Augmentin

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

Composition:

Active substances: amoxicillin, clavulanic acid;

One tablet contains amoxicillin (as amoxicillin trihydrate) 500 mg, clavulanic acid (as potassium clavulanate) 125 mg;

Excipients: colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), magnesium stearate, microcrystalline cellulose, titanium dioxide (E 171), hydroxypropylmethylcellulose, macrogol 4000, macrogol 6000, dimethicone.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or off-white oval-shaped film-coated tablets with "AC" imprint and a break line on one side.

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 organisms 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

Time above the minimum inhibitory concentration (T>MIC) is considered the primary 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 themselves inhibited by clavulanic acid, including Class B, C, and D enzymes;
• modification of PBPs, reducing the affinity of the antibacterial agent for its target.

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

Breakpoints

MIC breakpoints for amoxicillin/clavulanic acid established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)

The prevalence of resistance may vary geographically and over time for individual species, so local information on susceptibility is desirable, especially when treating severe infections. Expert advice should be sought when local resistance prevalence is such that the benefit of the drug, at least for certain types of infections, is questionable.

Pharmacokinetics.

Absorption. Amoxicillin and clavulanic acid are completely dissociated in aqueous solutions at physiological pH. 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.

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

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.

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

Animal studies have shown no evidence of significant retention of substances derived from either component 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 breastfeeding").

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

Metabolism. 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 is 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 renal, whereas clavulanic acid is eliminated both renally and via 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 amounts to 50–85% for amoxicillin and 27–60% for clavulanic acid over a 24-hour period. For clavulanic acid, the majority of the substance 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").

Age. The elimination half-life of amoxicillin is identical in children aged 3 months to 2 years, older children, and adults. For neonates (including premature infants) during the first week of life, the dosing frequency should not exceed twice daily due to immaturity of the renal elimination pathway. Since elderly patients are more likely to have decreased renal function, dosage selection should be cautious, and monitoring of renal function is recommended.

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, as 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 "Dosage and administration").

Hepatic impairment. Caution is recommended when administering the drug to patients with hepatic impairment, and regular monitoring of liver function is advised.

Clinical characteristics.

Indications.

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 dentofacial abscesses with spreading cellulitis;
• bone and joint infections, including osteomyelitis.

Contraindications.

Hypersensitivity to any component of the drug 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 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-type 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 drugs is necessary, prothrombin time or INR should be closely monitored when starting or stopping amoxicillin. Additionally, dose adjustment of oral anticoagulants may be required (see sections "Special precautions for use" and "Adverse reactions").

Methotrexate

Penicillins may reduce methotrexate excretion, potentially increasing its toxicity.

Probenecid

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

Myfortic (mycophenolate mofetil)

In patients receiving mycophenolate mofetil, initiation 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 transplant dysfunction. However, close monitoring is necessary during concomitant use and for some time after antibiotic therapy.

Special precautions for use

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

Serious and occasionally fatal hypersensitivity reactions (including anaphylactic reactions and severe skin adverse reactions) have been reported in patients receiving penicillin therapy. Hypersensitivity reactions may also progress to Cowling's 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 or those with atopic diseases. If an allergic reaction occurs, amoxicillin/clavulanic acid should be discontinued immediately and appropriate alternative therapy initiated.

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

This formulation of Augmentin is not suitable for use when there is a high risk that the likely pathogens have reduced susceptibility or resistance to beta-lactam agents not mediated by beta-lactamases that are susceptible to inhibition by clavulanic acid. This formulation should not be used for the treatment of penicillin-resistant S. pneumoniae.

Seizures may occur in patients with impaired renal function and in those receiving high doses of the drug (see section "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 morbilliform rash.

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

Prolonged use may occasionally 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 to further use of amoxicillin.

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

Hepatic complications have been reported primarily in males and elderly patients, which may be associated with prolonged therapy. Reports in children are very rare. In all patient groups, symptoms typically occur during or shortly after treatment, although in some cases they may appear several weeks after completion of therapy. These events are usually reversible. Hepatic complications may be severe and, in exceptionally rare cases, fatal. Such events have almost always occurred in patients with severe underlying disease or those receiving concomitant medications known to have potential hepatotoxic effects (see section "Side effects").

