Amoxiclav 2X film-coated tablets 500 mg + 125 mg No. 14

Instructions Amoxiclav 2X film-coated tablets 500 mg + 125 mg No. 14

Composition

active ingredients: amoxicillin, clavulanic acid;

1 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;

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

Dosage form

Film-coated tablets.

Main physicochemical properties: white to slightly yellowish oval, biconvex tablets, film-coated, embossed with GG N6 on one side.

Pharmacotherapeutic group

Antibacterials for systemic use. Beta-lactam antibiotics, penicillins. Combinations of penicillins with beta-lactamase inhibitors. ATX code J01C R02.

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) in the biosynthetic metabolism of bacterial peptidoglycan, an integral 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 cleavage by beta-lactamases produced by resistant bacteria, therefore the spectrum of activity of amoxicillin as monotherapy does not include organisms that produce these enzymes.

Clavulanic acid is a beta-lactam structurally related to the penicillins. It inactivates some beta-lactamase enzymes, thereby preventing the inactivation of amoxicillin. Clavulanic acid as monotherapy does not exhibit clinically useful antibacterial effects.

PK/PD ratio. The time above the minimum inhibitory concentration (C>MIC) is considered the main factor determining the efficacy of amoxicillin.

Mechanisms of resistance.

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

- inactivation by bacterial beta-lactamases that are not inhibited by clavulanic acid themselves, including classes B, C and D;

- conversion of penicillin-binding proteins, which reduces the affinity of the antibacterial drug to the target.

Bacterial permeability or the reflux pump mechanism can cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.

Limit values.

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 susceptibility information is desirable, particularly when treating severe infections. Expert opinion should be sought when the local prevalence of resistance is such that the utility of the agent, at least in some types of infections, is questionable.

Gram-negative aerobes: Acinetobacter spp., Citrobacter freundii, Enterobacter spp., Legionella pneumophila, Morganella morganii, Providencia spp., Pseudomonas spp., Serratia spp., Stenotrophomonas maltophilia.

Other microorganisms:

Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetti, Mycoplasma pneumoniae.

Pharmacokinetics.

Absorption. Amoxicillin and clavulanic acid completely dissociate in aqueous solution at physiological pH. Both components are rapidly and well absorbed after 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 maximum plasma concentration (Tmax) for each component is approximately one hour.

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

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

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

Both amoxicillin and clavulanic acid are known to cross the placental barrier (see section "Use during pregnancy or lactation").

Biotransformation: Amoxicillin is partially excreted in the urine as inactive penicilloic acid in amounts equivalent to 10-25% of the initial dose. Clavulanic acid is extensively metabolized in humans and is excreted in the urine and feces and as carbon dioxide in exhaled air.

Excretion: The primary route of excretion of amoxicillin is the kidney, while clavulanic acid is excreted both renally and by 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 is 50-85% for amoxicillin and 27-60% for clavulanic acid over a 24-hour period. In the case of clavulanic acid, the largest amount of the substance is excreted within the first 2 hours after administration.

Concomitant use of probenecid slows down the elimination of amoxicillin, but does not delay the renal excretion of clavulanic acid (see section "Interaction with other medicinal products and other types of interactions").

Age. The half-life of amoxicillin is identical for children aged 3 months to 2 years, older children and adults. For children (including premature infants) in the first week of life, the frequency of administration should not exceed 2 times a day due to the immaturity of the renal excretion pathway. Since elderly patients are more prone to decreased renal function, dosage should be selected with caution, and monitoring of renal function is also recommended.

Renal impairment. The total serum clearance of amoxicillin/clavulanic acid decreases proportionally with decreasing renal function. The decrease in clearance is more pronounced for amoxicillin than for clavulanic acid, since a greater proportion of amoxicillin is excreted by the kidneys. In renal insufficiency, the dosage should prevent excessive accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2).

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

Indication

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 dentoalveolar abscesses with widespread cellulitis;

– infections of bones and joints, including osteomyelitis.

