Augmentin® 2x

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMOKSIKLAV® 2X (AMOKSIKLAV®2X)

Composition:

Active substances: amoxicillin, clavulanic acid;

One tablet contains 500 mg of amoxicillin in the form of trihydrate and 125 mg of clavulanic acid in the form of potassium salt;

Excipients: colloidal anhydrous silicon dioxide, magnesium stearate, sodium starch glycolate (type A), microcrystalline cellulose PH-112;

Coating: triethyl citrate, hypromellose 2910, talc, titanium dioxide (E 171), aqueous dispersion of ethylcellulose.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval, biconvex, film-coated tablets of white to slightly yellowish color, with embossing GG N6 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) 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 alone has no clinically useful antibacterial activity.

PK/PD relationship. The time above the minimum inhibitory concentration (T>MIC) is considered the primary factor determining the efficacy of amoxicillin.

Mechanisms of resistance.

There are two main mechanisms of resistance to amoxicillin/clavulanic acid:

• Inactivation by bacterial beta-lactamases that are not themselves inhibited by clavulanic acid, including classes B, C, and D;
• Alteration of penicillin-binding proteins leading to reduced affinity of the antibacterial agent for its target.

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

Clinical breakpoints.

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

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 solution at physiological pH. Both components are rapidly and well absorbed following oral administration. The bioavailability of amoxicillin and clavulanic acid is approximately 70% after oral administration. The plasma profiles of both components are identical, and the time to 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.

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 any 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 is known 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 via the kidneys and through extrarenal mechanisms.

In healthy volunteers, the mean elimination half-life of amoxicillin/clavulanic acid is approximately 1 hour, and the mean total clearance is approximately 25 L/hour. Various studies have shown that urinary excretion amounts to 50–85% for amoxicillin and 27–60% for clavulanic acid over a 24-hour period. In the case of 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. Patients with hepatic impairment should be treated with caution and require regular monitoring of liver function.

Clinical characteristics.

Indications.

Treatment of bacterial infections caused by microorganisms sensitive to the drug:

• 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.

Contraindications.

Hypersensitivity to any component of the drug or to any penicillin antibacterial agents.

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

History of cholestatic 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 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. If concomitant use is necessary, prothrombin time or INR should be carefully monitored when starting or stopping amoxicillin. Additionally, dose adjustment of oral anticoagulants may be required (see sections "Special precautions for use" and "Adverse reactions").

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.

Concurrent use of allopurinol during amoxicillin therapy may increase the likelihood of allergic skin reactions. There are no data on the concomitant use of allopurinol and Amoxiclav® 2X.

Like other antibiotics, Amoxiclav® 2X may affect gut flora, leading to reduced reabsorption of estrogens and decreased effectiveness of combined oral contraceptives.

Amoxiclav® 2X 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.

Methotrexate. Penicillins may reduce methotrexate excretion, potentially increasing its toxicity.

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 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 the drug, it is essential to determine accurately whether the patient has a history of hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam antibiotics (see sections "Contraindications" and "Adverse reactions").

Serious hypersensitivity reactions, occasionally resulting in fatal outcomes (including anaphylactoid reactions and severe skin adverse reactions), have been reported in patients receiving penicillin therapy. Hypersensitivity reactions may also progress to Kounis syndrome—a serious allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). Such reactions are more likely in patients with a history of penicillin hypersensitivity and in those with atopic diseases. In case of an allergic reaction, amoxicillin should be discontinued immediately and appropriate alternative therapy initiated.

If it has been established that the infection is caused by microorganisms susceptible to amoxicillin, consideration should be given to switching from the combination amoxicillin/clavulanic acid to amoxicillin alone, in accordance with official guidelines.

This medicinal product formulation should not be used when there is a high likelihood that pathogens are resistant to beta-lactams, and it should not be used for the treatment of pneumonia caused by penicillin-resistant S. pneumoniae strains.

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

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.

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

Prolonged use of the drug may occasionally lead to overgrowth of microorganisms insensitive to Amoxiclav® 2X and to the 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 stopped immediately, medical advice sought, and appropriate therapy initiated.

With prolonged use of the drug, as with other broad-spectrum antibiotics, superinfection with resistant bacteria and fungi (Pseudomonas spp., Candida albicans) may occur, necessitating discontinuation of therapy and initiation of alternative treatment.

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

Development of erythema multiforme with pustules at the beginning of treatment may be a sign of acute generalized exanthematous pustulosis. In such cases, treatment must be discontinued, and further use of amoxicillin is contraindicated.

Rarely, patients receiving Amoxiclav® 2X 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 impairment (see sections "Contraindications," "Dosage and administration," and "Adverse reactions"). Hepatic adverse reactions have occurred primarily in males and elderly patients and have been associated with prolonged treatment. Such events have been reported very rarely in children. In all patient groups, symptoms and signs usually appeared during or immediately after treatment, although in some cases they emerged several months after discontinuation of therapy. These events were generally reversible. Hepatic adverse reactions may be severe and very rarely may be fatal. They have always occurred in patients with serious underlying diseases or concomitant use of medicinal products known to have potential hepatotoxic effects (see section "Adverse reactions").

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

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

When high doses of amoxicillin are administered, precipitation in urinary catheters may occur. Regular monitoring of catheter status is required in such cases.