Antibiotic-associated colitis, with severity ranging 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 therapy. If antibiotic-associated colitis develops, Augmentin should be discontinued immediately, medical advice 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.

Rare cases of prolonged prothrombin time have been reported 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").

Dosage adjustment is required in patients with impaired renal function depending on the degree of impairment (see section "Dosage and administration").

Crystalluria (including acute kidney injury) has been very rarely observed in patients with low 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 urinary glucose, 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, potentially resulting in false-positive Coombs test results.

Positive results in the Platelia Aspergillus enzyme immunoassay (Bio-Rad Laboratories) have been reported in patients receiving amoxicillin/clavulanic acid, despite subsequent confirmation of absence of Aspergillus infection. Cross-reactions with polysaccharides and non-Aspergillus polyfuranoses have been reported when using the Platelia Aspergillus immunoassay (Bio-Rad Laboratories).

Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted with caution and confirmed by alternative diagnostic methods.

Use during pregnancy or breastfeeding

Pregnancy. Reproductive studies in animals with oral and parenteral forms of Augmentin revealed no teratogenic effects. In one study involving women with premature rupture of membranes, prophylactic use of Augmentin was associated with an increased risk of neonatal necrotizing enterocolitis. As with other medicinal products, Augmentin should be avoided during pregnancy, especially in the first trimester, unless in the opinion of the physician the benefits outweigh the risks.

Breastfeeding. Both active components of the drug are excreted in breast milk (no information is available regarding the effect of clavulanic acid on breastfed infants). Diarrhea and fungal mucosal infections may therefore occur in breastfed infants, and breastfeeding should be discontinued. The possibility of allergic reactions should also be considered. Augmentin may be used during breastfeeding only if, in the opinion of the physician, the benefit justifies the potential risk.

Ability to affect driving and use of machines

No studies on the ability of the drug to affect driving or operating machinery have been conducted. However, undesirable effects (such as allergic reactions, dizziness, seizures) that may impair the ability to drive or operate machinery may occur (see section "Side effects").

Method of Administration and Dosage

The drug should be used in accordance with official recommendations on antibiotic therapy and local antibiotic susceptibility patterns. Susceptibility to amoxicillin/clavulanate varies across different regions and may change over time. When necessary, reference should be made to local susceptibility data, and microbiological identification and susceptibility testing should be performed if indicated.

When appropriate, consideration should be given to using alternative formulations of Augmentin (i.e., those providing higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) (see sections "Special Warnings" and "Pharmacodynamics").

The recommended dosage range depends on the expected pathogens and their susceptibility to antibacterial agents, the severity of the disease, the site of infection, as well as the patient's age, body weight, and renal function.

For adults and children with body weight ≥ 40 kg, the total daily dose is 1500 mg of amoxicillin/375 mg of clavulanic acid (3 tablets), administered as described below.

For children aged 6 years and older with body weight between 25 and 40 kg, the maximum daily dose is 2400 mg of amoxicillin/600 mg of clavulanic acid (4 tablets), administered as described below.

If higher doses of amoxicillin are required for treatment, alternative formulations of Augmentin should be used to avoid excessive doses of clavulanic acid.

The duration of treatment should be determined based on the patient's clinical response. Some infections (e.g., osteomyelitis) may require prolonged treatment. Treatment should not exceed 14 days without re-evaluation (see section "Special Warnings" regarding prolonged therapy).

Adults and children with body weight ≥ 40 kg

1 tablet of Augmentin 500 mg/125 mg three times daily.

Children aged 6 years and older with body weight from 25 to 40 kg

Dosage from 20 mg/5 mg/kg body weight/day to 60 mg/15 mg/kg body weight/day, divided into three doses.

Since the tablet cannot be divided, this formulation of Augmentin is not recommended for children with body weight below 25 kg.

