Product Overview
Structure
One 875 mg + 125 mg tablet contains:
Active substances:
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amoxicillin trihydrate in terms of amoxicillin - 1004.43 mg (875.00 mg);
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potassium clavulanate + microcrystalline cellulose (1: 1) in terms of clavulanic acid - 297.82 mg (125.00 mg).
Excipients:
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microcrystalline cellulose 302 - 1.70 mg;
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crospovidone - 421.51 mg;
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vanillin - 1.00 mg;
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saccharin - 16.11 mg;
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magnesium stearate - 7.43 mg;
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tangerine flavoring - 9.00 mg,
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lemon flavor - 11.00 mg.
pharmachologic effect
The antibiotic is penicillin semisynthetic + beta-lactamase inhibitor.
ATX Code: J01CR02
Pharmacological properties
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 destruction by beta-lactamases, and therefore the spectrum of activity of amoxicillin does not extend to microorganisms that produce this enzyme.
Clavulanic acid, a beta-lactamase inhibitor structurally related to penicillins, has the ability to inactivate a wide range of beta-lactamases found in penicillin and cephalosporin resistant microorganisms.
Clavulanic acid has sufficient efficacy against plasmid beta-lactamases, which most often determine the resistance of bacteria, and is not effective against chromosomal beta-lactamases type 1, which are not inhibited by clavulanic acid.
The presence of clavulanic acid in the preparation Amoxicillin + Clavulanic acid EXPRESS protects amoxicillin from destruction by enzymes - beta-lactamases, which allows to expand the antibacterial spectrum of amoxicillin.
The following is the in vitro combination activity of amoxicillin with clavulanic acid.
Bacteria commonly susceptible to a combination of amoxicillin with clavulanic acid
Gram-positive aerobes:
Bacillus anthracis
Enterococcus faecalis
Listeria monocytogenes
Nocardia asteroides
Streptococcus pyogenes 1.2
Streptococcus agalactiae 1.2
Streptococcus spp. (other beta hemolytic streptococci) 1,2
Staphylococcus aureus (methicillin sensitive) 1
Staphylococcus saprophyticus (methicillin sensitive)
Coagulase-negative staphylococci (sensitive to methicillin).
Gram-positive anaerobes:
Clostridium spp.
Peptococcus niger
Peptostreptococcus magnus
Peptostreptococcus micros
Peptostreptococcus spp.
Gram-negative aerobes:
Bordetella pertussis
Haemophilus influenzae 1
Helicobacter pylori
Moraxella catarrhalis 1
Neisseria gonorrhoeae
Pasteurella multocida
Vibrio cholerae.
Gram-negative anaerobes:
Bacteroides fragilis
Vasteroides spp.
Capnocytophaga spp.
Eikenella corrodens
Fusobacterium nucleatum
Fusobacterium spp.
Porphyromonas spp.
Prevotella spp.
Other:
Borrelia burgdorferi
Leptospira icterohaemorrhagiae
Treponema pallidum.
Bacteria for which acquired resistance to a combination of amoxicillin with clavulanic acid is likely
Gram-negative aerobes:
Escherichia coli 1
Klebsiella oxytoca
Klebsiella pneumoniae 1
Klebsiella spp.
Proteus mirabilis
Proteus vulgaris
Proteus spp.
Salmonella spp.
Shigella spp.
Gram-positive aerobes:
Corynebacterium spp.
Enterococcus faecium
Streptococcus pneumoniae 1.2
Streptococcus group Viridans 2 .
Bacteria that are naturally resistant 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 burnetti
Mycoplasma spp.
1 - for these types of microorganisms, the clinical efficacy of a combination of amoxicillin with clavulanic acid has been demonstrated in clinical studies.
2 - strains of these types of bacteria do not produce β-lactamases. Sensitivity with amoxicillin monotherapy suggests a similar sensitivity to the combination of amoxicillin with clavulanic acid.
Pharmacokinetics
Suction
Amoxicillin and clavulanic acid completely dissociate in an aqueous solution at physiological pH values. Both active components of the drug, amoxicillin and clavulanic acid, are quickly and well absorbed from the gastrointestinal tract (GIT) after oral administration. The absorption of active substances is optimal at the beginning of a meal.
