Augmentin, 400 mg+57 mg/5 ml 12.6g

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 studies.

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

Pharmacokinetics

Intake

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

The data of pharmacokinetic parameters of amoxicillin and clavulanic acid obtained in various studies in healthy volunteers aged 2-12 years on an empty stomach at three doses of 40 mg + 10 mg/kg/day of Augmentin®, oral suspension powder, 125 mg + 31.25 mg in 5 ml (156.25 mg) are shown below.

Table 1

Primary pharmacokinetic parameters

The pharmacokinetic parameters of amoxicillin and clavulanic acid obtained in different studies when healthy volunteers aged 2-12 years received Augmentin®, oral suspension powder, 200 mg+28.5 mg in 5 ml (228.5 mg) at a dose of 45 mg+6.4 mg/kg/day divided into two doses, on an empty stomach, are shown below.

Table 2

Main pharmacokinetic parameters

The pharmacokinetic parameters of amoxicillin and clavulanic acid obtained in different studies when healthy volunteers took a single dose of Augmentin®, oral suspension powder, 400 mg+57 mg in 5 mL (457 mg), are shown below.

Table 3

Main pharmacokinetic parameters

The pharmacokinetic parameters of amoxicillin and clavulanic acid obtained in different studies with healthy volunteers on an empty stomach are shown below:

– 1 tablet. Augmentin®, 250 mg+125 mg (375 mg);

– 2 tablets of Augmentin®, 250 mg+125 mg (375 mg);

– 1 tablet. of the drug Augmentin®, 500 mg+125 mg (625 mg);

– 500 mg of amoxicillin;

– 125 mg of clavulanic acid.

Table 4

Primary pharmacokinetic parameters

.

When using Augmentin®, plasma concentrations of amoxicillin are similar to those of equivalent oral doses of amoxicillin.

The pharmacokinetic parameters of amoxicillin and clavulanic acid obtained in separate studies when healthy volunteers on an empty stomach took:

Two tablets of Augmentin®, 875 mg+125 mg (1000 mg) are shown below.

Table 5

Main 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 tissue, skin, fatty and muscular tissue, synovial and peritoneal fluid, 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 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 approximately 40-65% of clavulanic acid are excreted unchanged by the kidneys in the first 6 hours after ingestion of 1 tablet of 250 mg+125 mg or 1 tablet of 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 treatment of bacterial infections of the following localizations caused by microorganisms sensitive to amoxicillin-clavulanic acid combination:

Infections of the upper respiratory tract (including ENT organ 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, lobular pneumonia, and bronchopneumonia, usually caused by Streptococcus pneumoniae, Haemophilus influenzae1 and Moraxella catarrhalis1;

infections of the urogenital tract, such as cystitis, urethritis, pyelonephritis, and infections of the female genitalia, usually caused by species of the family Enterobacteriaceae1 (primarily Escherichia coli1), Staphylococcus saprophyticus and species of the genus Enterococcus, and gonorrhea caused by Neisseria gonorrhoeae1;

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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, may require long-term therapy if necessary.

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

Other mixed infections (e.g., septic abortion, postpartum sepsis, intra-abdominal sepsis) as part of stepwise therapy (only for Augmentin 250 mg/125 mg, 500 mg/125 mg, 875 mg/125 mg tablet forms);

1 Certain members of these microorganisms, produce beta-lactamase, which makes them insensitive to amoxicillin (see “Pharmacodynamics and Pharmacodynamics of Amoxicillin”). “Pharmacodynamics).

Infections caused by amoxicillin-sensitive microorganisms 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 amoxicillin-sensitive microorganisms as well as by beta-lactamase producing microorganisms 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 samples should be collected and bacteriological sensitivity testing should be performed.

Active ingredient

Composition

5 ml of the ready-made suspension contain:

Active substance:

amoxicillin (in the form of trihydrate) 400 mg;

clavulanic acid (in the form of potassium salt) 57 mg.

Auxiliary substances:

xanthan gum – 12.5 mg,

aspartame – 12.5 mg,

succinic acid – 0.84 mg,

colloidal silica – 25 mg,

hypromellose – 79.65 mg,

orange flavoring 1 – 15 mg,

orange flavoring 2 – 11.25 mg,

Raspberry flavoring – 22.5 mg,

Light molasses flavoring – 23.75 mg,

Silica dioxide – up to 900 mg.

How to take, the dosage

The dosing regimen is adjusted individually depending on the patient’s age, body weight, kidney function, and the severity of the infection.

For optimal absorption and to reduce possible digestive side effects, Augmentin® is recommended to be taken at the beginning of meals.

The minimum course of antibiotic therapy is 5 days.

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

If necessary, step therapy (parenteral administration of the drug at the beginning of therapy followed by switch to oral administration) is possible.