Elderly patients

Dosage adjustment in elderly patients is not usually required. Dose may be adjusted as necessary according to renal function.

Dosing in Renal Impairment

Dosing is based on the maximum concentration of amoxicillin. Dose adjustment is not required in patients with creatinine clearance > 30 mL/min.

Adults and children with body weight ≥ 40 kg

Children aged 6 years and older with body weight between 25 and 40 kg

Since the tablet cannot be divided, this formulation of Augmentin should not be prescribed to children with body weight between 25 and 40 kg who have a creatinine clearance of less than 30 mL/min or to children undergoing hemodialysis.

Dosing in hepatic impairment

Use with caution; liver function should be monitored regularly.

The tablet should be swallowed whole without chewing. If necessary, to facilitate swallowing, the tablet may be split in half and the halves swallowed without chewing.

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

The duration of treatment is determined individually. Treatment should not continue for more than 14 days without reassessment of the patient's condition.

Treatment may be initiated parenterally and then continued orally.

Children

This formulation of Augmentin is indicated for children aged 6 years and older with body weight of at least 25 kg.

Overdose

Symptoms

Gastrointestinal disturbances and disturbances in fluid and electrolyte balance may occur. Crystalluria associated with amoxicillin has been observed, which in some cases led to renal failure (see section "Special precautions").

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

Amoxicillin precipitation in urinary catheters has been reported, primarily after high-dose intravenous administration. Catheter patency should be checked regularly (see section "Special precautions").

Treatment

Gastrointestinal disturbances can be treated symptomatically, with attention to fluid and electrolyte balance.

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

Adverse Reactions

The most commonly reported adverse reactions to the medicinal product (AR) are diarrhea, nausea, and vomiting.

The list of adverse drug reactions known 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 and < 1/10;
Uncommon ≥ 1/1000 and < 1/100;
Rare ≥ 1/10,000 and < 1/1000;
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 microorganisms not sensitive to the drug.

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: Kounis syndrome.

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, aseptic meningitis.

Gastrointestinal disorders

Common: Diarrhea, nausea³, vomiting.
Uncommon: Gastrointestinal discomfort.
Not known: Antibiotic-associated colitis⁴, "black hairy tongue", discoloration of tooth enamel¹¹, 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 disorders⁷

Uncommon: Skin rashes, pruritus, urticaria.
Rare: Erythema multiforme.
Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative bullous dermatitis, acute generalized exanthematous pustulosis⁹, drug reaction with eosinophilia and systemic symptoms (DRESS), linear immunoglobulin A (IgA) disease.

Renal and urinary disorders

Very rare: Interstitial nephritis, crystalluria⁸ (including acute kidney injury).

¹ See section "Special precautions and warnings for use".
² See section "Special precautions and warnings for use".
³ Nausea is more frequently associated with higher oral doses of the drug. Gastrointestinal reactions may be reduced in severity by taking Augmentin with food.
⁴ Including pseudomembranous colitis and hemorrhagic colitis (see section "Special precautions and warnings for use").
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 and warnings for use").
⁷ If hypersensitivity reactions (dermatitis) occur, the drug should be discontinued (see section "Special precautions and warnings for use").
⁸ See section "Overdose".
⁹ See section "Special precautions and warnings for use".
¹⁰ See section "Contraindications" and "Special precautions and warnings for use".
¹¹ Tooth discoloration has been very rarely reported in children. Careful oral hygiene may prevent this effect, as it is removable by tooth brushing.

Shelf life

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 per blister in an aluminum foil pouch with desiccant sachets. 2 blisters per pouch in a cardboard pack.

Prescription status

Prescription only.

Manufacturer

Glaxo Wellcome Production, France.
Glaxo Wellcome Production, France.