Contraindication

Hypersensitivity to any components 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 jaundice or liver dysfunction associated with the use of amoxicillin/clavulanate.

Interaction with other medicinal products and other types of interactions

Oral anticoagulants.

Oral anticoagulants and penicillin antibiotics are widely used in clinical practice without any reports of interactions. However, cases of increased international normalization ratio have been described in patients taking acenocoumarol or warfarin and who were prescribed a course of amoxicillin. If concomitant use of such drugs is necessary, the prothrombin index or international normalization ratio should be carefully monitored when amoxicillin is added or discontinued. In addition, dose adjustment of oral anticoagulants may be required (see sections 4.4 and 4.8).

Concomitant use of probenecid is not recommended. Probenecid reduces the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin.

Concomitant use of allopurinol during treatment with amoxicillin 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 the intestinal flora, leading to reduced reabsorption of estrogens and reduced effectiveness of combined oral contraceptives.

Amoxiclav® 2X should not be used together with bacteriostatic chemotherapeutic agents/antibiotics (chloramphenicol, macrolides, tetracyclines or sulfonamides), since antagonistic effects have been observed in vitro with such combinations.

Methotrexate: Penicillins may reduce the excretion of methotrexate, which may lead to a potential increase in toxicity.

Mycophenolate mofetil. In patients treated with mycophenolate mofetil, the overdosage concentration of the active metabolite mycophenolic acid may decrease by approximately 50% after initiation of oral amoxicillin/clavulanic acid. This change in overdosage level may not fully reflect the change in total mycophenolic acid exposure. Therefore, a change in mycophenolate mofetil dosage is not usually necessary unless there is clinical evidence of graft dysfunction. However, close monitoring is necessary during concomitant use and for some time after antibiotic therapy.

Application features

Before starting therapy with the drug, it is necessary to accurately determine the presence of a history of hypersensitivity reactions to penicillins, cephalosporins, other beta-lactam drugs (see sections "Contraindications" and "Adverse Reactions").

Serious hypersensitivity reactions, some of which were fatal (including anaphylactoid and severe cutaneous adverse reactions), have been reported in patients treated with penicillin. Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction (see section 4.8). Such reactions are more likely to occur in patients with a history of penicillin hypersensitivity and in patients with atopic diseases. If an allergic reaction occurs, amoxicillin should be discontinued and appropriate alternative therapy should be initiated.

If the infection is proven to be caused by microorganisms susceptible to amoxicillin, consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in accordance with official recommendations.

This dosage form of the drug should not be used in cases of high risk of pathogens being resistant to beta-lactams and should not be used to treat pneumonia caused by penicillin-resistant strains of S. pneumoniae.

In patients with impaired renal function and in patients taking high doses of the drug, seizures may occur (see section "Adverse reactions").

The drug should not be prescribed if infectious mononucleosis is suspected, since cases of choreoid rashes have been observed when amoxicillin was used for this pathology.

Concomitant use of allopurinol during treatment with amoxicillin increases the likelihood of allergic skin reactions.

With long-term use of the drug, as with other broad-spectrum antibiotics, superinfection with resistant bacteria and fungi (Pseudomonas spp., Candida albicans) may occur, which requires discontinuation of therapy and the use of other drugs.

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

The development of erythema multiforme associated with pustules at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis. In such cases, treatment should be discontinued and further use of amoxicillin is contraindicated.

Occasionally, patients taking Amoxiclav® 2X and oral anticoagulants may experience an abnormal prolongation of prothrombin time (increased INR). Appropriate monitoring is necessary when anticoagulants are taken concomitantly. Dose adjustment of oral anticoagulants may be necessary to maintain the required level of anticoagulation.

The drug should be administered with caution to patients with signs of hepatic insufficiency (see sections "Contraindications", "Dosage and administration", "Adverse reactions"). Adverse reactions from the liver occurred mainly in men and elderly patients and were associated with long-term treatment. Such events have been reported very rarely in children. In all patient groups, symptoms and signs usually occurred during or immediately after treatment, but in some cases they appeared several months after discontinuation of treatment. In general, these events were reversible. Adverse reactions from the liver can be severe and very rarely fatal. They always occurred in patients with severe concomitant diseases or with concomitant use of drugs known to have a potential negative effect on the liver (see section "Adverse reactions").

