Augmentin

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

Composition:

Active substances: amoxicillin, clavulanic acid;

5 ml of suspension contain amoxicillin (as amoxicillin trihydrate) 200 mg and clavulanic acid (as potassium clavulanate) 28.5 mg;

Excipients: xanthan gum, aspartame (E 951), succinic acid, colloidal anhydrous silicon dioxide, hydroxypropylmethylcellulose, dried orange flavorings (1 and 2), dried raspberry flavoring, dried "Light Molasses" flavoring, silicon dioxide.

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties: white or off-white free-flowing powder.

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 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 Class B, C, and D enzymes;
• Alteration of PBPs, leading to reduced affinity of the antimicrobial agent for its target.

Reduced bacterial permeability or efflux pump mechanisms may contribute to or cause 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 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.

Following intravenous administration, amoxicillin and clavulanic acid have been detected in the gallbladder, peritoneal tissue, 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 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 expired 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 affect the 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 similar 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 "Method of administration and dosage").

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 in adults and children 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 dentatoalveolar abscesses with spreading cellulitis;
• bone and joint infections, including osteomyelitis.

When prescribing antibacterial agents, appropriate use guidelines should be followed.

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-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 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.

Mycofenolate 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 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, 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 history of previous hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents should be obtained (see sections "Contraindications" and "Side effects").

Severe and, in some cases, fatal hypersensitivity reactions (including anaphylactic 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 "Side effects"). Such reactions are more likely 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. Serious cases have been documented, including progression to shock.

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

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

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

Amoxicillin/clavulanic acid should be avoided in patients suspected of having 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 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 "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 men and elderly patients, which may be associated with 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 appear several weeks after completion of therapy. These events are usually reversible. Hepatic complications may be severe and, in extremely rare cases, fatal. Such events have almost always occurred in patients with serious underlying diseases 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.

During prolonged therapy, periodic assessment 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 should be adjusted 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 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 "Side effects" and "Overdose").

During amoxicillin therapy, enzymatic methods (glucose oxidase) should be used for glucose testing 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 erythrocyte 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 who were later confirmed not to have Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses have been reported when using the Platelia Aspergillus immunoassay (Bio-Rad Laboratories). Therefore, positive results in patients treated with amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.

Augmentin 228.5 mg/5 ml suspension contains aspartame (E951) 2.5 mg/mL—a source of phenylalanine; therefore, the drug should be administered with caution to patients with phenylketonuria.

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

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 fetal membranes, prophylactic use of Augmentin was associated with an increased risk of necrotizing enterocolitis in newborns. As with other medicinal products, Augmentin should be avoided during pregnancy, especially in the first trimester, unless in the physician’s judgment the use is clearly 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 breastfed infants). Therefore, diarrhea and fungal mucosal infections may 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 physician’s opinion, the benefit outweighs the risk.

Ability to affect 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 (see section "Side effects").

Dosage and Administration

The drug should be used in accordance with official recommendations on antibiotic therapy and local antibiotic susceptibility data, where available. Susceptibility to amoxicillin/clavulanate varies across different regions and may change over time. If necessary, microbial susceptibility testing to the antibiotic should be performed.

The dosage of the drug should be determined by the physician depending on the suspected microorganisms and their susceptibility to antibacterial agents, severity and site of infection, as well as the patient's age, body weight, and renal function.

If necessary, 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 Instructions" and "Pharmacodynamics").

For children weighing <40 kg, this dosage form of Augmentin provides a maximum daily dose of 1000–2800 mg amoxicillin/143–400 mg clavulanic acid when administered as recommended below. If a higher dose of amoxicillin is considered necessary, an alternative Augmentin formulation should be selected to avoid excessively high daily doses of clavulanic acid (see sections "Special Instructions" and "Pharmacodynamics").

The duration of treatment should be based on the patient's clinical response. Some infections (e.g., osteomyelitis) 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: other formulations of Augmentin should be used.

Children with body weight < 40 kg:

Recommended daily doses: from 25/3.6 mg/kg body weight to 45/6.4 mg/kg body weight, divided into two doses.

For children weighing < 40 kg, the drug should be administered at a maximum daily dose of 1000–2800 mg amoxicillin/143–400 mg clavulanic acid when used as described below.

Approximate calculation of Augmentin suspension volume (mL) per day (based on amoxicillin)

For the treatment of certain infections such as otitis media and sinusitis, lower respiratory tract infections, children aged 2 years and older may be given daily doses up to 70 mg/10 mg/kg body weight divided into two doses.