Manufacturer's address

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

PACKAGE INSERT

for medical use

AUGMENTIN

(AUGMENTIN)

Composition:

Active substances: amoxicillin, clavulanic acid;

One tablet contains amoxicillin (as amoxicillin trihydrate) 500 mg, clavulanic acid (as potassium clavulanate) 125 mg;

Excipients: colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), magnesium stearate, microcrystalline cellulose, titanium dioxide (E 171), hydroxypropylmethylcellulose, macrogol 4000, macrogol 6000, dimethicone.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, oval-shaped, film-coated tablets, marked with "AC" and a breakline on one side.

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 organisms 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

Time above the minimum inhibitory concentration (T>MIC) is considered the primary pharmacokinetic/pharmacodynamic parameter determining the efficacy of 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 Class B, C, and D enzymes;
• Alteration of PBPs, leading to reduced affinity of the antibacterial agent for its target.

Impermeability of bacterial cell membranes or efflux pump mechanisms may contribute to or cause bacterial resistance, particularly in Gram-negative bacteria.

Breakpoints

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

The prevalence of resistance may vary geographically and over time for individual species, so local information on susceptibility is desirable, especially when treating severe infections. Expert advice should be sought when local resistance prevalence is such that the benefit of the drug, at least for certain types of infections, is questionable.

Pharmacokinetics.

Absorption. Amoxicillin and clavulanic acid are completely dissociated in aqueous solutions at physiological pH. 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.

Serum concentrations of amoxicillin and clavulanic acid achieved after administration of amoxicillin/clavulanic acid are identical to those achieved following 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 about 0.2 L/kg for clavulanic acid.

Following intravenous administration, amoxicillin and clavulanic acid have been detected in the gallbladder, abdominal tissue, 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 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 breastfeeding").

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

Metabolism. 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 renal, whereas clavulanic acid is eliminated both renally and via 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 amounts to 50–85% for amoxicillin and 27–60% for clavulanic acid over a 24-hour period. For clavulanic acid, the greatest amount of the substance 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").

Age. The elimination half-life of amoxicillin is identical in children aged 3 months to 2 years, older children, and adults. For neonates (including premature infants) during the first week of life, the dosing frequency should not exceed twice daily due to immaturity of the renal elimination pathway. Since elderly patients are more likely to have decreased renal function, dosage selection should be cautious, and monitoring of renal function is recommended.

Renal impairment. Total serum clearance of amoxicillin/clavulanic acid decreases proportionally with decreasing 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, dosing 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 when administering the drug to patients with hepatic impairment, and regular monitoring of liver function is advised.

Clinical characteristics.

Indications.

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 spreading cellulitis;
• bone and joint infections, including osteomyelitis.

Contraindications.

Hypersensitivity to any component of the drug, or 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 hepatic dysfunction associated with the use of amoxicillin/clavulanate.

Interaction with other medicinal products and other forms of interaction.

Oral anticoagulants

Oral anticoagulants and penicillin-type 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 initiating or discontinuing amoxicillin. Additionally, dosage adjustment of oral anticoagulants may 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 reduces renal tubular secretion of amoxicillin. Concurrent administration of probenecid may lead to increased levels and prolonged presence of amoxicillin (but not clavulanic acid) in the blood.

Mycophenolate mofetil

In patients receiving mycophenolate mofetil, the pre-dose concentration of the active metabolite mycophenolic acid may decrease by approximately 50% following initiation of oral amoxicillin with clavulanic acid. 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 transplant dysfunction. However, close monitoring is necessary during concomitant use and for some time after antibiotic therapy.

Special precautions for use.

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

Severe and, in rare cases, fatal hypersensitivity reactions (including anaphylactic reactions and severe skin adverse reactions) have been reported in patients receiving penicillin therapy. Hypersensitivity reactions may also progress to DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) — 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. If an allergic reaction occurs, amoxicillin/clavulanic acid should be discontinued immediately and appropriate alternative therapy should be initiated.

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 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. Serious cases have been reported, including progression to shock.

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

This dosage form of Augmentin is not suitable for use when there is a high risk that the likely pathogens have reduced susceptibility or resistance to beta-lactam agents not mediated by beta-lactamases that are susceptible to inhibition by clavulanic acid. This dosage form should not be used to treat penicillin-resistant S. pneumoniae.

