, patients should be warned to take precautions when driving or operating moving machinery.

Active ingredient

Amoxicillin, Clavulanic acid

Composition

5 ml of the finished suspension contains:

Active substances:

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

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

Excipients:

xanthan gum – 3.26 mg,

aspartame – 13.6 mg,

silicon dioxide – 153.29 mg,

colloidal silicon dioxide – 38.08 mg,

carmellose sodium – 32.64 mg,

strawberry flavoring – 28.29 mg.

Pregnancy

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 developing necrotizing enterocolitis in newborns. Like all medicinal products, Augmentin® EC is not recommended for use during pregnancy, unless the expected benefit to the mother outweighs the potential risk to the fetus.

Augmentin® EC can be used during breastfeeding. With the exception of the possibility of diarrhea or candidiasis of the oral mucosa associated with the penetration of trace amounts of the active ingredients 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.

Contraindications

history of hypersensitivity to amoxicillin, clavulanic acid, other components of the drug, beta-lactam antibiotics (for example, penicillins, cephalosporins);
history of previous episodes of jaundice or impaired liver function when using a combination of amoxicillin and clavulanic acid;
children up to 3 months;
impaired renal function (Cl creatinine <30 ml/min); phenylketonuria.

With caution: Augmentin® EC should be used with caution in patients with impaired liver function.

Side Effects

The adverse events presented below are listed depending on the anatomical and physiological classification and frequency of occurrence. The frequency of occurrence is determined as follows: very often – ≥1/10; often – ≥1/100 and <1/10; not often - ≥1/1000 and <1/100; rarely - ≥1/10000 and <1/1000; very rarely - <1/10000, including isolated cases.

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

Frequency of occurrence of adverse events

Infectious and parasitic diseases: often – candidiasis of the skin and mucous membranes.

Disorders of the blood and lymphatic system: rarely – reversible leukopenia (including neutropenia) and reversible thrombocytopenia; very rarely – reversible agranulocytosis and reversible hemolytic anemia, prolongation of PT and bleeding time, anemia, eosinophilia, thrombocytosis.

Immune system disorders: very rarely – angioedema, anaphylactic reactions, a syndrome similar to serum sickness, allergic vasculitis.

Nervous system disorders: infrequently – dizziness, headache; very rarely – reversible hyperactivity, convulsions (convulsions can be observed in patients with impaired renal function, as well as in those receiving high doses of the drug); insomnia, agitation, anxiety, behavior changes.

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

Disorders of the liver and biliary tract: uncommon – moderate increase in AST and/or ALT activity. This phenomenon has been observed in patients receiving beta-lactam antibiotic therapy, but its clinical significance is unknown; very rarely – hepatitis and cholestatic jaundice (noted with concomitant therapy with other penicillins and cephalosporins), increased concentrations of bilirubin and alkaline phosphatase. Adverse liver events have been observed primarily in men and elderly patients and may be associated with long-term therapy.

These adverse events are very rarely observed in children. The listed signs and symptoms usually occur during or immediately after completion of therapy, but in some cases they may not appear for several weeks after completion of therapy. Adverse effects are usually reversible. Hepatic adverse events can be severe and death has been reported in extremely rare cases. In almost all cases, these were persons with serious comorbidities or persons receiving concomitantly potentially hepatotoxic drugs.

Disorders of the skin and subcutaneous tissues: infrequently – rash, itching, urticaria; rarely – erythema multiforme; very rarely – Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis. If allergic skin reactions occur, treatment with Augmentin® EC should be discontinued.

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

Interaction

The simultaneous use of Augmentin® EC and probenecid is not recommended. Probenecid reduces the tubular secretion of amoxicillin, and therefore the simultaneous use of Augmentin® EC and probenecid may lead to an increase and persistence in the blood concentration of amoxicillin, but not clavulanic acid.

Concomitant use of allopurinol and amoxicillin may increase the risk of allergic skin reactions. Currently, there is no data in the literature on the simultaneous use of a combination of amoxicillin with clavulanic acid and allopurinol.

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

Like other antibacterial drugs, Augmentin® EC can affect the intestinal microflora, leading to a decrease in the absorption of estrogens from the gastrointestinal tract and a decrease in the effectiveness of combined oral contraceptives.

The literature describes rare cases of increased INR in patients with the combined use of acenocoumarol or warfarin and amoxicillin. If it is necessary to simultaneously prescribe Augmentin® EC with anticoagulants, the PT or INR should be carefully monitored when prescribing or discontinuing the drug Augmentin® EC; dose adjustment of anticoagulants for oral administration may be required.

Overdose

Gastrointestinal disorders and disturbances in water and electrolyte balance may occur.

Symptoms: gastrointestinal symptoms and water and electrolyte imbalance may be observed. Amoxicillin crystalluria has been described, in some cases leading to the development of renal failure (see “Special Instructions”).

Convulsions may occur in patients with impaired renal function, as well as in those receiving high doses of the drug.

Treatment: symptoms from the gastrointestinal tract – symptomatic therapy, paying special attention to normalizing water and electrolyte balance. Amoxicillin and clavulanic acid can be removed from the bloodstream by hemodialysis. The results of a prospective study that was conducted in 51 children at a poison control center showed that amoxicillin administered at a dose of less than 250 mg/kg did not lead to significant clinical symptoms and did not require gastric lavage.

Storage conditions

Store at a temperature not exceeding 25°C.

The prepared suspension should be stored in the refrigerator at a temperature of 2° to 8°C.

Keep out of the reach of children.

Shelf life

2 years Prepared suspension – 10 days

Manufacturer

Glaxo Wellcome Production, France