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Amoksiklav Ò Trade name Amoksiklav Ò 2x 1000mg film-coated tablets Non-proprietary international name Amoxicillin, Clavulanic acid Dosage form Film-coated tablets. Description White to off-white, oval, film-coated tablets with a score line on both sides. The score line is intended for breaking the tablet to facilitate swallowing and not for dividing into equal doses. Composition Active substance: Amoxicillin and Clavulanic acid. Each tablet contains 875mg of amoxicillin in the form of trihydrate and 125mg of clavulanic acid in the form of potassium salt (in a 7:1 ratio). Excipients Core: Colloidal anhydrous silica, magnesium stearate, talc, povidone K25, microcrystalline cellulose, crospovidone; Film coating: Triethyl citrate, hypromellose, talc, ethylcellulose, titanium dioxide (E171). Pharmacotherapeutic group Antibacterial agent for systemic use; Beta-lactam antibacterial agents, penicillins; Penicillin combinations, including beta-lactamase inhibitors. ATC code: J01CR02. Pharmacological properties Pharmacodynamics Amoxicillin is a semi-synthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins) in the process of biosynthesis of peptidoglycan, an integral component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to loss of cell wall integrity, which usually results in cell lysis and death. Amoxicillin is degraded by beta-lactamases produced by resistant bacteria, so it is inactive against microorganisms that produce these enzymes. Clavulanic acid is structurally a beta-lactam similar to penicillins. It inhibits some beta-lactamases and prevents the inactivation of amoxicillin. Clavulanic acid itself does not have clinically useful antibacterial activity. The time above the minimum inhibitory concentration (T > MIC) is considered the main determinant of amoxicillin efficacy. The prevalence of resistance to individual species is characterized by geographical and temporal variations, so it is advisable to obtain local information on antibiotic resistance, especially in cases of severe infections. In cases where local indicators of antibiotic resistance cast doubt on the appropriateness of using the drug, at least for some types of infections, it is necessary to consult with appropriate specialists. Usually susceptible species Gram-positive aerobes: Enterococcus faecalis, Gardnerella vaginalis, Staphylococcus aureus (methicillin-susceptible strains)*, coagulase-negative staphylococci (methicillin-susceptible), Streptococcus agalacticae, Streptococcus pneumoniae1, Streptococcus pyogenes and other beta-hemolytic streptococci, viridans group streptococci. Gram-negative aerobes: Capnocytophaga spp., Eikenella corrodens, Haemophilus influenzae2, Moraxella catarrhalis, Pasteurella multocida. Anaerobes: Bacteroides fragilis, Fusobacterium nucleatum, Prevotella spp. Species with potential for acquired resistance Gram-positive aerobes: Enterococcus faecium#. Gram-negative aerobes: Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris. Species with intrinsic resistance 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. # Naturally intermediate susceptibility in the absence of acquired resistance mechanisms. * All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid. 1 Treatment of infections caused by penicillin-resistant Streptococcus pneumoniae with this drug should not be undertaken. 2 In some countries, strains of H. influenzae with reduced susceptibility have been identified, occurring with a frequency of more than 10%. Pharmacokinetics Amoxicillin and clavulanic acid are fully dissociated in water at physiological pH. After oral administration, both components are rapidly and well absorbed, with bioavailability reaching approximately 70%. The plasma concentration profiles of both components are similar, with the time to reach peak concentration (Tmax) for each substance being approximately one hour. When a group of healthy volunteers took the combination drug in tablet form 875 mg/125 mg twice daily on an empty stomach, peak serum concentrations (Cmax) were 11.64 ± 2.78 mcg/mL for amoxicillin and 2.18 ± 0.99 mcg/mL for clavulanic acid, with the time to reach peak serum concentrations (Tmax) being 1.5 hours (range 1.0–2.5) for amoxicillin and 1.25 hours (range 1.0–2.0) for clavulanic acid, with mean T1/2 values of 1.19 ± 0.21 hours for amoxicillin and 0.96 ± 0.12 hours for clavulanic acid. Approximately 25% of the total clavulanic acid content in plasma and approximately 18% of the total amoxicillin content in plasma are protein-bound. After intravenous administration, amoxicillin and clavulanic acid are found in the gallbladder, abdominal wall tissues, skin, adipose tissue, muscle tissue, synovial and peritoneal fluids, bile, and pus. Amoxicillin penetrates the cerebrospinal fluid only insignificantly. Amoxicillin and clavulanic acid are excreted into breast milk (clavulanic acid in trace amounts). Both active substances cross the placental barrier. The main route of amoxicillin excretion is the kidneys, while clavulanic acid is eliminated from the body by renal and extrarenal mechanisms. Age The half-life of amoxicillin is similar in children from three months to two years of age, in older children and adults. In elderly patients, the dose should be selected with caution due to possible impaired renal function; renal function monitoring is recommended. Impaired renal function The total plasma clearance of amoxicillin and clavulanic acid is reduced proportionally to the reduction in renal function. The reduction in clearance is more pronounced