Augmentin es

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AUGMENTIN ES (AUGMENTINES)

Composition:

Active substances: amoxicillin, clavulanic acid;

1 vial contains powder for the preparation of 100 ml of suspension with the following composition:

5 ml of suspension contain amoxicillin (as amoxicillin trihydrate) 600 mg and clavulanic acid (as potassium clavulanate) 42.9 mg;

Excipients: silicon dioxide colloidal anhydrous, sodium carboxymethylcellulose 12, aspartame (E 951), xanthan gum, silicon dioxide, artificial strawberry flavoring.

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties: free-flowing, nearly white powder with a characteristic strawberry odor.

Pharmacotherapeutic group. Antibacterials for systemic use. Beta-lactam antibiotics. Penicillins. Combinations of penicillins with beta-lactamase inhibitors. ATC code J01CR02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Amoxicillin is a semisynthetic penicillin (a beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) involved in the biosynthetic metabolism of bacterial peptidoglycan, an essential 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 degradation by beta-lactamases produced by resistant bacteria; therefore, the antimicrobial spectrum of amoxicillin as monotherapy does not include microorganisms that produce these enzymes.

Clavulanic acid is a beta-lactam compound structurally related to penicillins. It inactivates certain beta-lactamase enzymes, thereby preventing the inactivation of amoxicillin. Clavulanic acid has no clinically useful antibacterial activity when used alone.

PK/PD relationship

The time during which drug concentration remains above the minimum inhibitory concentration (T>MIC) 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 themselves inhibited by clavulanic acid, including classes B, C, and D;
• Alteration of PBPs, leading to reduced affinity of the antibacterial agent for its target.

Bacterial impermeability or efflux pump mechanisms may contribute to or cause bacterial resistance, particularly in Gram-negative bacteria.

Clinical breakpoints

The minimum inhibitory concentration (MIC) clinical breakpoints for amoxicillin/clavulanic acid, established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)

1 For susceptibility testing, the concentration of clavulanic acid is set at 2 mg/l.

2 Most S. aureus produce penicillinase, and some are methicillin-resistant. Either mechanism confers resistance to benzylpenicillin, phenoxymethylpenicillin, ampicillin, amoxicillin, piperacillin, and ticarcillin. Isolates susceptible to benzylpenicillin and cefoxitin may be reported as susceptible to all penicillins. Isolates resistant to benzylpenicillin but susceptible to cefoxitin are susceptible to beta-lactamase inhibitor combinations, isoxazolylpenicillins (oxacillin, cloxacillin, dicloxacillin, and flucloxacillin), and nafcillin. When using oral agents, caution should be exercised to ensure adequate exposure at the site of infection. Isolates resistant to cefoxitin are resistant to all penicillins.

3 Most staphylococci produce penicillinase, and some are methicillin-resistant. Either mechanism confers resistance to benzylpenicillin, phenoxymethylpenicillin, ampicillin, amoxicillin, piperacillin, and ticarcillin. None of the currently available methods can reliably detect penicillinase production in all staphylococcal species, but methicillin resistance can be detected using cefoxitin, as described.

4 S. saprophyticus susceptible to ampicillin are mecA-negative and susceptible to ampicillin, amoxicillin, and piperacillin (with or without beta-lactamase inhibitor).

5 Aminopenicillin breakpoints for enterococci are defined for intravenous administration. Oral administration is relevant only for urinary tract infections.

6 Susceptibility to ampicillin, amoxicillin, and piperacillin (with or without beta-lactamase inhibitor) can be inferred from ampicillin testing. Resistance to ampicillin is rare in E. faecalis (confirm by MIC), but common in E. faecium.

7 Addition of a beta-lactamase inhibitor provides no clinical benefit.

8 Susceptibility of group A, B, C, and G streptococci to penicillins is based on susceptibility to benzylpenicillin (other indications except meningitis), except for phenoxymethylpenicillin and isoxazolylpenicillins for group B streptococci.

9 Benzylpenicillin (MIC or disk diffusion) can be used for screening beta-lactam resistance in Viridans group streptococci. Isolates classified as negative on screening may be reported as susceptible to beta-lactam agents for which clinical breakpoints are provided (including those with a "Note"). Isolates classified as positive on screening should be tested for susceptibility to individual agents or reported as resistant.

10 For isolates with a negative benzylpenicillin screening result (inhibition zone ≥ 18 mm or MIC ≤ 0.25 mg/l), susceptibility may be reported based on benzylpenicillin or ampicillin. For isolates positive to benzylpenicillin (inhibition zone < 18 mm or MIC > 0.25 mg/l), susceptibility should be determined based on ampicillin.

The prevalence of resistance may vary geographically and over time for individual species; therefore, local susceptibility data are desirable, especially when treating severe infections. Expert advice should be sought when local resistance prevalence is such that the utility of the agent, at least for certain types of infection, is questionable.

Pharmacokinetics.

Absorption. Amoxicillin and clavulanic acid completely dissociate in aqueous solution at physiological pH levels. Both components are rapidly and well absorbed following oral administration. The bioavailability of amoxicillin and clavulanic acid is approximately 70% following oral administration. The plasma profiles of both components are identical, and the time to reach maximum plasma concentration (T_max) for each component is approximately one hour.

