Instructions Augmentin film-coated tablets 500 mg + 125 mg blister No. 14
Composition
active ingredients: amoxicillin, clavulanic acid;
1 tablet contains amoxicillin (in the form of amoxicillin trihydrate) 500 mg, clavulanic acid (in the form of potassium clavulanate) 125 mg;
Excipients: colloidal anhydrous silica, sodium starch glycolate (type A), magnesium stearate, microcrystalline cellulose, titanium dioxide (E 171), hydroxypropylmethylcellulose, macrogol 4000, macrogol 6000, dimethicone.
Dosage form
Film-coated tablets.
Main physicochemical properties: white or off-white, oval-shaped, film-coated tablets, marked "AC" and scored on one side.
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 referred to as 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 organisms 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 exhibit clinically useful antibacterial effects.
FC/FD ratio
The time above the minimum inhibitory concentration (MIC) is considered the main factor determining the efficacy of amoxicillin.
Resistance mechanisms
There are two mechanisms of resistance to amoxicillin/clavulanic acid:
- inactivation by bacterial beta-lactamases that are not inhibited by clavulanic acid themselves, including class B, C and D;
- conversion of PZB, which reduces the affinity of the antibacterial drug to the target.
Bacterial impermeability or the reflux pump mechanism can cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.
Limit values
MIC breakpoints for amoxicillin/clavulanic acid established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)
| Microorganisms | Sensitivity breakpoints (μg/mL) |
| Sensitive | Moderately sensitive | Resistant | |
| Haemophilus influenzae1 | ≤1 | - | > 1 |
| Moraxella catarrhalis1 | ≤1 | - | > 1 |
| Staphylococcus aureus 2 | ≤2 | - | >2 |
| Coagulase-negative staphylococci 2 | ≤ 0.25 | > 0.25 | |
| Enterococcus1 | ≤4 | 8 | > 8 |
| Streptococcus A, B, C, G5 | ≤ 0.25 | - | > 0.25 |
| Streptococcus pneumoniae3 | ≤ 0.5 | 1–2 | >2 |
| Enterobacteriaceae 1, 4 | - | - | > 8 |
| Gram-negative anaerobic bacteria 1 | ≤4 | 8 | > 8 |
| Gram-positive anaerobic bacteria 1 | ≤4 | 8 | > 8 |
| Limit values not specific to specific species 1 | ≤2 | 4–8 | > 8 |
| 1 Reported values for amoxicillin concentrations. For the purpose of susceptibility testing, the clavulanic acid concentration was set at 2 mg/L.2 Reported values for oxacillin concentrations.3 The breakpoints in the table are calculated from the breakpoints for ampicillin.4 A resistance breakpoint of R>8 mg/L means that all strains with resistance mechanisms are declared resistant.5 The breakpoints in the table are calculated from the breakpoints 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: Enterococcus faecalis, Gardnerella vaginalis, Staphylococcus aureus (methicillin-susceptible)£, Coagulase-negative staphylococci (methicillin-susceptible), Streptococcus agalactiae, Streptococcus pneumoniae1, Streptococcus pyogenes and other beta-hemolytic streptococci, Streptococcus viridans group. Gram-negative aerobes: Capnocytophaga spp., Eikenella corrodens, Haemophilus influenzae2, Moraxella catarrhalis, Pasteurella multocida. Anaerobes: Bacteroides fragilis, Fusobacterium nucleatum, Prevotella spp. |
| Species for which resistance acquisition may be a problem |
| Gram-positive aerobes: Enterococcus faecium$. Gram-negative aerobes: Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris. |
| Naturally resistant microorganisms |
Gram-negative aerobes: Acinetobacter sp., Citrobacter freundii, Enterobacter sp., Legionella pneumophila, Morganella morganii, Providencia spp., Pseudomonas sp., Serratia sp., Stenotrophomonas maltophilia. Other microorganisms: Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetti, Mycoplasma pneumoniae | | $ Inherent moderate susceptibility in the absence of acquired resistance mechanisms.£ All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid.1 Streptococcus pneumoniae resistant to penicillin should not be treated with this formulation of amoxicillin/clavulanic acid (see sections 4.2 and 4.4).2 Strains with reduced susceptibility have been reported in some EU countries with a frequency above 10%. |
Pharmacokinetics.
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.
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, abdominal tissue, 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 penicilloic 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. In the case of clavulanic acid, the largest amount of the substance 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").