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

Prolonged use may occasionally 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 impaired liver function (see sections "Dosage and administration", "Contraindications", and "Adverse reactions").

Hepatic complications have been reported primarily in men and elderly patients, which may be associated with prolonged therapy. Reports in children are very rare. In all patient groups, symptoms typically occur during or shortly after treatment, although in some cases they may appear only several weeks after completion of therapy. These events are usually reversible. Hepatic complications may be severe and, in exceptionally rare cases, fatal. Such events have almost always occurred in patients with severe underlying disease or those receiving concomitant medications known to have potential hepatotoxic effects (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 should be considered in patients presenting with diarrhea during or after antibiotic therapy. If antibiotic-associated colitis is suspected, 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.

Rare cases of prolonged prothrombin time have been reported in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring is recommended when anticoagulants are co-administered. Dose adjustment of oral anticoagulants may be required to maintain the desired level of anticoagulation (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Dosage adjustment is required in patients with impaired renal function depending on the degree of impairment (see section "Dosage and administration").

Crystalluria (including acute renal injury) has been very rarely observed 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 "Adverse reactions" and "Overdose").

During amoxicillin therapy, enzymatic glucose oxidase methods should be used for urine glucose testing, 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 Platelia Aspergillus enzyme immunoassay (Bio-Rad Laboratories) have been reported in patients receiving amoxicillin/clavulanic acid, despite subsequent confirmation of absence of Aspergillus infection. Cross-reactions with polysaccharides and polyfuranoses from non-Aspergillus species have been reported during immunoassay testing using Platelia Aspergillus (Bio-Rad Laboratories).

Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.

Use during pregnancy or breastfeeding.

Pregnancy. Reproductive studies in animals with oral and parenteral forms of Augmentin revealed no teratogenic effects. In one study involving women with premature rupture of membranes, prophylactic use of Augmentin was associated with an increased risk of necrotizing enterocolitis in neonates. As with other medicinal products, Augmentin should be avoided during pregnancy, especially in the first trimester, unless in the opinion of the physician the benefits outweigh the risks.

Breastfeeding period. Both active components of the drug are excreted in breast milk (no information is available on the effect of clavulanic acid on breastfed infants). 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. Augmentin may be used during breastfeeding only if, in the opinion of the physician, the benefit justifies the potential risk.

Ability to affect the ability to drive and use machines.

Studies on the effect of the drug on the ability to drive vehicles or operate 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 (see section "Adverse reactions").

Method of administration and dosage.

The drug should be used in accordance with official recommendations on antibiotic therapy and local antibiotic susceptibility data. Susceptibility to amoxicillin/clavulanate varies across different regions and may change over time. When necessary, local susceptibility data should be consulted, and, if indicated, microbiological identification and susceptibility testing should be performed.

When necessary, consider the possibility of using alternative formulations of Augmentin (i.e., those providing higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) (see sections "Special instructions" and "Pharmacodynamics").

The recommended dosage range depends on the expected pathogens and their susceptibility to antibacterial agents, severity of the disease, site of infection, patient's age, body weight, and renal function.

For adults and children with body weight ≥ 40 kg, the total daily dose is 1500 mg of amoxicillin/375 mg of clavulanic acid (3 tablets), administered as specified below.

For children aged 6 years and older with body weight between 25 and 40 kg, the maximum daily dose is 2400 mg of amoxicillin/600 mg of clavulanic acid (4 tablets), administered as specified below.

If higher doses of amoxicillin are required for treatment, alternative Augmentin formulations should be used to avoid administering unnecessarily high doses of clavulanic acid.

The duration of treatment should be determined based on the patient's clinical response. Certain infections (e.g., osteomyelitis) may require prolonged treatment. Treatment should not exceed 14 days without re-evaluation (see section "Special instructions" regarding prolonged therapy).

Adults and children with body weight ≥ 40 kg

1 tablet of Augmentin 500 mg/125 mg three times daily.