The oral bioavailability of amoxicillin and clavulanic acid is high. After a single dose of a fixed combination of amoxicillin and clavulanic acid (500 mg + 125 mg), the maximum plasma concentration of amoxicillin is created after 1.5 hours (1.0-2.5 hours), and is 7.19 ± 2.26 μg / ml (C max ), clavulanic acid - after 1.5 hours (1.0-2.0 hours), amounting to 2.4 ± 0.83 μg / ml.
PFC (indicator "area under the pharmacokinetic curve") of amoxicillin and clavulanic acid is 53.5 ± 8.87 μg * h / l and 15.72 ± 3.86 μg * h / l, respectively. The plasma concentrations of amoxicillin and clavulanic acid achieved with amoxicillin / clavulanate are similar to those given orally with equivalent doses of amoxicillin and clavulanic acid separately.
Distribution
About 18% of amoxicillin and 25% clavulanic acid bind to plasma proteins. The apparent volume of distribution is 0.3-0.4 l / kg for amoxicillin and about 0.2 l / kg for clavulanic acid. Amoxicillin is poorly distributed into the cerebrospinal fluid.
In animal studies, cumulation of the components of the drug in the tissues of the body was not detected.
Like most penicillins, amoxicillin passes into breast milk. Clavulanic acid is also found in breast milk in trace amounts. Amoxicillin and clavulanic acid cross the placental barrier.
Metabolism
10-25% of the initial dose of amoxicillin is excreted by the kidneys in the form of an inactive metabolite (penicilloic acid). Clavulanic acid is extensively metabolized and excreted by the kidneys, intestines, and also with expired air in the form of carbon dioxide.
Breeding
After a single dose of a fixed combination of amoxicillin and clavulanic acid (500 mg + 125 mg), the half-life of amoxicillin is 1.15 ± 0.20 h, clavulanic acid is 0.98 ± 0.12 h, and the total clearance is about 25 l / h.
About 60-70% of amoxicillin and about 40-65% of clavulanic acid are excreted by the kidneys unchanged during the first 6 hours after taking 1 tablet of the drug 500/125 mg.
The greatest amount of clavulanic acid is excreted during the first 2 hours after administration. Various studies have shown that within 24 hours up to 50-85% of amoxicillin and up to 27-60% of clavulanic acid are excreted through the kidneys.
The simultaneous administration of probenecid delays the excretion of amoxicillin, but does not affect the excretion of clavulanic acid by the kidneys (see the section “Interaction with other drugs”).
Pharmacokinetics in special cases
Age features
The half-life of amoxicillin in children from 3 months to 2 years does not differ from that in older children and adults. Children in the first week of life (including premature infants) should not be prescribed the drug more than 2 times a day due to the immaturity of the renal elimination pathway.
Due to a possible decrease in renal function, the dose of the drug for elderly patients should be selected with caution. Renal function monitoring may be required.
Gender Features
With oral administration of amoxicillin / clavulanic acid by healthy men and women, a significant effect of the patient's gender on the pharmacokinetics of the active components of the drug has not been established.
Impaired renal function
The total clearance of amoxicillin / clavulanic acid decreases in proportion to a decrease in renal function. The clearance of amoxicillin is especially noticeably disturbed, since most of it is excreted by the kidneys.
Thus, in case of impaired renal function, the dose of the drug should be adjusted to avoid an excessive concentration of amoxicillin and to maintain the required level of clavulanic acid.
Impaired liver function
In patients with impaired liver function, the drug should be prescribed with caution. It is necessary to regularly monitor liver function.