The mean pharmacokinetic parameters of Augmentin ES when administered to children at a dose of 45 mg/3.2 mg/kg body weight every 12 hours are presented in the table:

*Mean (range)

Serum concentrations of amoxicillin and clavulanic acid achieved after administration of amoxicillin/clavulanic acid are identical to those achieved after oral administration of equivalent doses of amoxicillin or clavulanic acid alone.

Distribution. Approximately 25% of total clavulanic acid in plasma and 18% of total amoxicillin in plasma 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 detected in the gallbladder, peritoneum, skin, adipose tissue, muscle tissue, synovial and peritoneal fluids, bile, and pus. Amoxicillin does not adequately distribute into cerebrospinal fluid.

Animal studies have not revealed any evidence of significant retention of substances derived from either component of the drug in body tissues. Amoxicillin, like most penicillins, may be detected in breast milk. A small amount of clavulanic acid may also be detected in breast milk (see section "Use during pregnancy or lactation").

It has been demonstrated that both amoxicillin and clavulanic acid cross the placental barrier (see section "Use during pregnancy or lactation").

Biological transformation. Amoxicillin is partially excreted in urine as inactive penicilloic acid in amounts equivalent to 10–25% of the initial dose. Clavulanic acid is extensively metabolized in the human body and excreted in urine and feces, as well as in the form of carbon dioxide in exhaled air.

Elimination. The primary route of elimination for amoxicillin is via the kidneys, whereas clavulanic acid is eliminated both by the kidneys and through 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 urinary excretion of 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 administration of probenecid slows the elimination of amoxicillin but does not delay the renal excretion of clavulanic acid (see section "Interaction with other medicinal products and other forms of interaction").

Renal impairment. Total serum clearance of amoxicillin/clavulanic acid decreases proportionally with reduced renal function. The reduction in clearance is more pronounced for amoxicillin than for clavulanic acid, since a larger fraction of amoxicillin is eliminated by the kidneys. In renal impairment, dosing should prevent excessive accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section "Method of administration and dosage").

Hepatic impairment. Caution is recommended in patients with hepatic impairment, with regular monitoring of liver function.

Clinical characteristics.

Indications.

Infections in children aged 3 months and older, whose body weight does not exceed 40 kg, caused or likely caused by penicillin-resistant strains of Streptococcus pneumoniae, such as:

• acute otitis media;
• community-acquired pneumonia.

When prescribing antibacterial agents, the principles of their appropriate use should be followed.

Contraindications.

Hypersensitivity to any component of the medicinal product, or to any penicillin-group antibacterial agents.

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 hepatic dysfunction associated with the use of amoxicillin/clavulanic acid.

Interaction with other medicinal products and other forms of interaction.

Oral anticoagulants

Oral anticoagulants and penicillin-class antibiotics are widely used in clinical practice without reports of interaction. However, cases of increased international normalized ratio (INR) have been reported in patients receiving acenocoumarol or warfarin who were prescribed a course of amoxicillin therapy. If concomitant use of these agents is necessary, prothrombin time or INR should be carefully monitored when initiating or discontinuing amoxicillin. Dose adjustment of oral anticoagulants may also be required (see sections "Special precautions for use" and "Adverse reactions").

Methotrexate

Penicillins may reduce the renal clearance of methotrexate, potentially increasing its toxicity.

Probenecid

Concomitant use of probenecid is not recommended. Probenecid decreases renal tubular secretion of amoxicillin. Concurrent administration may lead to increased levels and prolonged presence of amoxicillin (but not clavulanic acid) in the blood.

Mycophenolate mofetil

In patients receiving mycophenolate mofetil, administration of oral amoxicillin with clavulanic acid may reduce the pre-dose concentration of the active metabolite, mycophenolic acid, by approximately 50%. This change in pre-dose concentration may not fully reflect changes in total exposure to mycophenolic acid. Therefore, dosage adjustment of mycophenolate mofetil is usually not required unless there is clinical evidence of graft dysfunction. However, careful monitoring is necessary during concomitant use and for some time after completion of antibiotic therapy.

Special precautions for use

Before initiating therapy with amoxicillin/clavulanic acid, a careful assessment of previous hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents should be performed (see sections "Contraindications" and "Side effects").

Serious and, in some cases, fatal hypersensitivity reactions (including anaphylactoid reactions and severe skin adverse reactions) have been reported in patients receiving penicillin therapy. Hypersensitivity reactions may also progress to Kounis syndrome — a serious allergic reaction that may lead to myocardial infarction (see section "Side effects"). Such reactions are more likely to occur in patients with a history of penicillin hypersensitivity and in patients with atopic diseases. Cases of drug-induced enterocolitis syndrome (DIES) have been reported, primarily in children receiving amoxicillin/clavulanic acid (see section "Side effects"). Drug-induced enterocolitis syndrome is an allergic reaction characterized primarily by persistent vomiting (1–4 hours after drug administration) in the absence of allergic skin or respiratory symptoms. Additional symptoms may include abdominal pain, diarrhea, hypotension, or leukocytosis with neutrophilia. Severe cases have been reported, including progression to shock. If an allergic reaction occurs, amoxicillin/clavulanic acid should be discontinued and appropriate alternative therapy initiated.

If an infection is confirmed to be caused by microorganism(s) susceptible to amoxicillin alone, switching from amoxicillin/clavulanic acid to amoxicillin should be considered in accordance with established guidelines.

Seizures may occur in patients with impaired renal function and in those receiving high doses of the drug (see "Side effects").