Age. The half-life of amoxicillin is identical for children aged 3 months to 2 years, older children and adults. For children (including premature infants) in the first week of life, the frequency of administration should not exceed twice a day due to the immaturity of the renal excretion pathway. Since elderly patients are more prone to decreased renal function, dosage should be selected with caution, and monitoring of renal function is also recommended.
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. Patients with hepatic insufficiency are recommended to use the drug with caution and regularly monitor liver function.
Indication
Treatment of bacterial infections caused by microorganisms sensitive to Augmentin, such as:
- acute bacterial sinusitis (confirmed);
- acute otitis media;
- confirmed exacerbation of chronic bronchitis;
- community-acquired pneumonia;
- cystitis;
- pyelonephritis;
- skin and soft tissue infections, including cellulitis, animal bites, severe dentoalveolar abscesses with widespread cellulitis;
- infections of bones and joints, including osteomyelitis.
Contraindication
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/clavulanate.
Interaction with other medicinal products and other types of interactions
Oral anticoagulants
Oral anticoagulants and penicillin antibiotics are widely used in clinical practice without any reports of interactions. However, cases of increased international normalization ratio have been described in patients taking acenocoumarol or warfarin 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 4.4 and 4.8).
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 anaphylactic reactions and severe cutaneous adverse reactions) have been reported in patients treated with penicillin. 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.
This formulation of Augmentin is not suitable for use where there is a high risk that the likely causative agents have reduced susceptibility or resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. This formulation should not be used for the treatment of penicillin-resistant S. pneumoniae.
In patients with impaired renal function and in patients taking high doses of the drug, seizures may occur (see section "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.
Hepatic complications have been reported predominantly in men and elderly patients and may be associated with long-term treatment. Such complications have been reported very rarely in children. In all patient groups, symptoms usually occur during or shortly 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 extremely rare cases, fatal. Such events have almost always been observed in patients with severe underlying disease or in those taking concomitant medications with a known potential to cause hepatic complications (see section 4.8).
Antibiotic-associated colitis has been reported with nearly all antibacterial agents, including amoxicillin, and may range in severity from mild to life-threatening (see Adverse Reactions). Therefore, it is important to consider this diagnosis in patients who present with diarrhea during or after taking any antibiotic. If antibiotic-associated colitis occurs, Augmentin should be discontinued immediately, medical attention should be sought, and appropriate treatment should be initiated. The use of anti-peristaltic agents is contraindicated in such cases.
With prolonged therapy, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is recommended.
Prolonged prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring should be performed when anticoagulants are administered concomitantly. Dosage adjustment of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see Interactions with other medicinal products and other forms of interaction and Adverse reactions).
In patients with renal impairment, the dose should be adjusted depending on the degree of impairment (see section "Method of administration and dosage").
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 amoxicillin-associated crystalluria. 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 urine, since there is a possibility of obtaining false-positive results when using non-enzymatic methods.
The presence of clavulanic acid in Augmentin may lead to nonspecific binding of IgG and albumin to 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 using the Bio-Rad Laboratories Platelia Aspergillus enzyme immunoassay.
Therefore, positive test results in patients receiving amoxicillin/clavulanic acid treatment should be interpreted with caution and confirmed by other diagnostic methods.
Use during pregnancy or breastfeeding
Pregnancy. Animal reproduction studies with oral and parenteral forms of Augmentin have not revealed any teratogenic effects. In one study involving women with premature rupture of membranes, it was reported that prophylactic use of Augmentin may be associated with an increased risk of necrotizing enterocolitis in the newborn. As with other drugs, use of the drug should be avoided during pregnancy, especially during the first trimester, 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. Augmentin can be used during breastfeeding only if, in the opinion of the doctor, 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 reactions 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 (see the section "Adverse reactions").
Method of administration and doses
The product should be used in accordance with official antibiotic treatment guidelines and local antibiotic susceptibility data. Susceptibility to amoxicillin/clavulanate varies between regions and may change over time. Local susceptibility data should be consulted and, if necessary, microbiological identification and susceptibility testing should be performed.
If necessary, alternative formulations of Augmentin (i.e. those providing higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered (see sections 4.4 and 5.1).
The range of suggested doses depends on the expected pathogens and their sensitivity to antibacterial drugs, the severity of the disease and the location of the infection, the age, body weight and renal function of the patient.
For adults and children weighing ≥ 40 kg, the total daily dose is 1500 mg amoxicillin/375 mg clavulanic acid (3 tablets) when administered as indicated below.
For children aged 6 years and over with a body weight of 25 to 40 kg, the maximum daily dose is 2400 mg amoxicillin/600 mg clavulanic acid (4 tablets) when administered as indicated below.