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

Renal impairment.

For children with creatinine clearance (CrCl) greater than 30 mL/min, no dose adjustment is necessary. The use of Augmentin 228.5 mg/5 mL suspension is not recommended for the treatment of children with creatinine clearance (CrCl) less than 30 mL/min.

Hepatic impairment. Use with caution and monitor liver function regularly. Insufficient data are available to make dosage recommendations.

Method of administration

Augmentin is intended for oral administration.

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

Treatment may be initiated with parenteral administration of the drug and continued with an oral formulation.

Instructions for preparing the suspension.

The powder contained in the bottle should be reconstituted to form a suspension as described below.

1. Check the bottle cap for evidence of prior opening.
2. Invert and shake the bottle to loosen the powder.
3. Add boiled water to the bottle containing the powder up to the lower level marked by a red line with an arrow.
4. Close with the cap and shake the bottle until a suspension is formed.
5. Then add the remaining water up to the upper level marked by a black line with an arrow and shake again.
6. Allow the suspension to stand for 5 minutes to ensure complete dispersion of the powder.
7. Shake the suspension thoroughly before each dose.

To ensure accurate dosing, a measuring cap, measuring spoon, or oral syringe should be used, and each should be rinsed with water after every use.

Children.

Used in children aged 2 months and older. Children with body weight over 40 kg should be administered the drug in another pharmaceutical form.

Overdose.

Symptoms

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

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

Amoxicillin precipitation 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/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 effects is used:

very common ≥ 1/10;

common ≥ 1/100 and < 1/10;

uncommon ≥ 1/1000 and < 1/100;

rare ≥ 1/10000 and < 1/1000;

very rare < 1/10000;

unknown (frequency cannot be estimated from available data).

Infections and infestations.

Common: candidiasis of skin and mucous membranes.

Unknown: overgrowth of microorganisms not sensitive to the medicinal product.

Disorders of the blood and lymphatic system.

Rare: reversible leukopenia (including neutropenia) and thrombocytopenia.

Unknown: reversible agranulocytosis and hemolytic anemia; prolonged bleeding time and prothrombin index¹.

Cardiac disorders.

Unknown: Kounis syndrome.

Immune system disorders¹⁰.

Unknown: angioedema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.

Nervous system disorders.

Uncommon: dizziness, headache.

Unknown: reversible hyperactivity and convulsions², aseptic meningitis.

Gastrointestinal disorders.

Common: diarrhea, nausea³, vomiting.

Uncommon: gastric disturbances.

Unknown: 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.

Unknown: hepatitis⁶ and cholestatic jaundice⁶.

Skin and subcutaneous tissue disorders⁷.

Uncommon: skin rashes, pruritus, urticaria.

Rare: erythema multiforme.

Unknown: 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 for use".

2 See section "Special precautions for use".

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

4 Includes 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 Tooth discoloration has been very rarely reported in children. Careful oral hygiene may prevent this discoloration, as the condition can be removed by tooth brushing.

Shelf life.

2 years.

Storage conditions.

Keep original packaging tightly closed at temperatures below 25 °C in a dry place.

Reconstituted suspension should be stored in the refrigerator at 2 to 8 °C for up to 7 days. Keep out of reach of children.

Packaging. Powder for oral suspension to prepare 70 ml, in flasks made of clear glass with a screw metal cap (with tamper-evident seal and an internal polymer film), together with a measuring cap or dosing syringe, or a measuring spoon, placed in a cardboard box; or with a child-resistant closure together with a dosing syringe or a measuring spoon, placed in a cardboard box.

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.

INSTRUCTIONS

for medical use of medicinal product

AUGMENTIN

(AUGMENTIN)

Composition:

Active substances: amoxicillin, clavulanic acid;

5 ml of suspension contain amoxicillin (as amoxicillin trihydrate) 200 mg and clavulanic acid (as potassium clavulanate) 28.5 mg;

Excipients: xanthan gum, aspartame (E 951), succinic acid, colloidal anhydrous silicon dioxide, hydroxypropylmethylcellulose, dried orange flavorings (1 and 2), dried raspberry flavoring, dried "Light molasses" flavoring, silicon dioxide.

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties: white or almost white free-flowing powder.

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 pharmacodynamic 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 Class B, C, and D enzymes;
• Modification of PBPs, leading to reduced affinity of the antimicrobial agent for its target.

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

Breakpoints

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

The prevalence of resistance can vary geographically and over time for individual species, so local information on susceptibility is desirable, especially when treating severe infections. Expert guidance is needed if local resistance prevalence is such that the benefit of the drug, at least for some types of infections, is questionable.