When using amoxicillin for treatment, enzymatic glucose oxidase methods should be used to determine glucose levels in urine, as other methods may yield false-positive results.

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

Positive results in enzyme immunoassays using the Platelia Aspergillus kit (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 are known to occur with the Platelia Aspergillus immunoassay (Bio-Rad Laboratories). Therefore, positive results in patients treated with amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods.

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 administration of the drug) 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 the drug have not revealed any teratogenic effects. In one study involving women with premature rupture of fetal membranes, prophylactic use of the drug was reported to be associated with an increased risk of necrotizing enterocolitis in newborns. As with other medicinal products, the drug 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 breastfed infants). Diarrhea and fungal infections of mucous membranes may therefore occur in breastfed infants, and breastfeeding should be discontinued. The possibility of allergic reactions should also be considered. The drug 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 the speed of reaction while 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, adverse reactions (e.g., allergic reactions, dizziness, seizures) may occur that could impair the ability to drive or operate machinery.

Method of Administration and Dosage

The drug should be used in accordance with official recommendations for antibiotic therapy and local antibiotic susceptibility data. Susceptibility to amoxicillin/clavulanate varies across regions and may change over time. When necessary, local susceptibility data should be consulted, and microbiological identification and susceptibility testing should be performed. The recommended dosage range depends on the expected pathogens and their susceptibility to antibacterial agents, severity of the disease, 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 daily dose is 1500 mg amoxicillin/375 mg clavulanic acid (3 tablets), administered as described below.

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

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

The duration of treatment is determined by the physician based on the patient's clinical response. Some infections (e.g., osteomyelitis) require prolonged treatment.

Adults and children with body weight ≥ 40 kg: 1 tablet of 500 mg/125 mg three times daily.

Children aged 6 years and older with body weight from 25 to 40 kg: dose from 20 mg/5 mg/kg body weight/day to 60 mg/15 mg/kg body weight/day, divided into three doses.

Since the tablet cannot be divided, this formulation should not be administered to children with body weight below 25 kg.

Elderly patients. Dose adjustment in elderly patients is not required. Dose should be adjusted if necessary according to renal function.

Dosing in renal impairment. Dosing is based on calculation of maximum amoxicillin levels. 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 should not be administered to children aged 6 years 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. For optimal absorption and to minimize potential gastrointestinal adverse effects, the medication should be taken at the beginning of a meal.

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

Treatment may be initiated with parenteral administration, followed by continuation with oral therapy.

Children.

This medicinal product at this dosage strength may be used in children aged 6 years and older with body weight of at least 25 kg.

Overdose.

Symptoms. Symptoms of gastrointestinal disturbances and fluid and electrolyte imbalances 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.

Amoxicillin precipitation in urinary bladder 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 are diarrhea, nausea, and vomiting.

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

The following classification of frequency of adverse reactions is used: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Infections and infestations.
Common: candidiasis of the skin and mucous membranes.
Frequency not known: overgrowth of microorganisms not sensitive to the medicinal product.

Blood and lymphatic system disorders.
Rare: reversible leukopenia (including neutropenia) and thrombocytopenia.
Frequency not known: reversible agranulocytosis and hemolytic anemia; prolonged bleeding time and prothrombin time^1.

Nervous system disorders.
Uncommon: dizziness, headache.
Frequency not known: reversible hyperactivity and convulsions^2, aseptic meningitis.

Cardiac disorders.
Frequency not known: Kounis syndrome.

Gastrointestinal disorders.
Common: diarrhea, nausea^3, vomiting.
Uncommon: gastric disturbances.
Frequency not known: antibiotic-associated colitis^4, "black hairy tongue", discoloration of tooth enamel^11, drug-induced enterocolitis syndrome (DIES), acute pancreatitis.

Hepatobiliary disorders.
Uncommon: increased levels of AST and/or ALT^5.
Frequency not known: hepatitis^6 and cholestatic jaundice^6.

Skin and subcutaneous tissue disorders^7.
Uncommon: skin rashes, pruritus, urticaria.
Rare: erythema multiforme.
Frequency not known: Stevens–Johnson syndrome, toxic epidermal necrolysis, exfoliative bullous dermatitis, acute generalized exanthematous pustulosis^8, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), linear IgA disease.

Renal and urinary disorders.
Very rare: interstitial nephritis.
Frequency not known: crystalluria^9 (including acute kidney injury).

Immune system disorders^10.
Frequency not known: angioneurotic edema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.

^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 the medicinal product 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 "Special precautions for use".
^9 See section "Overdose".
^10 See sections "Contraindications" and "Special precautions for use".

^11 Tooth discoloration has been very rarely reported in children. Careful oral hygiene may prevent this effect, as discoloration is usually removable by tooth brushing.

Shelf life. 2 years.

Storage conditions.
Store at temperatures not exceeding 25 °C in the original packaging.
Keep out of the reach and sight of children.

Packaging.
7 tablets in a blister or strip; 2 blisters or strips (7 × 2) in a cardboard box.

Prescription status. Prescription only.

Manufacturer.
Sandoz GmbH – Manufacturing Division Anti-Infectives GLZ and Chemical Operations Kundl (AIH GLZ Kundl).

Manufacturer's address and place of business.
Biochemiestrasse 10, 6250 Kundl, Austria.