If higher doses of amoxicillin are required for treatment, other forms of Augmentin should be used to avoid prescribing excessively high doses of clavulanic acid.
The duration of treatment is determined by the patient's clinical response to treatment. Some infections (e.g. osteomyelitis) require longer treatment. Treatment should not exceed 14 days without review (see section 4.4 for long-term therapy).
Adults and children weighing ≥ 40 kg
1 tablet of Augmentin 500 mg/125 mg 3 times a day.
Children aged 6 years and over with a body weight of 25 to 40 kg
Dose from 20 mg/5 mg/kg body weight/day to 60 mg/15 mg/kg body weight/day, divided into 3 doses.
Since the tablet cannot be divided, this form of Augmentin is not prescribed to children weighing less than 25 kg.
Elderly patients
No dose adjustment is required for elderly patients. If necessary, the dose is adjusted depending on renal function.
Dosage in renal impairment
Dosage is based on the calculation of the maximum amoxicillin level. There is no need to change the dose for a patient with a creatinine clearance > 30 ml/min.
Adults and children weighing ≥ 40 kg
| Creatinine clearance 10–30 ml/min | 500 mg/125 mg twice daily |
| Creatinine clearance < 10 mL/min | 500 mg/125 mg once daily |
| Hemodialysis | 500 mg/125 mg every 24 hours plus 500 mg/125 mg during dialysis and again at the end of dialysis (as plasma concentrations of amoxicillin and clavulanic acid are reduced) |
Children aged 6 years and over with a body weight of 25 to 40 kg
Since the tablet cannot be divided, this form of Augmentin is not prescribed to children weighing 25 to 40 kg, with a creatinine clearance of less than 30 ml/min, or to children on hemodialysis.
Dosage in hepatic impairment
Use with caution; liver function should be monitored regularly.
The tablet should be swallowed whole without chewing. If necessary, to make swallowing easier, the tablet can be broken in half and the halves swallowed without chewing.
The drug should be taken with meals to minimize potential gastrointestinal intolerance.
The duration of treatment is determined individually. Treatment should not be continued for more than 14 days without assessing the patient's condition.
Treatment can be started parenterally and then continued orally.
Children.
This form of Augmentin is used in children aged 6 years and older with a body weight of at least 25 kg.
Overdose
Symptoms
Gastrointestinal symptoms and fluid and electrolyte imbalance may occur. Amoxicillin-associated crystalluria has been reported, leading in isolated 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.
Adverse reactions
The most frequently reported adverse drug reactions (ADRs) 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 provided 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.
Rare: reversible leukopenia (including neutropenia) and thrombocytopenia.
Not known: reversible agranulocytosis and haemolytic anaemia; increased bleeding time and prothrombin time1.
Immune system disorders10.
Not known: angioedema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.
Nervous system disorders.
Uncommon: dizziness, headache.
Not known: reversible hyperactivity and convulsions2.
Not known: aseptic meningitis.
Gastrointestinal disorders.
Common: diarrhea, nausea3, vomiting.
Uncommon: stomach upset.
Not known: antibiotic-associated colitis 4, "black hairy tongue", tooth enamel discoloration 11.
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 pustulosis9, drug reaction with eosinophilia and systemic symptoms (DRESS).
Kidney and urinary tract disorders.
Very rare: interstitial nephritis, crystalluria8.
1 See section "Application features".
2 See section "Application features".
3 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 Including pseudomembranous colitis and hemorrhagic colitis (see section "Special warnings and precautions for use").
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 "Application features".
10 See section “Contraindications” and “Special instructions for use”.
11 Discoloration of tooth enamel has been reported very rarely in children. Careful oral hygiene can prevent such discoloration, as it is removed by brushing.
Expiration date
3 years. After opening the foil package – 30 days.
Storage conditions
Store below 25 °C. Keep out of the reach of children.
Packaging
7 tablets in a blister in an aluminum foil bag together with moisture-proof granules-sachets. 2 blisters in bags in a cardboard box.
Vacation category
According to the recipe.
Producer
SmithKline Beecham Pharmaceuticals, United Kingdom.
SmithKline Beecham Pharmaceuticals, United Kingdom.
Location of the manufacturer and its business address
SmithKline Beecham Pharmaceuticals, Clarendon Road, Worthing, BN14 8QH, United Kingdom.
SmithKline Beecham Pharmaceuticals, Clarendon Road, Worthing, BN14 8QH, United Kingdom.