Amoxicillin/clavulanic acid should be avoided in suspected cases of infectious mononucleosis, as administration of amoxicillin has been associated with the development of a maculopapular rash.

Concomitant use of allopurinol during amoxicillin therapy increases the likelihood of developing skin allergic reactions.

Prolonged use may, in some cases, lead to overgrowth of microorganisms not susceptible to the drug.

The onset of fever-associated generalized erythema with pustule formation at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis (AGEP) (see section "Side effects"). This reaction requires discontinuation of Augmentin and constitutes a contraindication for further use of amoxicillin.

Amoxicillin/clavulanic acid should be used with caution in patients showing signs of hepatic impairment (see sections "Dosage and administration", "Contraindications", "Side effects").

Hepatic complications have been reported primarily in men and elderly patients receiving prolonged treatment. Reports in children are very rare. In all patient groups, symptoms typically occur during or after treatment, although in some cases they may only manifest several weeks after therapy has ended. These effects are usually reversible. Hepatic complications may be severe and, in very rare isolated cases, fatal. Such events have always occurred in patients with severe underlying disease or in those receiving concomitant medications known to cause hepatic complications (see section "Side effects").

Antibiotic-associated colitis, varying in severity from mild to life-threatening, has been reported with nearly all antibacterial agents, including amoxicillin (see section "Side effects"). Therefore, this diagnosis should be considered in patients presenting with diarrhea during or after antibiotic use. If antibiotic-associated colitis occurs, Augmentin should be discontinued immediately, medical advice should be sought, and appropriate treatment initiated. Antiperistaltic agents are contraindicated in such cases.

With prolonged therapy, periodic monitoring of organ system functions, including renal, hepatic, and hematopoietic function, is recommended.

Prolongation of the prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring is required when anticoagulants are co-administered. Dose adjustment of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").

Crystalluria (including acute kidney injury) has been observed very rarely in patients with reduced urine output, primarily during parenteral therapy. Adequate fluid intake and diuresis should be maintained during high-dose amoxicillin therapy to reduce the risk of amoxicillin-related crystalluria. In patients with urinary catheters, catheter patency should be checked regularly (see sections "Side effects" and "Overdose").

During amoxicillin therapy, enzymatic methods (glucose oxidase) should be used to test for glucose in urine, as non-enzymatic methods may yield false-positive results.

The presence of clavulanic acid in Augmentin may lead to non-specific binding of IgG and albumin to erythrocyte membranes, resulting in false-positive Coombs test results.

Positive results in the enzyme immunoassay using Platelia Aspergillus (Bio-Rad Laboratories) have been reported in patients receiving amoxicillin/clavulanic acid, despite subsequent confirmation of absence of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses have been reported when using the Platelia Aspergillus enzyme immunoassay (Bio-Rad Laboratories). 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, a source of phenylalanine; therefore, the product should be administered with caution to patients with phenylketonuria.

The medicinal product contains maltodextrin (glucose). It should not be used in patients with the rare hereditary fructose intolerance or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding

Pregnancy. Animal studies do not indicate any direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development. Limited human data on the use of amoxicillin/clavulanic acid during pregnancy do not suggest an increased risk of congenital malformations. In a single study in women with preterm rupture of membranes, prophylactic treatment with amoxicillin/clavulanic acid was associated with an increased risk of necrotizing enterocolitis in neonates. The drug should be avoided during pregnancy unless, in the opinion of the physician, its use is considered necessary.

Breastfeeding period . Both active components of the drug are excreted in breast milk (there is no information on the effect of clavulanic acid on the breastfed infant). Diarrhea and fungal infections of mucous membranes may therefore occur in the breastfed infant, and breastfeeding should be discontinued. The possibility of allergic reactions should also be considered. Amoxicillin/clavulanic acid may be used during breastfeeding only if, in the physician’s opinion, the benefit outweighs the risk.

Ability to affect reaction speed when driving vehicles or operating machinery

Studies on the ability of the drug to affect reaction speed while driving vehicles or operating machinery have not been conducted. However, undesirable effects (such as allergic reactions, dizziness, seizures) may occur, which could impair the ability to drive or operate machinery.

Dosage and Administration

Dosage is expressed in terms of amoxicillin/clavulanic acid content, except when dosage is specified in terms of a single component.

When selecting the dosage of Augmentin for treatment of a specific infection, the following should be considered:

• likely pathogens and their probable susceptibility to antibacterial agents (see section "Special Warnings and Precautions for Use");
• severity and site of infection;
• patient's age, body weight, and renal function, as indicated below.

The duration of treatment should not exceed 14 days without review (see section "Special Warnings and Precautions for Use" regarding prolonged therapy).

Adults and children with body weight ≥ 40 kg

There is no experience with the use of Augmentin oral suspension in adults and children with body weight ≥ 40 kg; therefore, dosage recommendations for these patient groups are not available.

Children aged 3 months to less than 40 kg body weight

The recommended dose of Augmentin oral suspension is 90/6.4 mg/kg body weight/day, divided into two doses.

Augmentin ES contains a different amount of clavulanic acid (in the form of potassium salt) compared to any other Augmentin suspension formulation. Augmentin ES contains 42.9 mg of clavulanic acid per 5 mL of suspension, whereas the Augmentin 200 mg/5 mL suspension contains 28.5 mg of clavulanic acid per 5 mL, and the 400 mg/5 mL suspension contains 57 mg of clavulanic acid per 5 mL. Therefore, Augmentin ES cannot be substituted with any other Augmentin suspension formulation.

