Amoxiclav®

for medical use of the medicinal product AMOKSIKLAV® (AMOKSIKLAV®)

Composition:

Active substances: amoxicillin, clavulanic acid;

5 ml of oral suspension contains 250.00 mg of amoxicillin, equivalent to 287.03 mg of amoxicillin trihydrate, and 66.88 mg (including 7% excess) of clavulanic acid, equivalent to 79.71 mg of potassium clavulanate;

Excipients: colloidal anhydrous silicon dioxide, xanthan gum, strawberry flavor, crospovidone, aspartame, sodium carmellose, anhydrous silicon dioxide.

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties: white to creamy-colored 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 (a beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) involved in the biosynthetic metabolism of bacterial peptidoglycan, an essential structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, resulting in cell lysis and death.

Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria; therefore, the antimicrobial spectrum of amoxicillin as monotherapy does not include organisms producing these enzymes.

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

PK/PD relationship

Time above the minimum inhibitory concentration (T > MIC) is considered the primary pharmacodynamic determinant of 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 antibacterial agent for its target.

Reduced bacterial permeability 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 can vary geographically and over time for individual species, so local information on susceptibility should be sought, 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 levels. Both components are rapidly and well absorbed following oral administration. The bioavailability of amoxicillin and clavulanic acid is approximately 70% following oral administration. The plasma profiles of both components are identical, and the time to reach maximum plasma concentration (Tmax) for each component is approximately one hour.

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 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 can 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 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 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 "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 in adults and children of bacterial infections caused by microorganisms sensitive to the drug, 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.

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

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 β-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 types of interactions.

Concomitant use of probenecid is not recommended. Probenecid reduces renal tubular secretion of amoxicillin. Concomitant administration of probenecid may lead to increased and prolonged blood levels of amoxicillin.

Concomitant use of allopurinol during amoxicillin therapy may increase the likelihood of allergic skin reactions. There are no data on concomitant use of allopurinol and Augmentin®.

Like other antibiotics, Augmentin® may affect the gut flora, leading to reduced reabsorption of estrogens and decreased efficacy of combined oral contraceptives.

Isolated reports indicate increased international normalized ratio (INR) in patients receiving acenocoumarol or warfarin and taking amoxicillin. If such concomitant use is necessary, prothrombin time or INR should be closely monitored when initiating or discontinuing treatment with the combination drug containing amoxicillin.

Augmentin® should not be used concomitantly with bacteriostatic chemotherapeutic agents/antibiotics (chloramphenicol, macrolides, tetracyclines, or sulfonamides), as an antagonistic effect has been observed in vitro with such combinations.

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

Concomitant use of amoxicillin with clavulanic acid and mycophenolate mofetil has been reported to reduce plasma concentrations of the active metabolite of mycophenolic acid by approximately 50%. This change in pre-dose levels may not fully reflect changes in total exposure to mycophenolic acid. Therefore, dosage adjustment of mycophenolate mofetil is usually not required unless there is clinical evidence of graft dysfunction. However, close monitoring is necessary during and for some time after antibiotic therapy.

Special precautions for use.

Prior to initiating therapy with the drug, it is necessary to accurately determine the history of hypersensitivity reactions to penicillins, cephalosporins, or other allergens.

Severe hypersensitivity reactions, occasionally resulting in fatalities (including anaphylactoid 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 in patients with a history of penicillin hypersensitivity and in patients with atopic diseases. In case of an allergic reaction, amoxicillin should be discontinued and appropriate alternative therapy initiated. If it is confirmed that the infection is caused by microorganisms sensitive to amoxicillin, consideration should be given to switching from the combination amoxicillin/clavulanic acid to amoxicillin alone, in accordance with official recommendations.

This dosage form of Augmentin® should not be used when there is a high risk of pathogen resistance to β-lactams, nor for the treatment of pneumonia caused by penicillin-resistant strains of S. pneumoniae. Inadequate efficacy of the drug due to microbial resistance has been reported.

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

The drug should not be prescribed if infectious mononucleosis is suspected, as rash resembling measles has been observed when amoxicillin is administered in this condition.

Prolonged use of the drug may occasionally lead to overgrowth of microorganisms insensitive to Augmentin® and development of pseudomembranous colitis of varying severity. In cases of severe persistent diarrhea following antimicrobial therapy, it is important to rule out this condition. Antiperistaltic agents are contraindicated. In the event of antibiotic-associated colitis, treatment with the drug should be immediately discontinued, medical advice should be sought, and appropriate therapy initiated.

With prolonged use of this and other broad-spectrum antibiotics, superinfection with resistant bacteria and fungi (Pseudomonas spp., Candida albicans) may occur, requiring discontinuation of therapy and administration of alternative agents.

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

Development of pustular lesions at the beginning of treatment, suggestive of multifocal erythema, may be a symptom of acute generalized exanthematous pustulosis (AGEP). In such cases, treatment must be discontinued, and further use of amoxicillin is contraindicated.