Children aged 6 years and older with body weight from 25 to 40 kg

Dosage from 20 mg/5 mg/kg body weight/day to 60 mg/15 mg/kg body weight/day, divided into three doses.

Since the tablet cannot be divided, this formulation of Augmentin is not recommended for children with body weight below 25 kg.

Elderly patients

Dosage adjustment in elderly patients is not required. If necessary, dosage should be adjusted according to renal function.

Dosing in renal impairment

Dosing is based on the maximum level of amoxicillin. There is no need to adjust the dose in patients with creatinine clearance > 30 mL/min.

Adults and children with body weight ≥ 40 kg

Children aged 6 years and older with body weight between 25 and 40 kg

Since the tablet cannot be divided, this formulation of Augmentin should not be prescribed to children with body weight between 25 and 40 kg who have a creatinine clearance of less than 30 mL/min or who are undergoing hemodialysis.

Dosing in hepatic impairment

Use with caution; liver function should be monitored regularly.

The tablet should be swallowed whole, without chewing. If necessary, to facilitate swallowing, the tablet may be split in half and the halves swallowed without chewing.

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

The duration of treatment should be determined individually. Treatment should not continue beyond 14 days without re-evaluation of the patient.

Treatment may be initiated parenterally and then continued orally.

Children

This formulation of Augmentin is indicated for children aged 6 years and older with body weight of at least 25 kg.

Overdose

Symptoms

Gastrointestinal disturbances and disturbances in fluid and electrolyte balance may occur. Crystalluria associated with amoxicillin has been observed, which in some cases led to renal failure (see section "Special precautions").

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

Amoxicillin precipitation in urinary catheters has been reported, primarily after high-dose intravenous administration. Catheter patency should be monitored regularly (see section "Special precautions").

Treatment

Gastrointestinal symptoms can be treated symptomatically, with attention to fluid and electrolyte balance.

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

Adverse Reactions.

The most commonly reported adverse reactions to the medicinal product (ARs) are diarrhea, nausea, and vomiting.

The list of adverse drug reactions known 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 and < 1/10;

uncommon ≥ 1/1000 and < 1/100;

rare ≥ 1/10,000 and < 1/1000;

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 microorganisms not sensitive to the medicinal product.

Disorders of the blood and lymphatic system.

Rare: reversible leukopenia (including neutropenia) and thrombocytopenia.

Not known: reversible agranulocytosis and hemolytic anemia; prolonged bleeding time and prothrombin index1.

Cardiac disorders.

Not known: Kounis syndrome.

Immune system disorders 10.

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

Nervous system disorders.

Uncommon: dizziness, headache.

Not known: reversible hyperactivity and convulsions2, aseptic meningitis.

Gastrointestinal disorders.

Common: diarrhea, nausea3, vomiting.

Uncommon: gastric disturbances.

Not known: antibiotic-associated colitis4, "black hairy tongue", discoloration of tooth enamel11, 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 pustulosis9, drug reaction with eosinophilia and systemic symptoms (DRESS), linear IgA disease.

Renal and urinary disorders.

Very rare: interstitial nephritis, crystalluria8 (including acute kidney injury).

1 See section "Special precautions for use".

2 See section "Special precautions for use".

3 Nausea is more frequently associated with higher oral doses of the medicinal product. Gastrointestinal reactions may be reduced in severity by taking Augmentin with food.

4 Including pseudomembranous colitis and hemorrhagic colitis (see section "Special precautions for use").

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 medicinal product should be discontinued (see section "Special precautions for use").

8 See section "Overdose".

9 See section "Special precautions for use".

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

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

Shelf life.

3 years. After opening the foil pack – 30 days.

Storage conditions.

Store below 25 °C. Keep out of reach of children.

Packaging.

7 tablets in a blister pack in an aluminum foil pouch with desiccant sachets. 2 blisters per pouch in a cardboard carton.

Prescription category. Prescription only.

Manufacturer.

SmithKline Beecham Pharmaceuticals, United Kingdom.

Manufacturer's name and address.

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