Renal impairment. Dose adjustment is not required in patients with creatinine clearance (CrCl) greater than 30 mL/min.

Augmentin ES is not recommended for patients with creatinine clearance less than 30 mL/min, as there are no recommendations for dose adjustment in this population.

Hepatic impairment. Caution is recommended with regular monitoring of liver function (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Administration

Augmentin ES is intended for oral administration.

The medicine should be taken with food to minimize potential gastrointestinal intolerance.

Instructions for reconstitution of 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 the bottle, and shake vigorously. Alternative method: fill the bottle with water up to slightly below the mark on the label, invert and shake thoroughly, then fill the bottle with water up to the mark, invert again, and shake thoroughly.

Shake the bottle well before each use.

Children.

The suspension formulation of the drug should be administered to children aged 3 months and older whose body weight does not exceed 40 kg. Children with body weight above 40 kg should be administered the drug in another pharmaceutical form.

Overdose.

Symptoms

Symptoms typical of gastrointestinal disturbances and fluid and electrolyte imbalance may occur. Crystalluria associated with amoxicillin intake has been observed, which in some cases led to the development of renal failure (see section "Special precautions for use").

Seizures may occur in patients with impaired renal function and in patients receiving high doses of the drug.

Precipitation of amoxicillin in urinary catheters has been reported, primarily after high-dose intravenous administration. The patency of catheters should be checked regularly (see section "Special precautions for use").

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 reactions to the medication are diarrhea, nausea, and vomiting.

The list of known adverse drug reactions from clinical trials of Augmentin and post-marketing surveillance, classified by MedDRA system organ class, is provided below.

The following classification of frequency of adverse reactions is used:

very common ≥ 1/10;
common ≥ 1/100 to < 1/10;
uncommon ≥ 1/1000 to < 1/100;
rare ≥ 1/10000 to < 1/1000;
very rare < 1/10000;
not known (frequency cannot be estimated from available data).

Infections and infestations.

Common: candidiasis of skin and mucous membranes.
Not known: overgrowth of microorganisms not sensitive to the medication.

Blood and lymphatic system disorders.

Rare: reversible leukopenia (including neutropenia) and thrombocytopenia.
Not known: reversible agranulocytosis and hemolytic anemia; prolonged bleeding time and prothrombin index1.

Cardiac disorders.

Not known: Quincke's syndrome.

Immune system disorders 9.

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 disorders.
Not known: antibiotic-associated colitis3, black hairy tongue, discoloration of tooth enamel4, drug-induced enterocolitis syndrome (DIES), acute pancreatitis.

Hepatobiliary disorders.

Uncommon: increased levels of AST and/or ALT5.
Not known: hepatitis6 and cholestatic jaundice6.

Skin and subcutaneous tissue disorders 7.

Uncommon: skin rashes, pruritus, urticaria.
Rare: erythema multiforme.
Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative bullous dermatitis, acute generalized exanthematous pustulosis1, drug reaction with eosinophilia and systemic symptoms (DRESS), linear IgA disease.

Renal and urinary disorders.

Not known: interstitial nephritis, crystalluria8 (including acute kidney injury).

1 See section "Special precautions for use".

2 Nausea is more frequently associated with higher oral doses of the medication. The severity of gastrointestinal reactions may be reduced by taking Augmentin with food.

3 Includes pseudomembranous colitis and hemorrhagic colitis (see section "Special precautions for use").

4 Discoloration of tooth enamel has been very rarely reported in children. Careful oral hygiene may prevent such discoloration, as this phenomenon can be resolved by tooth brushing.

5 Mild elevations in AST and/or ALT levels have been more frequently observed in patients receiving beta-lactam antibiotics, but the clinical significance of these findings is unknown.

6 These events have been observed with other penicillin and cephalosporin antibiotics (see section "Special precautions for use").

7 If hypersensitivity reactions (dermatitis) occur, the medication should be discontinued (see section "Special precautions for use").

8 See section "Overdose".

9 See section "Contraindications" and "Special precautions for use".

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life.

2 years. Prepared suspension – 10 days.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep out of reach of children.

The prepared suspension should be stored in a refrigerator at 2 to 8 °C and used within 10 days. Do not freeze.

Packaging. Glass bottle with a screw aluminum cap (containing an internal polymer (polyvinyl chloride or polyolefin) film), with a tamper-evident seal or with a child-resistant plastic cap, and a plastic measuring spoon marked with 2.5 mL and 5 mL graduations, in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Glaxo Wellcome Production, France.

Manufacturer's address and place of business.

Glaxo Wellcome Production, ZI de la Peyenniere, 53100 Mayenne, France.

Marketing Authorization Holder's representative.

LLC "GlaxoSmithKline Pharmaceuticals Ukraine".

Address of the Marketing Authorization Holder's representative.

1-V, Pavla Tychyny Avenue, Kyiv, 02152, Ukraine. Tel: (044) 585-51-85, Fax: (044) 585-51-92.

Additionally, all cases of suspected adverse reactions and lack of efficacy may be reported to LLC "GlaxoSmithKline Pharmaceuticals Ukraine" via the 24-hour hotline (044) 585-51-85 or by email at [email protected].

