Instructions Augmentin ES powder for oral suspension 600 mg / 42.9 mg in 5 ml bottle 100 ml
Composition
active ingredients: amoxicillin, clavulanic acid;
1 bottle contains powder for the preparation of 100 ml of suspension of the following composition:
5 ml of suspension contain amoxicillin (as amoxicillin trihydrate) 600 mg and clavulanic acid (as potassium clavulanate) 42.9 mg;
Excipients: colloidal anhydrous silicon dioxide, sodium carboxymethylcellulose 12, aspartame (E 951), xanthan gum, silicon dioxide, artificial strawberry flavor.
Dosage form
Powder for oral suspension.
Main physicochemical properties: almost white loose powder with a characteristic strawberry odor.
Pharmacotherapeutic group
Antibacterials for systemic use. Beta-lactam antibiotics. Penicillins. Combinations of penicillins with beta-lactamase inhibitors. ATX code J01C R02.
Pharmacological properties
Pharmacodynamics
Mechanism of action
Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often called penicillin-binding proteins, PBPs) in the biosynthetic metabolism of bacterial peptidoglycan, an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, resulting in cell lysis and death.
Amoxicillin is susceptible to cleavage by beta-lactamases produced by resistant bacteria, therefore, the spectrum of activity of amoxicillin as monotherapy does not include microorganisms that produce these enzymes.
Clavulanic acid is a beta-lactam structurally related to the penicillins. It inactivates some beta-lactamase enzymes, thereby preventing the inactivation of amoxicillin. Clavulanic acid as monotherapy does not have a clinically useful antibacterial effect.
FC/FD ratio
The time at which drug concentrations exceed the minimum inhibitory concentration (C>MIC) is maintained is considered the primary factor determining efficacy for amoxicillin.
Resistance mechanisms
There are two main mechanisms of resistance to amoxicillin/clavulanic acid:
inactivation by bacterial beta-lactamases that are not inhibited by clavulanic acid themselves, including classes B, C and D;
conversion of PZB, which reduces the affinity of the antibacterial drug to the target.
Bacterial impermeability or efflux pump mechanism can cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.
Checkpoints
MIC breakpoints for amoxicillin/clavulanic acid established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)
| Microorganisms | Sensitivity cut-off points (µg/mL) |
| Sensitive | Moderately sensitive | Resistant | |
| Haemophilus influenzae1 | ≤1 | - | > 1 |
| Moraxella catarrhalis1 | ≤1 | - | > 1 |
| Staphylococcus aureus 2 | ≤2 | - | >2 |
| Streptococcus A, B, C, G 4 | ≤ 0.25 | - | > 0.25 |
| Streptococcus pneumoniae3 | ≤ 0.5 | 1–2 | >2 |
1 Values reported for amoxicillin concentrations. For the purpose of determining susceptibility, the clavulanic acid concentration was set at 2 mg/L. 2 Reported values for oxacillin concentrations. 3 Control points calculated from control points for ampicillin. 4 Control points calculated from control points for benzylpenicillin. |
The prevalence of resistance may vary geographically and over time for individual species, so local susceptibility information is desirable, particularly when treating severe infections. Expert opinion should be sought when the local prevalence of resistance is such that the utility of the agent, at least in some types of infections, is questionable.
| Typically sensitive species |
Gram-positive aerobes: Staphylococcus aureus (methicillin-susceptible) £, Streptococcus pneumoniae1, Streptococcus pyogenes and other beta-hemolytic streptococci. Gram-negative aerobes: Haemophilus influenzae2, Moraxella catarrhalis. |
| Species for which resistance development may be a problem |
| Gram-negative aerobes: Klebsiella pneumoniae. |
| Naturally resistant microorganisms |
Gram-negative aerobes: Legionella pneumophila. Other microorganisms: Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetti, Mycoplasma pneumoniae. |
$ All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid. 1 This formulation of amoxicillin/clavulanic acid may be used for the treatment of penicillin-resistant Streptococcus pneumoniae only according to the approved indications (see section “Method of administration and dosage”). 2 Strains with reduced susceptibility have been reported in some EU countries with a frequency above 10%. |
Absorption. Amoxicillin and clavulanic acid completely dissociate in aqueous solution at physiological pH. Both components are rapidly and well absorbed after oral administration. The bioavailability of amoxicillin and clavulanic acid is approximately 70% after oral administration. The plasma profiles of both components are identical and the time to maximum plasma concentration (Tmax) for each component is approximately one hour.