Indications
The combination of amoxicillin with clavulanic acid is indicated for the treatment of bacterial infections of the following locations caused by microorganisms sensitive to the combination of amoxicillin with clavulanic acid:
upper respiratory tract infections (including ENT infections), for example, recurrent tonsillitis, sinusitis, otitis media, commonly caused by Streptococcus pneumoniae, Haemophilus influenzae *, Moraxella catarrhalis *, and Streptococcus pyogenes;
lower respiratory tract infections, for example, exacerbations of chronic bronchitis, lobar pneumonia and bronchopneumonia, usually caused by Streptococcus pneumoniae, Haemophilus influenzae * and Moraxella catarrhalis *;
urogenital tract infections, for example, cystitis, urethritis, pyelonephritis, infections of the female genital organs, usually caused by species of the Enterobacteriaceae family (mainly Escherichia coli *), Staphylococcus saprophyticus and Enterococcus species, as well as gonorrhea caused by Neisseria gonorrhoeae *;
- infections of the skin and soft tissues, usually caused by Staphylococcus aureus *, Streptococcus pyogenes and species of the genus Bacteroides *;
- infections of bones and joints, for example: osteomyelitis, usually caused by Staphylococcus aureus *, if necessary, prolonged therapy is possible;
- odontogenic infections, for example: periodontitis, odontogenic maxillary sinusitis, severe dental abscesses with spreading cellulitis;
- other mixed infections (for example: septic abortion, postpartum sepsis, intra-abdominal sepsis) as part of step therapy.
* Some representatives of this type of microorganism produce beta-lactamase, which makes them insensitive to amoxicillin (see also the section "Pharmacological properties").
Infections caused by microorganisms sensitive to amoxicillin can be treated with Amoxicillin + Clavulanic acid EXPRESS, since amoxicillin is one of its active ingredients.
Amoxicillin + Clavulanic acid EXPRESS is also indicated for the treatment of mixed infections caused by microorganisms sensitive to amoxicillin, as well as microorganisms producing beta-lactamase, sensitive to the combination of amoxicillin with clavulanic acid.
The sensitivity of bacteria to the combination of amoxicillin with clavulanic acid varies depending on the region and over time. Where possible, local sensitivity data should be taken into account.
If necessary, microbiological samples should be collected and analyzed for bacteriological sensitivity.
Pregnancy and lactation
Pregnancy
In studies of reproductive function in animals, oral and parenteral administration of amoxicillin + clavulanic acid did not cause teratogenic effects.
In a single study in women with premature rupture of the membranes, it was found that prophylactic drug therapy may be associated with an increased risk of necrotizing enterocolitis in newborns.
The drug is not recommended for use during pregnancy, unless the expected benefit to the mother outweighs the potential risk to the fetus.
Breastfeeding period
The drug Amoxicillin + Clavulanic acid EXPRESS can be used during breastfeeding.
With the exception of the possibility of sensitization, diarrhea, or candidiasis of the oral mucous membranes associated with the penetration of trace amounts of the active ingredients of this drug into breast milk, no other adverse effects were observed in breast-fed children.
In the event of adverse effects in breast-fed infants, breast-feeding should be discontinued.
Contraindications
- Hypersensitivity to amoxicillin, clavulanic acid, other penicillins or any other component of the drug;
- a history of severe immediate hypersensitivity reactions (e.g., anaphylaxis) to other beta-lactam antibiotics (e.g., cephalosporins, carbapenems or monobactams);
- a history of jaundice or liver failure due to the use of amoxicillin / clavulanic acid;
- children's age up to 1 year and / or body weight up to 10 kg (due to the impossibility of dosing the dosage form in this category of patients).
The drug at a dose of 875 mg + 125 mg is contraindicated in children under 12 years old or with a body weight of less than 40 kg; in case of impaired renal function (creatinine clearance ≤30 ml / min).
Carefully
Severe liver failure, diseases of the gastrointestinal tract (including history of colitis associated with the use of penicillins), chronic renal failure.
Side effects
Frequency categories were formed on the basis of clinical studies of the drug and post-registration observation.
Frequency of occurrence of adverse reactions
Infectious and parasitic diseases:
often: candidiasis of the skin and mucous membranes;
unknown: excessive growth of insensitive microorganisms.
Disorders from the blood and lymphatic system:
rarely: reversible leukopenia (including neutropenia), thrombocytopenia;
unknown: reversible agranulocytosis and reversible hemolytic anemia, prolonged bleeding time and prothrombin time.
Disorders of the immune system:
unknown: angioedema, anaphylactic reactions, a syndrome similar to serum sickness, allergic vasculitis; acute coronary syndrome associated with hypersensitivity (Kounis syndrome).