For patients with renal impairment, the dose should be adjusted according to the degree of impairment (see section "Method of administration and dosage").

In patients with reduced urine output, crystalluria (including acute kidney injury) has been observed very rarely, mainly with parenteral therapy. Adequate fluid intake and diuresis should be maintained during high doses of amoxicillin to reduce the likelihood of amoxicillin crystalluria. In patients with bladder catheterization, the patency of the catheters should be checked regularly (see sections "Adverse Reactions" and "Overdose").

When using high doses, amoxicillin may precipitate in a catheter inserted into the bladder. In such cases, regular monitoring of the condition of the catheter is necessary.

During treatment with amoxicillin, enzymatic reactions with glucose oxidase should be used to determine the level of glucose in the urine, as other methods may give false-positive results.

The presence of clavulanic acid in the drug may cause nonspecific binding of IgG and albumin on erythrocyte membranes, therefore, as a result, a false-positive result is possible when performing the Coombs test.

Positive results have been reported in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection using the Bio-Rad Laboratories Platelia Aspergillus enzyme immunoassay. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses have been reported in patients receiving Bio-Rad Laboratories Platelia Aspergillus enzyme immunoassay. Therefore, such positive results in patients receiving amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.

Drug-induced enterocolitis syndrome (DIES) has been reported, mainly in children receiving amoxicillin/clavulanic acid (see section 4.8). Drug-induced enterocolitis syndrome is an allergic reaction with the main symptom being prolonged vomiting (1-4 hours after the drug) in the absence of allergic skin or respiratory symptoms. Additional symptoms may include abdominal pain, diarrhoea, hypotension or leukocytosis with neutrophilia. Serious cases, including progression to shock, have been reported.

Use during pregnancy or breastfeeding

Breastfeeding. Both active components of the drug are excreted in breast milk (there is no information on the effect of clavulanic acid on a breastfed infant). Accordingly, diarrhea and fungal infection of the mucous membranes may occur in a breastfed infant, so breastfeeding should be discontinued. The possibility of allergic reactions should be taken into account. The drug can be used during breastfeeding only if, in the opinion of the doctor, the benefit of use outweighs the risk.

Ability to influence reaction speed when driving vehicles or other mechanisms

Studies on the ability of the drug to affect the reaction speed when driving or using other mechanisms have not been conducted. However, adverse reactions (e.g. allergic reactions, dizziness, convulsions) may occur, which may affect the ability to drive or use other mechanisms.

Method of administration and doses

The drug should be used in accordance with official recommendations for antibiotic therapy and local antibiotic susceptibility data. Susceptibility to amoxicillin/clavulanate varies between regions and may change over time. Local susceptibility data should be consulted if necessary and, if necessary, microbiological determination and susceptibility testing should be performed. The suggested dose range depends on the expected pathogens and their susceptibility to antibacterial drugs, the severity of the disease and the location of the infection, the age, body weight and renal function of the patient.

For adults and children weighing ≥ 40 kg, the daily dose is 1500 mg amoxicillin/375 mg clavulanic acid (3 tablets) when administered as indicated below.

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

If higher doses of amoxicillin are required for treatment, other forms of the drug should be used to avoid prescribing excessively high doses of clavulanic acid.

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

Adults and children weighing ≥ 40 kg: 1 tablet of 500 mg/125 mg 3 times a day.

Children aged 6 years and over with a body weight of 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 3 doses.

Since the tablet cannot be divided, children weighing less than 25 kg should not be given this form of the drug.

Elderly patients. No dose adjustment is required for elderly patients. If necessary, adjust the dose depending on renal function.