INSTRUCTION

for medical use of the medicinal product

AUGMENTIN ES

(AUGMENTINES)

Composition:

Active substances: amoxicillin, clavulanic acid;

1 vial contains powder for the preparation of 100 ml of suspension with 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 flavoring.

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties: free-flowing, almost white-colored powder with a characteristic strawberry odor.

Pharmacotherapeutic group. Antibacterials for systemic use. Beta-lactam antibiotics. Penicillins. Combinations of penicillins with beta-lactamase inhibitors. ATC code J01CR02.

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) involved in the biosynthetic metabolism of bacterial peptidoglycan, an essential 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 degradation by beta-lactamases produced by resistant bacteria; therefore, the antimicrobial spectrum of amoxicillin as monotherapy does not include microorganisms producing these enzymes.

Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates certain beta-lactamase enzymes, thereby preventing the inactivation of amoxicillin. Clavulanic acid has no clinically useful antibacterial activity when used alone.

PK/PD relationship

The time during which the drug concentration remains above the minimum inhibitory concentration (T>MIC) 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 themselves inhibited by clavulanic acid, including classes B, C, and D;
• Modification of PBPs, reducing the affinity of the antibacterial agent for its target.

Reduced bacterial permeability or efflux pump mechanisms may contribute to or cause bacterial resistance, particularly in Gram-negative bacteria.

Clinical breakpoints

The minimum inhibitory concentration (MIC) breakpoints for amoxicillin/clavulanic acid established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

1 For susceptibility testing, the concentration of clavulanic acid is set at 2 mg/l.

2 Most S. aureus produce penicillinase, and some are methicillin-resistant. Either mechanism confers resistance to benzylpenicillin, phenoxymethylpenicillin, ampicillin, amoxicillin, piperacillin, and ticarcillin. Isolates susceptible to both benzylpenicillin and cefoxitin may be reported as susceptible to all penicillins. Isolates resistant to benzylpenicillin but susceptible to cefoxitin are susceptible to beta-lactamase inhibitor combinations, isoxazolylpenicillins (oxacillin, cloxacillin, dicloxacillin, and flucloxacillin), and nafcillin. When administering oral agents, caution should be exercised to ensure adequate exposure at the site of infection. Isolates resistant to cefoxitin are resistant to all penicillins.

3 Most staphylococci produce penicillinase, and some are methicillin-resistant. Either mechanism confers resistance to benzylpenicillin, phenoxymethylpenicillin, ampicillin, amoxicillin, piperacillin, and ticarcillin. None of the currently available methods can reliably detect penicillinase production in all staphylococcal species, but methicillin resistance can be detected using cefoxitin as described.

4 S. saprophyticus susceptible to ampicillin are mecA-negative and susceptible to ampicillin, amoxicillin, and piperacillin (with or without beta-lactamase inhibitor).

5 Aminopenicillin breakpoints for enterococci are defined for intravenous administration. Oral administration is relevant only for urinary tract infections.

6 Susceptibility to ampicillin, amoxicillin, and piperacillin (with or without beta-lactamase inhibitor) can be inferred from ampicillin testing. Resistance to ampicillin is rare in E. faecalis (confirm by MIC), but common in E. faecium.

7 Addition of a beta-lactamase inhibitor provides no clinical benefit.

8 Susceptibility of groups A, B, C, and G streptococci to penicillins is determined based on susceptibility to benzylpenicillin (other indications except meningitis), except for phenoxymethylpenicillin and isoxazolylpenicillins for group B streptococci.

9 Benzylpenicillin (MIC or disk diffusion) can be used for screening beta-lactam resistance in Viridans group streptococci. Isolates classified as negative on screening may be reported as susceptible to beta-lactam agents for which clinical breakpoints are provided (including those with a "Note"). Isolates classified as positive on screening must be tested for susceptibility to individual agents or reported as resistant.

10 For isolates with a negative benzylpenicillin screening result (inhibition zone ≥ 18 mm or MIC ≤ 0.25 mg/l), susceptibility may be reported based on benzylpenicillin or ampicillin. For isolates positive to benzylpenicillin (inhibition zone < 18 mm or MIC > 0.25 mg/l), susceptibility is determined based on ampicillin.

Resistance prevalence may vary geographically and over time for individual species; therefore, local susceptibility data are desirable, especially when treating severe infections. Expert advice should be sought when local resistance prevalence is such that the utility of the agent, at least for certain types of infections, is questionable.

Pharmacokinetics.

Absorption. Amoxicillin and clavulanic acid completely dissociate in aqueous solution at physiological pH levels. Both components are rapidly and well absorbed following oral administration. The bioavailability of amoxicillin and clavulanic acid is approximately 70% following oral administration. The plasma profiles of both components are identical, and the time to reach maximum plasma concentration (Tmax) for each component is approximately one hour.

The mean pharmacokinetic parameters of Augmentin ES when administered to children at a dose of 45 mg/3.2 mg/kg body weight every 12 hours are presented in the table:

*Mean (range)

Serum concentrations of amoxicillin and clavulanic acid achieved after administration of amoxicillin/clavulanic acid are identical to those achieved after oral administration of equivalent doses of amoxicillin or clavulanic acid alone.

Distribution. Approximately 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin are protein-bound. The apparent volume of distribution is approximately 0.3–0.4 L/kg for amoxicillin and about 0.2 L/kg for clavulanic acid.