Adults and children over 12 years of age or with a body weight of 40 kg or more

Individuals. 1 tablet 250 mg/125 mg 3 times/day (in mild to moderate infections), or 1 tablet 500 mg/125 mg 3 times/day, or 1 tablet 875 mg/125 mg 2 times/day, or 11 ml of 400 mg/57 mg/5 ml suspension 2 times/day (equivalent to 1 tablet 875 mg/125 mg).

Two 250 mg/125 mg tablets are not equivalent to 1 500 mg/125 mg tablet.

Children from 3 months to 12 years of age with a body weight of less than 40 kg

The drug is indicated in oral suspension form.

The dose is calculated depending on age and body weight, stated in mg/kg body weight/day (calculation for amoxicillin) or in ml of suspension.

The frequency of administration of 125 mg/31.25 mg suspension in 5 ml is 3 times/day every 8 hours.

The frequency of administration of 200 mg/28.5 mg suspension in 5 ml or 400 mg/57 mg suspension in 5 ml is 2 times daily every 12 hours.

The recommended dosing regimen and dosing frequency are as follows:

The dosing frequency is 3 times/day; 4:1 suspension (125 mg/31.25 mg in 5 ml):

The frequency of administration is 2 times/day; 7:1 suspension (200 mg/28.5 mg in 5 ml or 400 mg/57 mg in 5 ml):

Low doses of Augmentin® are used to treat skin and soft tissue infections and recurrent tonsillitis.

High doses of Augmentin® are used for the treatment of conditions such as otitis media, sinusitis, lower respiratory and urinary tract infections, and bone and joint infections.

There is insufficient clinical evidence to recommend the use of Augmentin® at a dose greater than 40 mg/kg/day in 3 doses (4:1 suspension) in children less than 2 years of age.

In children from birth to 3 months

In view of immaturity of renal excretory function, the recommended dose of Augmentin® (amoxicillin calculation) is 30 mg/kg/day in 2 doses as a 4:1 suspension.

The use of 7:1 suspension (200 mg/28.5 mg in 5 ml or 400 mg/57 mg in 5 ml) is not recommended in this population.

Children born prematurely

There are no dosing recommendations.

Patients in the elderly

There is no need to adjust the dose of the drug. In elderly patients with impaired renal function, the dose should be adjusted as indicated below for adults with impaired renal function.

Patients with impaired renal function

Dose adjustment is based on the maximum recommended dose of amoxicillin and is based on CK values.

Adults

Tablets 250 mg+125 mg or 500 mg+125 mg:

4:1 suspension (125 mg/31.25 mg in 5 ml):

Tablets 875 mg+125 mg and 7:1 suspension (200 mg/28.5 mg in 5 ml or 400 mg/57 mg in 5 ml) should be used only in patients with CK > 30 ml/min, and no dose adjustment is required.

In most cases, parenteral therapy should be preferred if possible.

Patients on hemodialysis

Dose adjustments are based on the maximum recommended dose of amoxicillin: 2 tablets. 250 mg/125 mg at a single dose every 24 hours, or 1 tablet. 500 mg/125 mg at a single dose every 24 hours, or 15 mg/3.75 mg/kg suspension once daily.

Tablets: During a hemodialysis session, an additional dose (one tablet) and another dose (one tablet) at the end of the dialysis session (to compensate for the decrease in serum concentrations of amoxicillin and clavulanic acid).

Suspension: One additional dose of 15 mg/3.75 mg/kg should be administered before a hemodialysis session. A second additional dose of 15 mg/3.75 mg/kg should be administered after hemodialysis to restore the blood concentrations of the active components of Augmentin®.

Patients with hepatic impairment

Treatment should be performed with caution; hepatic function should be monitored regularly. There is insufficient data to support dosing adjustments in this category of patients.

Regulations for preparing the suspension

The suspension is prepared immediately before the first use.

The suspension (125 mg/31.25 mg in 5 ml): in a vial with the powder add approximately 60 ml of boiled water, cooled to room temperature, then close the vial with the lid and shake until the powder is completely diluted, letting the vial stand for 5 minutes to ensure complete dilution. Then add water to the mark on the bottle and shake the bottle again. In total, about 92 ml of water is required to prepare the suspension. The bottle should be shaken well before each use. For precise dosage of the drug the measuring cap should be used, which should be well washed with water after each use. After dilution the suspension should be stored no more than 7 days in the refrigerator, but not frozen.

In children under 2 years of age the measured single dose of Augmentin® suspension can be doubled with water.

The suspension (200 mg/28.5 mg in 5 ml or 400 mg/57 mg in 5 ml): in a vial with the powder add approximately 40 ml of boiled water which has been cooled to room temperature, close the vial with the cap and shake until the powder is completely diluted, letting the vial stand for 5 minutes to ensure complete dilution. Then add water to the mark on the bottle and shake the bottle again. In total, about 64 ml of water is required to prepare the suspension. The bottle should be shaken well before each use. For precise dosage of the drug a measuring cap or dispensing syringe should be used, which should be well washed with water after each use. After dilution, the suspension should be stored for no more than 7 days in the refrigerator, but not frozen.