There have been isolated reports of severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis) during treatment, necessitating immediate discontinuation of the drug.

Use of the drug may be associated with an increased risk of necrotizing enterocolitis in newborns (see section "Use during pregnancy or breastfeeding").

Occasionally, patients receiving Augmentin® and oral anticoagulants may experience excessive prolongation of prothrombin time (elevated INR levels). Appropriate monitoring is required when anticoagulants are used concomitantly. Dose adjustment of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

The drug should be prescribed with caution in patients showing signs of hepatic insufficiency. Hepatic adverse reactions have occurred mainly in males and elderly patients and have been associated with prolonged treatment. Such events have been very rarely reported in children. In all patient groups, symptoms and signs usually appeared during or immediately after treatment, although in some cases they occurred several months after discontinuation. These events were generally reversible. Hepatic adverse reactions may be severe and very rarely fatal. They have always occurred in patients with severe underlying diseases or concomitant use of drugs known to have potential hepatotoxic effects.

Dosage adjustment is required in patients with impaired renal function according to the degree of impairment.

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

Amoxicillin may precipitate in catheters inserted into the urinary bladder when high doses are used. Regular monitoring of catheter status is required in such cases.

When using amoxicillin for glucose testing in urine, enzymatic methods based on glucose oxidase should be used, as other methods may yield false-positive results.

The presence of clavulanic acid in the drug may cause non-specific binding of IgG and albumin to erythrocyte membranes, potentially resulting in a false-positive Coombs test.

False-positive results in tests for Aspergillus have been reported in patients receiving amoxicillin/clavulanic acid (using the Bio-Rad Laboratories Platelia Aspergillus EIA test), despite subsequent absence of aspergillosis. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses have been reported during immunoassay testing for Aspergillus. Therefore, such positive results should be interpreted cautiously and confirmed by other diagnostic methods.

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

Prolonged use may, in individual cases, lead to overgrowth of microorganisms insensitive to the drug.

Antibiotic-associated colitis, varying in severity 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. In case of suspected antibiotic-associated colitis, Augmentin should be discontinued immediately, medical attention should be sought, and appropriate treatment initiated. Antiperistaltic agents are contraindicated in such cases.

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 of the medicinal product) 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 documented, including progression to shock.

Use during pregnancy or breastfeeding.

Pregnancy. Reproductive studies in animals with oral and parenteral forms of Augmentin did not reveal any 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, use of the drug during pregnancy, especially in the first trimester, should be avoided unless, in the opinion of the physician, such use is necessary.

Breastfeeding period. Both active components of the drug are excreted in breast milk (there is no information regarding 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 outweighs the risk.

Ability to influence reaction speed when driving or operating machinery.

No studies have been conducted to assess the drug’s effect on the ability to drive or operate machinery. However, adverse reactions (e.g., allergic reactions, dizziness, convulsions) may occur, which could impair the ability to drive or operate machinery.

Method of Administration and Dosage

Dosages are indicated in units of amoxicillin/clavulanic acid.

When selecting the dose of Amoxiclav®, the following should be considered:

• Expected pathogenic microorganisms and their likely susceptibility to the active substances;
• Severity and site of infection;
• Age, body weight, and renal function status of the patient.

If necessary, consider the appropriateness of using alternative formulations of Amoxiclav® (e.g., those containing higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid).

The duration of therapy depends on the course of the disease. Treatment should not be continued for more than 14 days without re-evaluation of the patient's condition.

Adults and children with body weight ≥ 40 kg: 500 mg/125 mg three times daily.

Children with body weight < 40 kg: from 20 mg/5 mg per 1 kg of body weight per day (for mild to moderate infections) up to 60 mg/15 mg per 1 kg of body weight per day (for severe infections) given in three separate doses. The maximum daily dose of the drug is 2400 mg/600 mg.

For children under 2 years of age, the dose should not exceed 40 mg/10 mg/kg body weight per day.

There are no clinical data on the use of Amoxiclav® suspension for the treatment of children under 2 months of age; therefore, dosage recommendations are not available.

An oral dosing spoon marked with graduations of 1.25 / 2.5 / 5 mL or a 5 mL oral syringe with 0.1 mL graduations is provided for measuring the suspension.

The oral syringe is calibrated to ensure accurate and reproducible dosing. The volume of suspension should be calculated according to the child's body weight, not age. Equal doses of the drug should be administered every 8 hours.

Elderly patients. Dose adjustment is not required.

Renal impairment. Dose adjustment is based on the maximum recommended doses of amoxicillin and depends on glomerular filtration rate. For patients with creatinine clearance above 30 mL/min, no dose adjustment is necessary.

Adults and children with body weight ≥ 40 kg

Children with body weight < 40 kg

Hepatic impairment. Use the drug with caution. Liver function should be monitored regularly.

