Augmentin, 875 mg+125 mg 14 pcs

Pharmacological action Pharmacological action – broad spectrum antibacterial, bactericidal.
Pharmacodynamics

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 that most often cause bacterial resistance and is less effective against chromosomal beta-lactamases of type 1 that are not inhibited by clavulanic acid.

The presence of clavulanic acid in Augmentin® protects amoxicillin from degradation by beta-lactamase enzymes, which allows the antibacterial spectrum of amoxicillin to be expanded.

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 spp, including Streptococcus pyogenes1,2, Streptococcus agalactiae1,2 (other beta-hemolytic streptococci)1,2, Staphylococcus aureus (sensitive to methicillin)1, Staphylococcus saprophyticus (sensitive to methicillin), coagulazonegative staphylococci (sensitive to methicillin).

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

Gram-negative aerobes: Bordetella pertussis, Haemophilus influenzae1, Helicobacter pylori, Moraxella cafarrhalis1, Neisseria gonorrhoeae, Pasteurella multocida, Vibrio cholerae.

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

Others: Borrelia burgdorferi, Leptospira icterohaemorrhagiae, Treponema pallidum.

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

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

Gram-positive aerobes: Corynebacterium spp., Enterococcus faecium, Streptococcus pneumoniae1,2, Streptococcus group Viridans.

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 spp. including Chlamydia pneumoniae, Chlamydia psittaci, 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. The sensitivity with amoxicillin monotherapy suggests similar sensitivity to the combination of amoxicillin with clavulanic acid

Pharmacokinetics

Pharmacokinetics

Amoxicillin and clavulanic acid, both active substances of Augmentin® preparation, are rapidly and completely absorbed from gastrointestinal tract after oral administration. Absorption of active ingredients of Augmentin® is optimal if the drug is taken at the beginning of a meal.

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 (gall bladder, abdominal cavity tissue, skin, fat and muscle tissue, synovial and peritoneal fluid, bile, purulent 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 the components of the drug Augmentin® was found in any organ.

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 other adverse effects of amoxicillin and clavulanic acid on the health of breastfed infants.

Reproductive studies 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-3H-pyrrol-3-carboxylic acid and -amino-4-hydroxy-butane-2-one and is excreted by the kidneys, through the gastrointestinal tract, and with exhaled air as carbon dioxide.

Elevation

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 administration of 1 tablet 250 mg+125 mg or 1 tablet 500 mg+125 mg.

Concomitant administration of probenecid slows the excretion of amoxicillin but not clavulanic acid (see “Interaction”).

Indications

The combination of amoxicillin with clavulanic acid is indicated for the treatment of bacterial infections of the following localizations caused by microorganisms sensitive to the combination of amoxicillin with clavulanic acid:

upper respiratory tract infections (including ENT infections), such as recurrent tonsillitis, sinusitis, otitis media, usually caused by Streptococcus pneumoniae, Haemophilus influenzae1, Moraxella catarrhalis1 and Streptococcus pyogenes; (except Augmentin 250 mg/125 mg tablets);

lower respiratory tract infections, such as exacerbations of chronic bronchitis, lobar pneumonia and bronchopneumonia, usually caused by Streptococcus pneumoniae, Haemophilus influenzae1 and Moraxella catarrhalis1;

infections of the genitourinary tract, for example cystitis, urethritis, pyelonephritis, infections of the female genital organs, usually caused by species of the family Enterobacteriaceae1 (mainly Escherichia coli1), Staphylococcus saprophyticus and species of the genus Enterococcus, as well as gonorrhea caused by Neisseria gonorrhoeae1;

infections of the skin and soft tissues, usually caused by Staphylococcus aureus1, Streptococcus pyogenes and species of the genus Bacteroides1;

infections of bones and joints, such as osteomyelitis, usually caused by Staphylococcus aureus1, long-term therapy is possible if necessary.

odontogenic infections, such as periodontitis, odontogenic maxillary sinusitis, severe dental abscesses with spreading cellulite (only for tablet forms of Augmentin, dosages 500 mg/125 mg, 875 mg/125 mg);

other mixed infections (for example, septic abortion, postpartum sepsis, intra-abdominal sepsis) as part of step-down therapy (only for tablet forms of Augmentin dosages 250 mg/125 mg, 500 mg/125 mg, 875 mg/125 mg);

1 Certain representatives of this genus of microorganisms produce beta-lactamase, which makes them insensitive to amoxicillin (see “Pharmacodynamics”).

Infections caused by microorganisms sensitive to amoxicillin can be treated with Augmentin®, since amoxicillin is one of its active ingredients. The drug Augmentin® 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
Pharmacological action – broad spectrum antibacterial, bactericidal.
Pharmacodynamics

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® 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 spp., incl. Streptococcus pyogenes1,2, Streptococcus agalactiae1,2 (other beta-hemolytic streptococci)1,2, Staphylococcus aureus (methicillin-sensitive)1, Staphylococcus saprophyticus (methicillin-sensitive), coagulase-negative staphylococci (methicillin-sensitive).

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

Gram-negative aerobes: Bordetella pertussis, Haemophilus influenzae1, Helicobacter pylori, Moraxella cafarrhalis1, Neisseria gonorrhoeae, Pasteurella multocida, Vibrio cholerae.

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

Other: Borrelia burgdorferi, Leptospira icterohaemorrhagiae, Treponema pallidum.

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

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

Gram-positive aerobes: Corynebacterium spp., Enterococcus faecium, Streptococcus pneumoniae1,2, Viridans group streptococci.

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 spp., incl. Chlamydia pneumoniae, Chlamydia psittaci, Coxiella burnetii, Mycoplasma spp.