The average pharmacokinetic parameters of Augmentin ES when used for the treatment of children at a dose of 45 mg/3.2 mg/kg body weight every 12 hours are presented in the table:
| Preparation | Cmax (μg/ml) | Tmax* (hours) | AUC(0-t) (μg.h/ml) | T 1/2 (hours) |
Augmentin ES Dose: 45 mg/kg body weight amoxicillin and 3.2 mg/kg body weight clavulanic acid every 12 hours | amoxicillin |
15.7 ± 7.7 | 2.0 (1.0–4.0) | 59.8 ± 20.0 | 1.4 ± 0.35 |
| clavulanic acid |
1.7 ± 0.9 | 1.1 (1.0–4.0) | 4.0 ± 1.9 | 1.1 ± 0.29 |
*Average (range)
Serum concentrations of amoxicillin and clavulanic acid achieved with amoxicillin/clavulanic acid are identical to those achieved with oral administration of equivalent doses of amoxicillin or clavulanic acid alone.
Distribution: Approximately 25% of the total plasma clavulanic acid and 18% of the total plasma amoxicillin are protein bound. The apparent volume of distribution is approximately 0.3–0.4 L/kg for amoxicillin and approximately 0.2 L/kg for clavulanic acid.
After intravenous administration, amoxicillin and clavulanic acid have been found in the gallbladder, peritoneum, skin, adipose tissue, muscle tissue, synovial and peritoneal fluids, bile and pus. Amoxicillin does not distribute sufficiently in the cerebrospinal fluid.
Animal studies have not revealed any evidence of significant retention of substances derived from any component of the drug in body tissues. Amoxicillin, like most penicillins, can be found in breast milk. Small amounts of clavulanic acid can also be found in breast milk (see section "Use during pregnancy or lactation").
Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see section “Use during pregnancy or lactation”).
Biotransformation: Amoxicillin is partially excreted in the urine as inactive penicillic acid in amounts equivalent to 10-25% of the initial dose. Clavulanic acid is extensively metabolized in humans and is excreted in the urine and feces and as carbon dioxide in exhaled air.
Excretion: The primary route of excretion of amoxicillin is the kidney, while clavulanic acid is excreted both renally and by extrarenal mechanisms.
In healthy volunteers, the mean elimination half-life of amoxicillin/clavulanic acid is approximately one hour and the mean total clearance is approximately 25 l/h. Various studies have shown that urinary excretion is 50-85% for amoxicillin and 27-60% for clavulanic acid over a 24-hour period. The greatest amount of clavulanic acid is excreted within the first 2 hours after administration.
Concomitant use of probenecid slows down the elimination of amoxicillin, but does not delay the renal excretion of clavulanic acid (see section "Interaction with other medicinal products and other types of interactions").
Renal impairment. The total serum clearance of amoxicillin/clavulanic acid decreases proportionally with decreasing renal function. The decrease in drug clearance is more pronounced for amoxicillin than for clavulanic acid, since a greater proportion of amoxicillin is excreted by the kidneys. In renal insufficiency, the dosage should prevent excessive accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2).
Hepatic impairment: Caution is recommended in patients with hepatic impairment and regular monitoring of liver function is recommended.
Indication
Infections in children aged 3 months and older weighing less than 40 kg caused or suspected to be caused by penicillin-resistant strains of Streptococcus pneumoniae, such as:
acute otitis media;
community-acquired pneumonia.
When prescribing antibacterial drugs, one should follow the rules for their proper use.
Contraindication
Hypersensitivity to any components of the drug, to any antibacterial agents of the penicillin group.
History of severe hypersensitivity reactions (including anaphylaxis) associated with the use of other beta-lactam agents (including cephalosporins, carbapenems or monobactams).
History of jaundice or liver dysfunction associated with the use of amoxicillin/clavulanic acid.