After intravenous administration, amoxicillin and clavulanic acid have been detected in the gallbladder, peritoneum, skin, adipose tissue, muscle tissue, synovial and peritoneal fluid, bile, and pus. Amoxicillin does not distribute adequately into cerebrospinal fluid.

Animal studies have not revealed any evidence of significant retention of substances derived from either component of the drug in body tissues. Amoxicillin, like most penicillins, may be detected in breast milk. A small amount of clavulanic acid may also be detected in breast milk (see section "Use in pregnancy or lactation").

It has been demonstrated that both amoxicillin and clavulanic acid cross the placental barrier (see section "Use in pregnancy or lactation").

Biological transformation. Amoxicillin is partially excreted in urine as inactive penicilloic acid in amounts equivalent to 10–25% of the initial dose. Clavulanic acid is extensively metabolized in the human body and excreted in urine and feces, as well as in the form of carbon dioxide in expired air.

Elimination. The primary route of elimination for amoxicillin is via the kidneys, whereas clavulanic acid is eliminated both by the kidneys and through extrarenal mechanisms.

In healthy volunteers, the mean elimination half-life of amoxicillin/clavulanic acid is approximately one hour, and the mean total clearance is about 25 L/h. Various studies have shown that urinary excretion amounts to 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 administration of probenecid slows the elimination of amoxicillin but does not delay renal excretion of clavulanic acid (see section "Interaction with other medicinal products and other forms of interaction").

Renal impairment. Total serum clearance of amoxicillin/clavulanic acid decreases proportionally with reduction in renal function. The reduction in clearance is more pronounced for amoxicillin than for clavulanic acid, as a larger fraction of amoxicillin is eliminated by the kidneys. In renal impairment, dosage adjustment should prevent excessive accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section "Posology and method of administration").

Hepatic impairment. Caution is recommended in patients with hepatic impairment, and regular monitoring of liver function is advised.

Clinical characteristics.

Indications.

Infections in children aged 3 months and older, whose body weight does not exceed 40 kg, caused or likely caused by penicillin-resistant strains of Streptococcus pneumoniae, such as:

• acute otitis media;
• community-acquired pneumonia.

When prescribing antibacterial agents, the principles of proper use should be followed.

Contraindications.

Hypersensitivity to any component of the medicinal product or to any antibacterial agent 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 hepatic dysfunction associated with the use of amoxicillin/clavulanic acid.

Interaction with other medicinal products and other forms of interaction.

Oral anticoagulants

Oral anticoagulants and penicillin-class antibiotics are widely used in clinical practice without reports of interaction. However, cases of increased international normalized ratio (INR) have been reported in patients receiving acenocoumarol or warfarin who were prescribed a course of amoxicillin therapy. If concomitant use is necessary, prothrombin time or INR should be closely monitored when starting or stopping amoxicillin. Dose adjustment of oral anticoagulants may also be required (see sections "Special precautions" and "Adverse reactions").

Methotrexate

Penicillins may reduce the renal clearance of methotrexate, potentially increasing its toxicity.

Probenecid

Concomitant use of probenecid is not recommended. Probenecid reduces the renal tubular secretion of amoxicillin. Concurrent administration may lead to increased levels and prolonged presence of amoxicillin (but not clavulanic acid) in the blood.

Mycophenolate mofetil

In patients treated with mycophenolate mofetil, administration of oral amoxicillin with clavulanic acid may reduce the pre-dose concentration of the active metabolite—mycophenolic acid—by approximately 50%. This change in pre-dose levels may not fully reflect changes in total exposure to mycophenolic acid. Therefore, dosage adjustment of mycophenolate mofetil is usually not required unless there is clinical evidence of graft dysfunction. However, careful monitoring is necessary during concomitant use and for some time after completion of antibiotic therapy.

Special precautions for use.

Before initiating therapy with amoxicillin/clavulanic acid, a careful history of previous hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents should be obtained (see sections "Contraindications" and "Adverse reactions").

Severe and, in some cases, fatal hypersensitivity reactions (including anaphylactoid reactions and severe cutaneous adverse reactions) have been reported in patients receiving penicillin therapy. Hypersensitivity reactions may also progress to Kounis syndrome – a serious allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). Such reactions are more likely to occur in patients with a history of penicillin hypersensitivity and in patients with atopic diseases. Cases of drug-induced enterocolitis syndrome (DIES) have been reported, primarily in children receiving amoxicillin/clavulanic acid (see section "Adverse reactions"). Drug-induced enterocolitis syndrome is an allergic reaction whose main symptom is persistent vomiting (within 1–4 hours after drug administration) in the absence of allergic skin or respiratory symptoms. Additional symptoms may include abdominal pain, diarrhea, hypotension, or leukocytosis with neutrophilia. Severe cases have been reported, including progression to shock. If an allergic reaction occurs, amoxicillin/clavulanic acid should be discontinued and appropriate alternative therapy initiated.

If the infection is proven to be caused by a microorganism(s) sensitive to amoxicillin alone, consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin monotherapy in accordance with established guidelines.

Seizures may occur in patients with impaired renal function and in those receiving high doses of the drug (see "Adverse reactions").

Amoxicillin/clavulanic acid should be avoided in suspected cases of infectious mononucleosis, as administration of amoxicillin has been associated with the development of maculopapular rash.

Concomitant administration of allopurinol during amoxicillin therapy increases the likelihood of developing skin allergic reactions.