Route of administration. To ensure optimal absorption and reduce the potential for gastrointestinal adverse effects, the drug should be taken at the beginning of a meal.

Treatment may be initiated with parenteral administration of the drug, followed by continuation with the oral formulation.

Preparation of suspension. After opening the screw cap, ensure that the bottle cap seal is intact and securely attached to the neck of the bottle. After removing the screw cap, verify that the bottle cap seal is intact and firmly affixed to the bottle rim.

Shake the vial to loosen the powder from the walls and bottom. Add drinking water in two portions (first up to 2/3 of the vial, then up to the circular mark on the label), shaking the vial each time. SHAKE WELL BEFORE EACH USE.

Do not use this medicinal product if lumps of powder are visible in the vial before reconstitution.

After reconstitution, the suspension should be white to creamy in color.

Do not use the reconstituted suspension if its color differs from that described above.

Children.

The suspension formulation of the drug may be administered to children aged 2 months and older.

Overdose.

Symptoms

Symptoms of gastrointestinal disturbances and fluid and electrolyte imbalance may occur. Amoxicillin crystalluria 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.

Precipitation of amoxicillin in urinary bladder 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.

Side effects.

Adverse effects have been classified according to their frequency of occurrence – from very common to very rare. The following classification of adverse event frequency is used:

very common ≥ 1/10; common ≥ 1/100 and < 1/10; uncommon ≥ 1/1,000 and < 1/100; rare ≥ 1/10,000 and < 1/1,000; very rare < 1/10,000.

Infections and infestations. Common – candidiasis of the skin and mucous membranes. Very rare – overgrowth of non-susceptible microorganisms.

Blood and lymphatic system disorders. Rare – reversible leukopenia (including neutropenia) and thrombocytopenia. Very rare – reversible agranulocytosis and hemolytic anemia. Prolongation of bleeding time and prothrombin index.

Immune system disorders. Very rare – angioneurotic edema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.

Nervous system disorders. Uncommon – dizziness, headache. Very rare – reversible hyperactivity, aseptic meningitis, and convulsions. Seizures may occur in patients with impaired renal function or in those receiving high doses of the drug. Unknown: aseptic meningitis.

Cardiac disorders. Unknown – Kounis syndrome.

Gastrointestinal disorders. Adults: Very common – diarrhea. Common – nausea, vomiting.

Children: Common – diarrhea, nausea, vomiting. Isolated reports of tooth discoloration, which can be removed by tooth cleaning.

Nausea is more frequently associated with high doses of the drug. The above gastrointestinal symptoms may be reduced by taking the medication at the beginning of a meal.

Uncommon – digestive disturbances. Very rare – antibiotic-associated colitis (including pseudomembranous colitis and hemorrhagic colitis), black "hairy" tongue. Very rare in children – superficial tooth discoloration. Proper oral hygiene may prevent this phenomenon. Discoloration can be removed by tooth brushing.

In one study in women with preterm rupture of membranes, use of the drug was reported to be associated with an increased risk of necrotizing enterocolitis in newborns. Unknown – drug-induced enterocolitis syndrome (DIES), acute pancreatitis.

Hepatobiliary disorders. Uncommon – mild elevations in AST and/or ALT levels are observed in patients treated with β-lactam antibiotics. Very rare – hepatitis and cholestatic jaundice. These events have been reported with other penicillins and cephalosporins. Hepatitis occurs mainly in males and elderly patients, and may be associated with prolonged treatment with the drug.

These events have occurred very rarely in children.

Symptoms may appear during or immediately after treatment, but in some cases may occur several weeks after treatment has ended. These events are usually reversible. Fatal cases have been reported extremely rarely (less than 1 report per approximately 4 million prescriptions), always occurring in patients with severe underlying disease or in patients receiving concomitant medications with known hepatotoxic potential.

Skin and subcutaneous tissue disorders. Uncommon – skin rash, pruritus, urticaria. Rare – erythema multiforme. Very rare – Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative bullous dermatitis, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

If any allergic dermatitis occurs, treatment should be discontinued. Unknown – linear immunoglobulin A (IgA) disease.

Renal and urinary disorders. Very rare – interstitial nephritis. Unknown – crystalluria (including acute kidney injury).

Shelf life. 36 months.

Storage conditions.

Store at temperatures not exceeding 30 °C.

Keep out of reach of children.

The bottle containing the ready-to-use suspension should be stored at 2–8 °C for no more than 7 days.

Packaging. 15.8 g of powder in a bottle; 1 bottle with a measuring spoon or oral syringe in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Sandoz GmbH – Production Unit Anti-Infectives GMP & Chemical Operations Kufstein (AICH GMP Kufstein).

Manufacturer's address and location of operations.

Biochemistrasse 10, 6250 Kufstein, Austria.