1 For these bacteria, the clinical effectiveness of the combination of amoxicillin and clavulanic acid has been demonstrated in clinical studies.

2 Strains of these bacterial species do not produce beta-lactamase. Sensitivity during monotherapy with amoxicillin suggests similar sensitivity to the combination of amoxicillin with clavulanic acid.

Pharmacokinetics

Suction

Both active ingredients of Augmentin® – amoxicillin and clavulanic acid – are quickly and completely absorbed from the gastrointestinal tract after oral administration. Absorption of the active ingredients of Augmentin® is optimal if the drug is taken at the beginning of a meal.

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 fluid, 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 Augmentin® components 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 (penicilloic acid). Clavulanic acid undergoes intensive metabolism to 2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-3H-pyrrole-3-carboxylic acid and -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 taking 1 tablet. 250 mg+125 mg or 1 tablet. 500 mg+125 mg.

Concomitant administration of probenecid slows the elimination of amoxicillin, but not clavulanic acid (see “Interactions”).

Special instructions

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

Serious and sometimes fatal hypersensitivity reactions (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, treatment with Augmentin® should be discontinued and appropriate alternative therapy should be initiated. 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® if infectious mononucleosis is suspected, since amoxicillin can cause a measles-like rash in patients with this disease, which makes diagnosing the disease difficult.

Long-term treatment with Augmentin® sometimes leads to excessive proliferation of insensitive microorganisms.

In general, Augmentin® is well tolerated and has the low toxicity characteristic of all penicillins.

During long-term therapy with Augmentin®, 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 prothrombin time (increase in MHO) 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 impaired renal function, the dose of Augmentin® should be reduced according to the degree of impairment.

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® 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.

The tablets must be used within 30 days of opening the laminated aluminum foil package.

Drug abuse and dependence

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

Impact on the ability to drive vehicles and operate 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

Active ingredients:

amoxicillin (in trihydrate form) – 875 mg;

clavulanic acid (in the form of potassium salt) – 125 mg.

Excipients:

magnesium stearate – 14.5 mg,

sodium carboxymethyl starch – 29 mg,

colloidal silicon dioxide – 10 mg,

microcrystalline cellulose – 396.5 mg.

Film shell composition:

titanium dioxide – 13.76 mg,

hypromellose (5 cps) – 10.56 mg,

hypromellose (15 cps) – 3.52 mg,

macrogol 4000 – 2.08 mg,

macrogol 6000 – 2.08 mg,

dimethicone – 0.013 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 medications, Augmentin® is not recommended for use during pregnancy, unless the expected benefit to the mother outweighs the potential risk to the fetus.

Augmentin® 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

For all dosage forms

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.

Additionally for powder for oral suspension, 125 mg+31.25 mg

phenylketonuria.

Additionally for powder for oral suspension, 200 mg+28.5 mg, 400 mg+57 mg

phenylketonuria;
impaired renal function (creatinine Cl less than 30 ml/min);
children’s age up to 3 months.

Additionally for film-coated tablets, 250 mg+125 mg, 500 mg+125 mg

children under 12 years of age or body weight less than 40 kg.

Additionally for film-coated tablets, 875 mg+125 mg

impaired renal function (creatinine Cl less than 30 ml/min);
children under 12 years of age or body weight less than 40 kg.

With caution: liver dysfunction.

Side Effects

The adverse events presented below are listed according to the damage to organs and organ systems and the frequency of occurrence. The frequency of occurrence is determined as follows: very often – ≥1/10; often – ≥1/100 and <1/10; uncommon - ≥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.

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

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

From the immune system: very rarely – angioedema, anaphylactic reactions, a syndrome similar to serum sickness, allergic vasculitis.

From the nervous system: 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.

From the gastrointestinal tract:

– 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 starting to take the drug, adverse reactions from the gastrointestinal tract are observed, they can be eliminated if Augmentin® is taken at the beginning of the meal; infrequently – indigestion; very rarely – antibiotic-associated colitis (including pseudomembranous colitis and hemorrhagic colitis), black “hairy” tongue, gastritis, stomatitis; change in color of the surface layer of tooth enamel in children. Oral care helps prevent tooth discoloration by simply brushing your teeth.

From 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. These phenomena are observed in patients receiving therapy with penicillin antibiotics and cephalosporins. Increased concentration of bilirubin and alkaline phosphatase.

Adverse events from the liver are observed mainly 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 patients with serious comorbidities or patients receiving concomitantly potentially hepatotoxic drugs.

From 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® should be discontinued.

From the kidneys and urinary tract: very rarely – interstitial nephritis, crystalluria (see “Overdose”), hematuria.

Interaction

The simultaneous use of Augmentin® and probenecid is not recommended. Probenecid reduces the tubular secretion of amoxicillin, and therefore the simultaneous use of Augmentin® 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, so the simultaneous use of Augmentin and methotrexate may increase the toxicity of methotrexate.

Like other antibacterial drugs, Augmentin® 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 MHO in patients with the combined use of acenocoumarol or warfarin and amoxicillin. If it is necessary to simultaneously prescribe Augmentin® with anticoagulants, PT or MHO should be carefully monitored when prescribing or discontinuing Augmentin®, and dose adjustment of oral anticoagulants may be required.

Overdose

Symptoms: Gastrointestinal symptoms and fluid and electrolyte imbalance may occur. Amoxicillin crystalluria has been described, in some cases leading to the development of renal failure.

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 the normalization of water and electrolyte balance. In case of overdose, 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

At a temperature not exceeding 25 °C

Shelf life

2 years

Manufacturer

SmithKline Beecham, UK