Disorders from the nervous system:
infrequently: dizziness, headache.
unknown: reversible hyperactivity, aseptic meningitis, convulsions in cases of impaired renal function or overdose of the drug (see sections "Dosage and Administration", "Overdose", "Special Instructions").
Gastrointestinal disorders:
adults:
very often: diarrhea;
often: nausea, vomiting;
children:
often: diarrhea, nausea, vomiting;
entire population:
Nausea was most often associated with the use of high doses of the drug. If after the start of taking the drug there are undesirable reactions from the gastrointestinal tract, they can be eliminated if you take the drug Amoxicillin + Clavulanic acid EXPRESS at the beginning of the meal.
infrequently: indigestion;
unknown: antibiotic-associated colitis (including pseudomembranous colitis and hemorrhagic colitis) (see section "Special Instructions"), black “hairy” tongue.
Disorders from the liver and biliary tract:
infrequently: moderate increase in the activity of aspartate aminotransferase and / or alanine aminotransferase (ACT and / or ALT). This reaction is observed in patients receiving beta-lactam antibiotic therapy, but its clinical significance is unknown;
unknown: hepatitis and cholestatic jaundice. These reactions are observed in patients receiving therapy with penicillin antibiotics and cephalosporins.
Adverse reactions from the liver 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 the end of therapy, however in some cases they may not appear for several weeks after completion of therapy. Adverse reactions are usually reversible.
Adverse reactions from the liver can be severe, in extremely rare cases there have been reports of fatal outcomes. In almost all cases, these were people with serious concomitant pathology or patients receiving potentially hepatotoxic drugs.
Disorders from the skin and subcutaneous tissues:
infrequently: rash, itching, urticaria;
rarely: erythema multiforme;
unknown: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis (OGEP), drug rash with eosinophilia and systemic symptoms (DRESS syndrome).
In case of skin allergic reactions, treatment with Amoxicillin + Clavulanic acid EXPRESS should be discontinued.
Disorders from the kidneys and urinary tract:
unknown: interstitial nephritis, crystalluria (see section "Overdose").
Interaction
The simultaneous use of allopurinol and amoxicillin may increase the risk of skin allergic 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 the elimination of methotrexate from the body by inhibiting its tubular secretion, therefore, the simultaneous use of the drug Amoxicillin + Clavulanic acid EXPRESS and methotrexate can increase the toxicity of methotrexate.
Like other antibacterial drugs, the drug Amoxicillin + Clavulanic acid EXPRESS can affect the intestinal microflora, leading to a decrease in the absorption of estrogen from the gastrointestinal tract and a decrease in the effectiveness of combined oral contraceptives.
The literature describes rare cases of an increase in the international normalized ratio (INR) in patients with the combined use of acenocoumarol or warfarin and amoxicillin.
If it is necessary to simultaneously prescribe Amoxicillin + Clavulanic acid EXPRESS with anticoagulants, prothrombin time or INR should be carefully monitored when prescribing or canceling the drug Amoxicillin + Clavulanic acid EXPRESS, dose adjustment of anticoagulants for oral administration may be required.
In patients treated with mycophenolate mofetil, after the start of the combination of amoxicillin with clavulanic acid, a decrease in the concentration of the active metabolite, mycophenolic acid, was observed before the next dose of the drug by about 50%.
Changes in this concentration cannot accurately reflect the general changes in the exposure of mycophenolic acid.
How to take, course of administration and dosage
For oral administration.
The dosage regimen is set individually depending on the age, body weight, kidney function of the patient, as well as the severity of the infection.
To reduce potential possible gastrointestinal disturbances and to optimize absorption, the drug should be taken at the beginning of a meal. The tablet is swallowed whole, washed down with a glass of water, or dissolved in half a glass of water (minimum 30 ml), thoroughly stirring before use.
The minimum course of antibiotic therapy is 5 days.
Treatment should not continue for more than 14 days without a review of the clinical situation. If necessary, it is possible to carry out step-by-step therapy (first, parenteral administration of amoxicillin + clavulanic acid, followed by oral administration).