In children under 2 years of age, a measured single dose of Augmentin® suspension can be diluted with water at a ratio of 1:1.

Interaction

The concomitant use of Augmentin® and probenecid is not recommended. Probenecid decreases the tubular secretion of amoxicillin, and therefore concomitant use of Augmentin® 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 retard excretion of methotrexate by inhibiting its tubular secretion, so concomitant use of Augmentin and methotrexate may increase methotrexate toxicity.

As with other antibacterials, Augmentin® 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 MHO in patients when coadministering acenocoumarol or warfarin and amoxicillin. If concomitant administration of Augmentin® with anticoagulants is necessary, PV or MHO should be closely monitored when prescribing or cancelling Augmentin®, oral anticoagulants dose adjustment may be required.

Special Instructions

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

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. In case of allergic reactions it is necessary to stop the treatment with Augmentin® and start an appropriate alternative therapy.

In case of serious anaphylactic reactions the patient should be immediately given epinephrine. Oxygen therapy, IV GCS and airway management including intubation may also be necessary.

If infectious mononucleosis is suspected, Augmentin® should not be used because in patients with this disease amoxicillin may cause a skin rash which makes it difficult to diagnose the disease.

Long treatment with Augmentin® may cause overgrowth of insensitive microorganisms.

In general, Augmentin® is well tolerated and of low toxicity consistent with all penicillins. During long-term therapy with Augmentin® 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 MHO) 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 impaired renal function the dose of Augmentin® should be prescribed according to the degree of impairment (see “Dosage and administration”, Patients with impaired renal function).

In patients with decreased diuresis crystalluria is very rare, mainly during parenteral therapy. 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 (see “Overdose”).

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

Mouth care helps prevent discoloration of the teeth associated with taking the drug, as brushing is sufficient (for suspensions).

The drug Augmentin® must be used within 30 days of opening the laminated aluminum foil package (for tablets)

Abuse and drug dependence. There have been 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 about the precautions to be taken when driving a vehicle or operating moving mechanisms.

Contraindications

Advanced for oral suspension powder, 125 mg+31.25 mg

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

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

Advanced for film-coated tablets 875 mg+125 mg

With caution: liver function disorders.

Side effects

The undesired phenomena presented below are listed according to organ and organ system involvement and frequency of occurrence. The frequency of occurrence is defined as follows: very frequently, ≥1/10; frequently, ≥1/100 and < 1/10; infrequently, ≥1/1000 and < 1/100; rarely, ≥1/10000 and < 1/1000; very rarely, < 1/10000, including individual 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.

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

Immune system disorders: very rare – 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 impaired renal function and those who receive high doses of the drug), insomnia, agitation, anxiety, behavior changes.

Gastrointestinal disorders:

– adults: very often – diarrhea; often – nausea, vomiting;

– children: frequent – diarrhea, nausea, vomiting;

– whole population: nausea was most commonly associated with the use of high doses of the drug. If unwanted gastrointestinal reactions are observed after starting the drug, they may be eliminated if Augmentin® is taken at the beginning of meals; infrequent – digestive disorders; very rare – antibiotic-associated colitis (including pseudomembranous colitis and hemorrhagic colitis), black “hairy” tongue, gastritis, stomatitis; color changes in the surface layer of tooth enamel in children. Oral care can help prevent discoloration of teeth by simply brushing.

Hepatic 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 rare – hepatitis and cholestatic jaundice. These phenomena are observed in patients receiving therapy with penicillin-type antibiotics and cephalosporins. Increase of bilirubin and alkaline phosphate concentration.

Hepatic adverse events have been observed mainly in men and elderly patients and may be associated with long-term therapy. These adverse events are very rarely seen in children.

The signs and symptoms listed usually occur during or immediately after completion of therapy, but in some cases may not occur for several weeks after completion of therapy. The adverse events are usually reversible. Liver adverse events can be severe, and in exceptionally rare cases there have been reports of lethal outcomes. In almost all cases these were patients with severe comorbidities or patients receiving concomitant potentially hepatotoxic drugs.

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, treatment with Augmentin® should be discontinued.

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

Overdose

Symptoms: Gastrointestinal tract and water-electrolyte balance disorders may be observed.

Amoxicillin crystalluria has been described, in some cases leading to renal failure (see “Cautions”).

Convulsions in patients with impaired renal function and in those receiving high doses of the drug.

Treatment: gastrointestinal symptoms – symptomatic therapy, with special attention to the normalization of water-electrolyte balance. Amoxicillin and clavulanic acid may be removed from the bloodstream by hemodialysis.

The results of a prospective study involving 51 children in a toxicology center showed that administration of amoxicillin at a dose 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, prophylactic therapy with Augmentin® may be associated with an increased risk of necrotizing enterocolitis in the newborn. As all drugs, Augmentin® is not recommended for use during pregnancy unless the expected benefit to the mother outweighs the potential risk to the fetus.

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

Similarities