Prolonged use may, in some cases, lead to overgrowth of microorganisms not susceptible to the drug.

The onset of fever-associated generalized erythema with pustule formation at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis (AGEP) (see section "Adverse reactions"). This reaction requires discontinuation of Augmentin and constitutes a contraindication for further use of amoxicillin.

Amoxicillin/clavulanic acid should be used with caution in patients with signs of hepatic dysfunction (see sections "Dosage and administration", "Contraindications", "Adverse reactions").

Hepatic complications have been reported primarily in males and elderly patients following prolonged treatment. Reports in children are very rare. In all patient groups, symptoms typically occur during or shortly after treatment, although in some cases they may only manifest several weeks after treatment has ended. These events are usually reversible. Hepatic complications may be severe and, in exceptionally rare cases, fatal. Such events have always occurred in patients with severe underlying disease or in those receiving concomitant medications known to cause hepatic complications (see section "Adverse reactions").

Antibiotic-associated colitis, with severity ranging from mild to life-threatening, has been reported with nearly all antibacterial agents, including amoxicillin (see section "Adverse reactions"). Therefore, this diagnosis must be considered in patients presenting with diarrhea during or after antibiotic use. If antibiotic-associated colitis occurs, Augmentin should be discontinued immediately, medical attention sought, and appropriate treatment initiated. Antiperistaltic agents are contraindicated in such cases.

During prolonged therapy, periodic monitoring 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 is required when anticoagulants are co-administered. Dose adjustment of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Crystalluria (including acute kidney injury) has been very rarely observed in patients with reduced urine output, primarily during parenteral therapy. Adequate fluid intake and diuresis should be maintained when high doses of amoxicillin are administered to reduce the risk of amoxicillin-related crystalluria. In patients with urinary catheters, catheter patency should be checked regularly (see sections "Adverse reactions" and "Overdose").

During amoxicillin therapy, enzymatic methods (glucose oxidase) should be used to test for glucose in urine, as non-enzymatic methods may yield false-positive results.

The presence of clavulanic acid in Augmentin may lead to nonspecific binding of IgG and albumin to red blood cell membranes, potentially resulting in false-positive Coombs test results.

Positive results in the enzyme immunoassay using Platelia Aspergillus (Bio-Rad Laboratories) have been reported in patients receiving amoxicillin/clavulanic acid, despite subsequent confirmation of absence of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses have been reported when using the Platelia Aspergillus enzyme immunoassay (Bio-Rad Laboratories). 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, a source of phenylalanine; therefore, the product should be prescribed with caution to patients with phenylketonuria.

The medicinal product contains maltodextrin (glucose). It should not be administered to patients with rare hereditary glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonal/fetal development, parturition, or postnatal development. Limited human data on the use of amoxicillin/clavulanic acid during pregnancy do not suggest an increased risk of congenital malformations. In a single study in women with premature rupture of membranes, prophylactic treatment with amoxicillin/clavulanic acid was associated with an increased risk of necrotizing enterocolitis in newborns. The drug should be avoided during pregnancy unless, in the physician’s opinion, its use is considered necessary.

Breastfeeding period. Both active components of the drug are excreted in breast milk (there is no information on the effect of clavulanic acid on the breastfed infant). Diarrhea and fungal mucosal infections may therefore occur in the breastfed infant, and breastfeeding should be discontinued. The possibility of allergic reactions should also be considered. Amoxicillin/clavulanic acid may be used during breastfeeding only if, in the physician’s opinion, the benefit outweighs the risk.

Ability to influence reaction speed when driving or operating machinery.

Studies on the ability of the drug to affect reaction speed while driving or operating machinery have not been conducted. However, undesirable effects (such as allergic reactions, dizziness, seizures) may occur, which could impair the ability to drive or operate machinery.

Dosage and Administration

Dosage is expressed in terms of amoxicillin/clavulanic acid content, except when dosage is specified in terms of a single component.

When selecting the dosage of Augmentin for treatment of a specific infection, the following should be considered:

• likely pathogens and their probable susceptibility to antimicrobial agents (see section "Special Warnings and Precautions for Use");
• severity and site of infection;
• patient's age, body weight, and renal function, as indicated below.

The duration of treatment should not exceed 14 days without re-evaluation (see section "Special Warnings and Precautions for Use" regarding prolonged therapy).

Adults and children with body weight ≥ 40 kg

There is no experience with the use of Augmentin oral suspension in adults and children with body weight ≥ 40 kg; therefore, dosage recommendations for these patient groups are not available.

Children aged 3 months and older with body weight < 40 kg

The recommended dosage of Augmentin oral suspension is 90/6.4 mg/kg body weight/day, divided into two doses.

Augmentin ES contains a different amount of clavulanic acid (in the form of potassium salt) compared to any other Augmentin suspension formulation. 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 with any other Augmentin suspension formulation.

Renal impairment. No dosage adjustment is required in patients with creatinine clearance (CrCl) greater than 30 mL/min.

Augmentin ES is not recommended for use in patients with creatinine clearance less than 30 mL/min, as there are no dosage adjustment recommendations available.

Hepatic impairment. Use with caution and with regular monitoring of liver function (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Administration

Augmentin ES is for oral use.

The medicine should be taken with food 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 the bottle, and shake well. Alternatively: fill the bottle with water up to just below the mark indicated on the label, invert and shake thoroughly, then fill the bottle with water up to the mark, invert again, and shake thoroughly.