Interaction with other medicinal products and other types of interactions
Oral anticoagulants and penicillin antibiotics are widely used in practice without reports of interaction. However, cases of increased international normalization ratio have been described in patients taking acenocoumarol or warfarin and who were prescribed a course of amoxicillin. If concomitant use of such drugs is necessary, the prothrombin index or international normalization ratio should be carefully monitored when amoxicillin is added or discontinued. In addition, dose adjustment of oral anticoagulants may be required (see sections "Special instructions for use" and "Adverse reactions").
Methotrexate
Penicillins may reduce the excretion of methotrexate, causing a potential increase in toxicity.
Probenecid
Concomitant use of probenecid is not recommended. Probenecid reduces the renal tubular secretion of amoxicillin. Concomitant use of probenecid may lead to increased levels and duration of amoxicillin (but not clavulanic acid) in the blood.
Mycophenolate mofetil
In patients treated with mycophenolate mofetil, the overdosage concentration of the active metabolite, mycophenolic acid, may decrease by approximately 50% after initiation of oral amoxicillin/clavulanic acid. This change in overdosage level may not fully reflect the change in total mycophenolic acid exposure. Therefore, a change in mycophenolate mofetil dosage is not usually necessary unless there is clinical evidence of graft dysfunction. However, close monitoring is necessary during concomitant use and for some time after antibiotic therapy.
Application features
Before initiating therapy with amoxicillin/clavulanic acid, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam drugs (see sections 4.3 and 4.8).
Serious and in some cases fatal hypersensitivity reactions (including anaphylactoid reactions and severe cutaneous adverse reactions) have been reported in patients treated with penicillin. Hypersensitivity reactions may also progress to Kunis syndrome, a serious allergic reaction that may lead to myocardial infarction (see section 4.8). Such reactions are more likely to occur in patients with a history of hypersensitivity to penicillin and in patients with atopic diseases. If an allergic reaction occurs, amoxicillin/clavulanic acid should be discontinued and appropriate alternative therapy should be initiated.
If the infection is proven to be caused by an organism(s) susceptible to amoxicillin, a switch from amoxicillin/clavulanic acid to amoxicillin should be considered in accordance with generally accepted guidelines.
In patients with impaired renal function and in patients taking high doses of the drug, seizures may occur (see "Adverse reactions").
Amoxicillin/clavulanic acid should be avoided in suspected infectious mononucleosis, as a crust-like rash has been associated with the use of amoxicillin in this case.
Concomitant use of allopurinol during treatment with amoxicillin increases the likelihood of allergic skin reactions.
Prolonged use in some cases may lead to excessive reproduction of microorganisms insensitive to the drug.
The occurrence of febrile generalized erythema associated with pustular eruption at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis (AGEP) (see section 4.8). Such a reaction requires discontinuation of Augmentin and is a contraindication to further use of amoxicillin.
Amoxicillin/clavulanic acid should be used with caution in patients with signs of impaired liver function (see sections “Method of administration and dosage”, “Contraindications”, “Adverse reactions”).
Hepatic complications have been reported predominantly in men and elderly patients, with long-term treatment. Such complications have been reported very rarely in children. In all patient groups, symptoms usually occur during or after treatment, but in some cases may not appear until several weeks after the end of treatment. Such events are usually reversible. Hepatic complications can be severe and, in exceptional cases, fatal. Such events have always been observed in patients with severe underlying disease or in those who are taking concomitant medications known to cause hepatic complications (see section 4.8).
With prolonged therapy, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is recommended.
In patients receiving amoxicillin/clavulanic acid, prolongation of the prothrombin time has been reported in isolated cases. Appropriate monitoring should be carried out when anticoagulants are administered concomitantly. Dosage adjustment of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see sections 4.5 and 4.8).
Crystalluria has been observed very rarely in patients with reduced diuresis, mainly with parenteral therapy. Adequate fluid intake and diuresis should be maintained during high doses of amoxicillin to reduce the likelihood of crystalluria associated with amoxicillin. In patients with bladder catheterization, the patency of the catheters should be checked regularly (see section "Overdose").
During treatment with amoxicillin, enzymatic methods for determining glucose oxidase should be used when testing for the presence of glucose in the urine, since the use of non-enzymatic methods is likely to produce false-positive results.