Pharmacokinetics.

Absorption. Amoxicillin and clavulanic acid are completely dissociated in aqueous solutions at physiological pH levels. Both components are rapidly and well absorbed after 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 approximately 0.2 L/kg for clavulanic acid.

After 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 sufficiently 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 breastfeeding").

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

Biotransformation. 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 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 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 affect the 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 "Method of administration and dosage").

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 in adults and children 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 dentatoalveolar abscesses with spreading cellulitis;
• bone and joint infections, including osteomyelitis.

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

Contraindications.

Hypersensitivity to any component of the drug, to any antibacterial agents of the penicillin group.

History of severe hypersensitivity reactions (including anaphylaxis) associated with the use of other beta-lactam agents (including cephalosporins, carbapenems, or monobactams).

History of cholestatic jaundice or hepatic dysfunction associated with the use of amoxicillin/clavulanate.

Interaction with other medicinal products and other types of interactions.

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 drugs is necessary, prothrombin time or INR should be carefully 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 methotrexate excretion, 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, 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 level 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, 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 history of previous hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents should be obtained (see sections "Contraindications" and "Side effects").

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 Kounis syndrome—a serious allergic reaction that may lead to myocardial infarction (see section "Side effects"). Such reactions are more likely 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 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 "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. Serious cases have been documented, including progression to shock.

If an infection is proven 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 medicinal form of Augmentin is not suitable for use when there is a high risk that the likely pathogens are resistant to beta-lactam agents via mechanisms not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. This formulation 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 "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 administration of allopurinol during treatment with amoxicillin increases the likelihood of allergic skin 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 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 only several weeks after therapy has ended. These effects are usually reversible. Hepatic complications may be severe and, in extremely rare cases, fatal. Such events have almost always occurred in patients with severe underlying disease or those concurrently receiving drugs with known potential hepatotoxic effects (see section "Side effects").

When using nearly all antibacterial agents, including amoxicillin, antibiotic-associated colitis has been reported, with severity ranging from mild to life-threatening (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.

During prolonged therapy, periodic assessment of organ system functions—including renal, hepatic, and hematopoietic function—is recommended.

Rarely, prolonged prothrombin time has 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 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 "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, 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 non-Aspergillus polysaccharides and polyfuranoses have been reported when using the Platelia Aspergillus immunoassay (Bio-Rad Laboratories). Therefore, positive results in patients treated with amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.

Augmentin 228.5 mg/5 ml suspension contains aspartame (E951) 2.5 mg/mL—a source of phenylalanine; therefore, the product should be used with caution in patients with phenylketonuria.

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

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 newborns. As with other medicinal products, Augmentin should be avoided during pregnancy, especially in the first trimester, unless in the physician’s opinion the benefits outweigh the risks.

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). Therefore, diarrhea and fungal mucosal infections may 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 physician’s opinion, the benefit to the mother outweighs the potential risk to the infant.

Ability to affect reaction speed when driving or operating machinery.

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

Method of administration and dosage

The drug should be used in accordance with official recommendations on antibiotic therapy and taking into account local antibiotic susceptibility patterns, where available. Susceptibility to amoxicillin/clavulanate varies across different regions and may change over time. If necessary, microbial susceptibility to the antibiotic should be determined.

The dosage of the drug is determined by a physician depending on the expected microorganisms and their susceptibility to antibacterial agents, severity of the disease and site of infection, as well as the patient's age, body weight, and renal function.

If necessary, 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 instructions" and "Pharmacodynamics").

For children weighing <40 kg, this dosage form of Augmentin provides a maximum daily dose of 1000–2800 mg amoxicillin/143–400 mg clavulanic acid when administered as recommended below. If a higher dose of amoxicillin is considered necessary, an alternative Augmentin formulation is recommended to avoid excessively high daily doses of clavulanic acid (see sections "Special instructions" and "Pharmacodynamics").

The duration of treatment should be 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 instructions" regarding prolonged therapy).

Adults and children with body weight ≥ 40 kg: other formulations of Augmentin should be used.

Children with body weight < 40 kg

Recommended daily dosage: 25/3.6 mg/kg to 45/6.4 mg/kg body weight, divided into two doses.

For children with body weight < 40 kg, the drug is prescribed at a maximum daily dose of 1000–2800 mg amoxicillin/143–400 mg clavulanic acid when used as described below.