Before each use, the vial should be shaken thoroughly.

Children.

The suspension formulation of the drug is intended for children aged 3 months and older whose body weight does not exceed 40 kg. Children with body weight exceeding 40 kg should be prescribed the drug in another pharmaceutical form.

Overdose.

Symptoms

Symptoms typical of gastrointestinal disturbances and fluid and electrolyte imbalance may occur. Crystalluria associated with amoxicillin intake has been observed, which in individual cases led to the development of renal failure (see section "Special precautions").

Seizures may occur in patients with impaired renal function and in patients receiving high doses of the drug.

Precipitation of amoxicillin in urinary catheters has been reported, primarily after high-dose intravenous administration. The patency of catheters should be checked regularly (see section "Special precautions").

Treatment

Gastrointestinal disturbances can be treated symptomatically, with attention to fluid/electroly balance.

Amoxicillin/clavulanic acid can be removed from the bloodstream by hemodialysis.

Adverse Reactions

The most commonly reported adverse reactions to the medicinal product are diarrhoea, nausea, and vomiting.

The list of adverse reactions known from Augmentin clinical trials and post-marketing surveillance, classified by MedDRA System Organ Class, is provided below.

The following classification is used to describe the frequency of adverse reactions:

very common ≥ 1/10;

common ≥ 1/100 and < 1/10;

uncommon ≥ 1/1,000 and < 1/100;

rare ≥ 1/10,000 and < 1/1,000;

very rare < 1/10,000;

not known (frequency cannot be estimated from available data).

Infections and infestations

Common: candidiasis of skin and mucous membranes.

Not known: overgrowth of non-susceptible microorganisms.

Blood and lymphatic system disorders

Rare: reversible leucopenia (including neutropenia) and thrombocytopenia.

Not known: reversible agranulocytosis and haemolytic anaemia; prolonged bleeding time and prothrombin time^1.

Cardiac disorders

Not known: Kounis syndrome.

Immune system disorders^9

Not known: angioedema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.

Nervous system disorders

Uncommon: dizziness, headache.

Not known: reversible hyperactivity and convulsions^1.

Not known: aseptic meningitis.

Gastrointestinal disorders

Common: diarrhoea, nausea^2, vomiting.

Uncommon: gastric disturbances.

Not known: antibiotic-associated colitis^3, black hairy tongue, discolouration of tooth enamel^4, drug-induced enterocolitis syndrome (DIES), acute pancreatitis.

Hepatobiliary disorders

Uncommon: increased levels of AST and/or ALT^5.

Not known: hepatitis^6 and cholestatic jaundice^6.

Skin and subcutaneous tissue disorders^7

Uncommon: skin rashes, pruritus, urticaria.

Rare: erythema multiforme.

Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative bullous dermatitis, acute generalised exanthematous pustulosis^1, drug reaction with eosinophilia and systemic symptoms (DRESS), linear immunoglobulin A (IgA) disease.

Renal and urinary disorders

Not known: interstitial nephritis, crystalluria^8 (including acute kidney injury).

^1 See section "Special warnings and precautions for use".

^2 Nausea is more frequently associated with higher oral doses of the medicinal product. Gastrointestinal reactions may be minimized by taking Augmentin with food.

^3 Includes pseudomembranous colitis and haemorrhagic colitis (see section "Special warnings and precautions for use").

^4 Discolouration of tooth enamel has been very rarely reported in children. Careful oral hygiene may prevent this effect, as the phenomenon can be removed by tooth brushing.

^5 Mild elevations in AST and/or ALT levels have been more frequently observed in patients receiving beta-lactam antibiotics, but the clinical significance of these findings is unknown.

^6 These events have been observed with other penicillin and cephalosporin antibiotics (see section "Special warnings and precautions for use").

^7 If hypersensitivity reactions (dermatitis) occur, the medicinal product should be discontinued (see section "Special warnings and precautions for use").

^8 See section "Overdose".

^9 See section "Contraindications" and "Special warnings and precautions for use".

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

2 years. Prepared suspension – 10 days.

Storage conditions

Store at temperatures not exceeding 25 °C. Keep out of the reach of children.

The prepared suspension should be stored in a refrigerator at 2 to 8 °C and used within 10 days. Do not freeze.

Packaging

Glass vial with a screw aluminium cap (containing an internal polymer (polyvinyl chloride or polyolefin) film), with a tamper-evident seal or with a child-resistant plastic cap, and a plastic measuring spoon marked with 2.5 ml and 5 ml graduations, in a cardboard box.

Prescription status
By prescription only.

Manufacturer
SmithKline Beecham Pharmaceuticals, United Kingdom.

Manufacturer's address

SmithKline Beecham Pharmaceuticals, Clarendon Road, Worthing, BN14 8QH, United Kingdom.

Marketing Authorisation Holder's representative

LLC "GlaxoSmithKline Pharmaceuticals Ukraine".

Address of the representative

1-V Pavla Tychyny Avenue, Kyiv, 02152, Ukraine. Tel: (044) 585-51-85, Fax: (044) 585-51-92.

All suspected adverse reactions and lack of efficacy may also be reported to LLC "GlaxoSmithKline Pharmaceuticals Ukraine" via the 24-hour hotline (044) 585-51-85 or by email at [email protected].