The presence of clavulanic acid in Augmentin may lead to nonspecific binding of IgG and albumin on erythrocyte membranes, which may lead to false-positive Coombs test results.
Positive results have been reported in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection using the Bio-Rad Laboratories Platelia Aspergillus enzyme immunoassay. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses have been reported in patients receiving Bio-Rad Laboratories Platelia Aspergillus enzyme immunoassay. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.
Augmentin ES suspension contains aspartame (E 951) 2.72 mg/ml, which is a source of phenylalanine, therefore the drug should be prescribed with caution to patients with phenylketonuria.
The medicinal product contains maltodextrin (glucose). Do not use the medicinal product in patients with rare glucose-galactose malabsorption syndrome.
Use during pregnancy or breastfeeding
Pregnancy. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Limited human data on the use of amoxicillin/clavulanic acid during pregnancy do not indicate an increased risk of congenital malformations. A single study in women with premature rupture of membranes reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotizing enterocolitis in the newborn. Use during pregnancy should be avoided unless considered essential by the physician.
Breastfeeding. Both active components of the drug are excreted in breast milk (there is no information on the effect of clavulanic acid on a breastfed infant). Accordingly, diarrhea and fungal infection of the mucous membranes may occur in a breastfed infant, so breastfeeding should be discontinued. The possibility of allergic reactions should be taken into account. Amoxicillin/clavulanic acid should be used during breast-feeding only if, in the opinion of the physician, the benefit of use outweighs the risk.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the ability of the drug to affect the speed of reaction when driving vehicles and working with other mechanisms have not been conducted. However, undesirable effects (such as allergic reactions, dizziness, convulsions) may occur, which may affect the ability to drive a car and work with other mechanisms.
Method of administration and doses
Dosage is expressed in terms of amoxicillin/clavulanic acid content, except in cases where dosage is expressed in terms of a separate component.
When choosing the dosage of Augmentin for the treatment of a particular infection, the following should be considered:
probable pathogens and their likely sensitivity to antibacterial drugs (see section "Peculiarities of use");
severity and location of the infection;
the patient's age, body weight and renal function as indicated below.
The course of treatment should not exceed 14 days without review (see section "Special warnings and precautions for use" regarding long-term therapy).
Adults and children weighing ≥ 40 kg
There is no experience with the use of Augmentin, suspension, in adults and children weighing ≥ 40 kg, therefore no dosage recommendations are available for these patient groups.
Children from 3 months of age with a body weight < 40 kg
Augmentin ES contains a different amount of clavulanic acid (as the potassium salt) than any other form of Augmentin suspension. Augmentin ES contains 42.9 mg of clavulanic acid per 5 mL of suspension, whereas Augmentin 200 mg/5 mL suspension contains 28.5 mg of clavulanic acid per 5 mL, and Augmentin 400 mg/5 mL suspension contains 57 mg of clavulanic acid per 5 mL. Therefore, Augmentin ES cannot be substituted for any other form of Augmentin suspension.
Renal impairment: No dose adjustment is required for patients with creatinine clearance (CrCl) greater than 30 mL/min.
This form of Augmentin is not recommended for use in patients with creatinine clearance less than 30 ml/min, as there are no recommendations for dose adjustment.
Hepatic impairment: Caution is recommended with regular monitoring of liver function (see sections "Contraindications" and "Special warnings and precautions for use").
Method of application
Augmentin ES is intended for oral use.
The drug should be taken with meals to minimize potential gastrointestinal intolerance.
Instructions for preparing the suspension.
Before use, check the integrity of the seal on the cap. Shake the bottle to loosen the powder. Add the required amount of water (as indicated below), invert and shake thoroughly. Another method: fill the bottle with water to just below the mark on the label, invert and shake thoroughly, then fill the bottle with water to the mark, invert and shake thoroughly again.
| Dosage | Volume of water to be added for dissolution (ml) | Final volume of reconstituted oral suspension (mL) |
| 600 mg/42.9 mg/5 ml | 90 | 100 |
The bottle should be shaken thoroughly before each use.