Approximate calculation of Augmentin suspension volume (mL) per day (based on amoxicillin)

For the treatment of certain infections such as otitis media and sinusitis, lower respiratory tract infections, children aged 2 years and older may be administered daily doses up to 70 mg/10 mg/kg body weight, divided into two doses.

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

Renal impairment.

For children with creatinine clearance (CrCl) greater than 30 mL/min, no dose adjustment is necessary. The use of Augmentin 228.5 mg/5 mL suspension is not recommended for the treatment of children with creatinine clearance (CrCl) less than 30 mL/min.

Hepatic impairment. Use with caution and monitor liver function regularly. Insufficient data are available to provide dosing recommendations.

Method of administration

Augmentin is intended for oral administration.

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

Treatment may be initiated with parenteral administration of the drug and continued with the oral formulation.

Instructions for suspension preparation.

The powder contained in the bottle should be reconstituted to form a suspension as described below.

1. Check the bottle cap for evidence of prior opening.
2. Invert and shake the bottle to loosen the powder.
3. Add boiled water to the bottle containing the powder up to the lower level marked by the red line with an arrow.
4. Close the bottle with the cap and shake until a suspension is formed.
5. Then add the remaining water up to the upper level marked by the black line with an arrow and shake again.
6. Allow the suspension to stand for 5 minutes to ensure complete dispersion of the powder.
7. Shake the suspension well before each use.

To accurately measure the dose, a measuring cap, measuring spoon, or oral syringe should be used, and each should be rinsed with water after every use.

Children.

The medicine is used in children aged 2 months and older. Children weighing more than 40 kg should be administered another pharmaceutical formulation.

Overdose.

Symptoms

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

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

Amoxicillin precipitation 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 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 (MP) are diarrhoea, nausea, and vomiting.

Listed below are adverse drug reactions known from Augmentin clinical trials and post-marketing surveillance, classified by MedDRA system organ class.

The following frequency classification of adverse effects is applied:

very common ≥ 1/10;
common ≥ 1/100 to < 1/10;
uncommon ≥ 1/1,000 to < 1/100;
rare ≥ 1/10,000 to < 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 microorganisms not sensitive to the medicinal product.

Disorders of the blood and lymphatic system

Rare: reversible leucopenia (including neutropenia) and thrombocytopenia.
Not known: reversible agranulocytosis and haemolytic anaemia; prolonged bleeding time and prothrombin index(^1).

Cardiac disorders

Not known: Kounis syndrome.

Immune system disorders(^{10})

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

Nervous system disorders

Uncommon: dizziness, headache.
Not known: reversible hyperactivity and convulsions(^2), aseptic meningitis.

Gastrointestinal disorders

Common: diarrhoea, nausea(^3), vomiting.
Uncommon: gastric disturbances.
Not known: antibiotic-associated colitis(^4), "black hairy tongue", discolouration of tooth enamel(^{11}), 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, bullous exfoliative dermatitis, acute generalised exanthematous pustulosis(^9), drug reaction with eosinophilia and systemic symptoms (DRESS), linear IgA disease.

Renal and urinary disorders

Very rare: interstitial nephritis, crystalluria(^8) (including acute kidney injury).

(^1) See section "Special warnings and precautions for use".
(^2) See section "Special warnings and precautions for use".
(^3) Nausea is more frequently associated with higher oral doses of the medicinal product. The severity of gastrointestinal reactions may be reduced by taking Augmentin with food.
(^4) Including pseudomembranous colitis and haemorrhagic colitis (see section "Special warnings and 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 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 "Special warnings and precautions for use".
(^{10}) See section "Contraindications" and "Special warnings and precautions for use".
(^{11}) Discolouration of tooth enamel has very rarely been reported in children. Careful oral hygiene may prevent such discolouration, as this phenomenon can be removed by tooth brushing.

Shelf life

2 years.

Storage conditions

Store original packaging tightly closed at temperatures below 25°C in a dry place.

Reconstituted suspension should be stored in the refrigerator at 2–8°C for up to 7 days. Keep out of the reach of children.

Packaging

Powder for oral suspension to prepare 70 ml of suspension in flasks made of colourless glass with a metal screw cap (with tamper-evident seal and an internal polymer film), supplied with a measuring cap, dosing syringe, or measuring spoon, packed in a cardboard box; or with a child-resistant closure together with a dosing syringe or measuring spoon, packed in a cardboard box.

Prescription status

Prescription only.

Manufacturer

SmithKline Beecham Pharmaceuticals, United Kingdom.

Manufacturer's name and address

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