Dosage in renal impairment. Dosage is based on the calculation of the maximum amoxicillin level. There is no need to change the dose for patients with creatinine clearance > 30 ml/min.

Adults and children weighing ≥ 40 kg.

Children aged 6 years and over weighing 25 to 40 kg: Since the tablet cannot be divided, this formulation should not be administered to children aged 6 years and over weighing 25 to 40 kg with a creatinine clearance of less than 30 ml/min or to children on haemodialysis.

Dosage 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 reduce possible side effects from the digestive tract, the drug should be taken at the beginning of a meal.

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

Treatment can be initiated with parenteral administration and then continued with oral administration.

Children

The drug in this dosage can be used in children aged 6 years and older with a body weight of at least 25 kg.

Overdose

Symptoms: Gastrointestinal symptoms and fluid and electrolyte imbalance may occur. Amoxicillin crystalluria has been reported, leading in some cases to renal failure (see section 4.4).

In patients with impaired renal function and in patients taking high doses of the drug, seizures may occur.

Amoxicillin has been reported to settle in bladder catheters, mainly after intravenous administration at high doses. Catheter patency should be checked regularly (see section 4.4).

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 list of adverse drug reactions known from clinical studies and post-marketing surveillance and classified by MedDRA system organ class is given below.

The following classification of the frequency of side effects is used: very common (≥ 1/10); common (≥ 1/100 and < 1/10); uncommon (≥ 1/1000 and < 1/100); rare (≥ 1/10,000 and < 1/1000); very rare (< 1/10,000); frequency unknown (frequency cannot be estimated from the available data).

Infections and infestations: Common: candidiasis of the skin and mucous membranes.

Frequency unknown: overgrowth of microorganisms insensitive to the drug.

From the side of the hematopoietic and lymphatic system. Rare: reversible leukopenia (including neutropenia) and thrombocytopenia. Frequency unknown: reversible agranulocytosis and hemolytic anemia; increase in bleeding time and prothrombin index1.

Nervous system disorders: Uncommon: dizziness, headache. Frequency not known: reversible hyperactivity and convulsions2, aseptic meningitis.

Cardiac disorders: Frequency unknown – Kounis syndrome.

Gastrointestinal disorders: Common: diarrhoea, nausea3, vomiting. Uncommon: stomach upset.

Frequency not known: antibiotic-associated colitis4, black hairy tongue, tooth enamel discolouration11, drug-induced enterocolitis syndrome (DIES), acute pancreatitis.

Hepatobiliary disorders: Uncommon: increased AST and/or ALT5. Frequency not known: hepatitis6 and cholestatic jaundice6.

Skin and subcutaneous tissue disorders7. Uncommon: skin rash, pruritus, urticaria. Rare: erythema multiforme. Frequency not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis8, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), linear immunoglobulin A (IgA) disease.

Renal and urinary disorders: Very rare: interstitial nephritis,

Frequency unknown – crystalluria9 (including acute kidney injury).

Immune system disorders10. Frequency not known: angioedema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.

1 See section "Application features".

2 See section "Application features".

3 Nausea is more commonly associated with higher oral doses of the drug. If gastrointestinal reactions occur, their severity may be reduced by taking the drug with food.

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

5 Moderate elevations in AST and/or ALT levels were more frequently observed in patients treated with beta-lactam antibiotics, but the significance of these findings is unknown.

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

7 If hypersensitivity reactions (dermatitis) occur, the use of the drug should be discontinued (see section "Special instructions").

8 See section "Application features".

9 See section “Overdose”.

10 See sections “Contraindications” and “Special instructions for use”.

11 Tooth enamel discoloration has been reported very rarely in children. Careful oral hygiene can prevent such discoloration, as it is removed by brushing.

Expiration date

2 years.

Storage conditions

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging

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

Vacation category

According to the recipe.

Producer

Sandoz GmbH - Production site Anti-infectives and Chemical Operations Kundl (AIHO Kundl).

Location of the manufacturer and address of its place of business

Biochemiststrasse 10, 6250 Kundl, Austria.