Adults and children over 12 years of age with a body weight of ≥ 40 kg are prescribed 500 mg / 125 mg 3 times / day or 875 mg / 125 mg 2 times / day.
The maximum daily dose should not exceed 2400 mg / 600 mg per day.
For children aged 1 year to 12 years with a body weight of 10 to 40 kg, the dosage regimen is set individually based on the clinical situation and the severity of the infection.
The recommended daily dose is from 20 mg / 5 mg / kg per day to 60 mg / 15 mg / kg per day and is divided into 2-3 doses. Clinical data on the use of amoxicillin / clavulanic acid in a ratio of 4: 1 at doses> 40 mg / 10 mg / kg per day in children under two years of age are not. The maximum daily dose for children is 60 mg / 15 mg / kg per day.
Low doses of the drug are recommended for the treatment of infections of the skin and soft tissues, as well as recurrent tonsillitis; high doses of the drug are recommended for the treatment of diseases such as otitis media, sinusitis, lower respiratory tract and urinary tract infections, bone and joint infections.
There is insufficient clinical data to recommend the use of the drug at a dose of more than 40 mg / 10 mg / kg / day in 3 divided doses (4: 1 ratio) in children under 2 years of age. An approximate dosage dosage scheme for pediatric patients is presented in the table below:
| Child's weight, kg | Age (approximately) | The use of low doses of the drug | The use of high doses of the drug |
| 10-12 | 1-2 years | 2 times a day, 1 tablet 125 mg / 31.25 mg | 3 times a day, 1 tablet 125 mg / 31.25 mg * |
| 12-15 | 2-4 years | 3 times a day, 1 tablet 125 mg / 31.25 mg | 3 times a day, 1 tablet 250 mg / 62.5 mg |
| 15-20 | 4-6 years old | 3 times a day, 1 tablet 250 mg / 62.5 mg | 3 times a day, 1 tablet of 250 mg / 62.5 mg or 2 times a day, 500 mg / 125 mg |
| 20-30 | 6-10 years | 3 times a day, 1 tablet 250 mg / 62.5 mg | 2 times a day, 1 tablet 500 mg / 125 mg |
| 30-40 | 10-12 years old | 2 times a day, 1 tablet 500 mg / 125 mg | 3 times a day, 1 tablet 500 mg / 125 mg |
| ≥40 | ≥12 years | 3 times a day, 1 tablet 500 mg / 125 mg | 3 times a day, 1 tablet 500 mg / 125 mg |
* insufficient clinical data to recommend the use of the drug in a dose of more than 40 mg / 10 mg / kg / day in 3 divided doses (4: 1 ratio) in children under 2 years of age.
In children aged ≤ 6 years, it is preferable to take the drug in dissolved form.
Special patient groups
Elderly patients
No dosage adjustment is required. In elderly patients with impaired renal function, the dose should be adjusted as described below for adults with impaired renal function.
Patients with impaired renal function
In patients with renal failure, the excretion of clavulanic acid and amoxicillin through the kidneys is slow.
Depending on the severity of renal failure, the total dose of Amoxicillin + Clavulanic acid EXPRESS (expressed as a dose of amoxicillin) should not exceed the amounts shown in the table.
Tablets 875 mg / 125 mg should be used only in patients with creatinine clearance greater than 30 ml / min, while adjusting the dosage regimen is not required.
| Creatinine clearance | Adults and children over 12 years old with body weight ≥ 40 kg | Children aged 1 year to 12 years with a body weight of 10 kg to 40 kg |
| > 30 ml / min | No dosage adjustment required | No dosage adjustment required |
| 10-30ml / min | 500 mg / 125 mg 2 times a day | 15 mg / 3.75 mg / kg 2 times a day (maximum 500 mg / 125 mg 2 times a day) |
| <10 ml / min | 500 mg / 125 mg once daily | 15 mg / 3.75 mg / kg 1 time per day (maximum 500 mg / 125 mg 1 time per day) |
| Hemodialysis | 500 mg / 125 mg per day, plus an additional 500 mg / 125 mg during and after dialysis | 15 mg / 3.75 mg / kg once daily, plus an additional 15 mg / 3.75 mg / kg before and after dialysis |
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