Children
The drug in the form of a suspension should be prescribed to children aged 3 months and older whose body weight does not exceed 40 kg. Children weighing more than 40 kg should be prescribed the drug in another dosage form.
Overdose
Symptoms
Gastrointestinal symptoms and fluid and electrolyte imbalance may occur. Amoxicillin-associated crystalluria has been reported, leading in some cases to renal failure (see section 4.4).
In patients with impaired renal function and in patients taking high doses of the drug, seizures may occur.
Amoxicillin has been reported to settle in bladder catheters, mainly after intravenous administration at high doses. Catheter patency should be checked regularly (see section 4.4).
Treatment
Gastrointestinal disturbances can be treated symptomatically, with attention to fluid/electrolyte balance.
Amoxicillin/clavulanic acid can be removed from the bloodstream by hemodialysis.
Side effects
The most commonly reported adverse drug reactions were diarrhea, nausea, and vomiting.
The list of adverse drug reactions known from clinical studies of Augmentin and post-marketing surveillance and classified by MedDRA system organ class is listed below.
The following classification of the frequency of side effects is used:
very often ≥ 1/10;
often ≥ 1/100 and < 1/10;
uncommon ≥ 1/1000 and < 1/100;
rare ≥ 1/10,000 and < 1/1,000;
very rare < 1/10,000;
not known (frequency cannot be estimated from the available data).
Infections and invasions.
Common: candidiasis of the skin and mucous membranes.
Not known: overgrowth of microorganisms insensitive to the drug.
Disorders of the hematopoietic and lymphatic systems.
Rare: reversible leukopenia (including neutropenia) and thrombocytopenia.
Not known: reversible agranulocytosis and haemolytic anaemia; increased bleeding time and prothrombin time1.
Heart disorders.
Unknown: Kunis syndrome.
Immune system disorders9
Not known: angioedema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.
Nervous system disorders.
Uncommon: dizziness, headache.
Not known: reversible hyperactivity and convulsions1.
Not known: aseptic meningitis.
Gastrointestinal disorders.
Common: diarrhea, nausea2, vomiting.
Uncommon: stomach upset.
Not known: antibiotic-associated colitis 3, black hairy tongue, tooth enamel discoloration 4.
Hepatobiliary disorders.
Uncommon: increased AST and/or ALT5.
Not known: hepatitis6 and cholestatic jaundice6.
Skin and subcutaneous tissue disorders7
Uncommon: skin rash, itching, urticaria.
Rare: erythema multiforme.
Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis1, drug reaction with eosinophilia and systemic symptoms (DRESS).
Kidney and urinary tract disorders.
Not known: interstitial nephritis, crystalluria8.
1 See section "Application features".
2 Nausea is more commonly associated with higher oral doses of the drug. If gastrointestinal reactions occur, their severity may be reduced by taking Augmentin with food.
4 Discoloration of tooth enamel has been reported very rarely in children. Careful oral hygiene can prevent this discoloration, as it is removed by brushing.
5 Moderate elevations in AST and/or ALT levels were more frequently observed in patients treated with beta-lactam antibiotics, but the significance of these findings is unknown.
6 These phenomena have been observed with other penicillin and cephalosporin antibiotics (see section "Special warnings and precautions for use").
7 If hypersensitivity reactions (dermatitis) occur, the use of the drug should be discontinued (see section "Special instructions").
8 See section “Overdose”
9 See section “Contraindications” and “Special instructions for use”.
Expiration date
2 years. Prepared suspension – 10 days.
Storage conditions
Store at a temperature not exceeding 25 ° C. Keep out of the reach of children.
Store the prepared suspension in a refrigerator at a temperature of 2 to 8 °C and use within 10 days. Do not freeze.
Packaging
Glass bottle with an aluminum screw cap (containing a polymer (polyvinyl chloride or polyolefin) film inside), with first-opening control or with a child-resistant plastic cap and a plastic measuring spoon with 2.5 ml and 5 ml markings, in a cardboard box.
Vacation category
According to the recipe.
Producer
SmithKline Beecham Pharmaceuticals, United Kingdom.
Location of the manufacturer and address of its place of business
SmithKline Beecham Pharmaceuticals, Clarendon Road, Worthing, BN14 8QH, United Kingdom.