for amoxicillin than for clavulanic acid. In cases of impaired renal function, doses are selected to avoid excessive accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see "Dosage and Administration"). Impaired liver function Administer with caution and regularly monitor liver function. Indications Amoksiklav is indicated for the treatment of the following infections in adults and children: • Acute bacterial sinusitis (appropriately diagnosed); • Acute otitis media; • Acute exacerbation of chronic bronchitis (appropriately diagnosed); • Community-acquired pneumonia; • Cystitis; • Pyelonephritis; • Skin and soft tissue infections, particularly cellulitis, wounds from animal bites, severe dental abscess with spreading cellulitis; • Bone and joint infections, particularly osteomyelitis. Contraindications Hypersensitivity to the active or excipient substances of the drug, as well as to any penicillins. Severe immediate hypersensitivity reactions (e.g., anaphylaxis) to other beta-lactam drugs (e.g., cephalosporins, carbapenems, or monobactams) in the history. Jaundice or other liver damage in the history, following the use of amoxicillin/clavulanic acid. Special precautions and warnings Official recommendations on the appropriate use of antibacterial agents should be taken into account. Before starting treatment, a thorough medical history should be taken regarding hypersensitivity to penicillins, cephalosporins, or other beta-lactam drugs. Serious and sometimes fatal hypersensitivity reactions (including anaphylactic and severe skin adverse reactions) have been reported during penicillin therapy. Hypersensitivity reactions can also progress to Stevens-Johnson syndrome, a serious allergic reaction that can lead to myocardial infarction. They are most likely to develop in patients with a history of hypersensitivity reactions to penicillins and patients with atopy. In case of an allergic reaction, amoksiklav therapy should be discontinued and replaced with other appropriate antibacterial drugs. Drug-induced enterocolitis syndrome has been reported, mainly in children. This syndrome is an allergic reaction with prolonged vomiting as the leading symptom (1-4 hours after drug intake) in the absence of allergic skin or respiratory symptoms. Additional symptoms may include abdominal pain, diarrhea, hypotension, or leukocytosis with neutrophilia. Severe cases, including progression to shock, have also been reported. If such symptoms occur, discontinue the drug and seek immediate medical attention. In cases of proven susceptibility of the causative pathogens of the infection to amoxicillin, consider switching from amoksiklav to amoxicillin, in accordance with official guidelines. This drug is not suitable for use if there is a high risk that the suspected pathogens have reduced susceptibility or resistance to beta-lactam drugs, not sensitive to the beta-lactamase inhibitory action of clavulanic acid. This drug should not be used to treat infections caused by penicillin-resistant S. pneumoniae. Seizures may occur in patients with impaired renal function or those receiving high doses of the drug ("Adverse Reactions"). Amoksiklav therapy should be avoided if infectious mononucleosis is suspected, as a rash similar to measles may occur. Concomitant use of allopurinol during amoxicillin treatment potentially increases the likelihood of skin allergic reactions. Prolonged use of amoksiklav may lead to overgrowth of non-susceptible microorganisms. The development of generalized erythema with fever and pustules at the beginning of therapy is a potential symptom of acute generalized exanthematous pustulosis. Such a reaction requires discontinuation of amoksiklav therapy and is a contraindication for further use of amoxicillin. Treatment of patients with impaired liver function should be carried out with caution. Adverse liver events are primarily observed in men and elderly patients and are potentially associated with prolonged treatment. These adverse events have been very rarely observed in children. In all patient groups, signs and symptoms usually develop during or shortly after treatment, although in some cases they appear several weeks after discontinuation of therapy. They are usually reversible. Adverse liver events can be severe, with extremely rare reports of fatal outcomes. They have almost always occurred in patients with serious underlying disease or those taking concomitant medications with the potential to cause liver damage. Antibiotic-associated colitis has been reported with almost all antibacterial drugs; the severity can range from mild to life-threatening. Therefore, it is important to consider the presence of this diagnosis in patients with diarrhea during or after any course of antibiotic therapy. In case of development of antibiotic-associated colitis, amoksiklav intake should be immediately discontinued, a doctor should be consulted, and appropriate treatment initiated. In such situations, the use of intestinal peristalsis-inhibiting agents is contraindicated. During prolonged treatment, periodic evaluation of the function of various organ systems, including kidneys, liver, and hematopoietic organs, is recommended. When taken concurrently with anticoagulants, adequate control of coagulation parameters is mandatory (prolonged prothrombin time may occur). Dose adjustment of oral anticoagulants may be necessary to achieve the desired level of anticoagulation. For patients with renal insufficiency, dose adjustment is mandatory according to the degree of insufficiency (see "Dosage and Administration"). In patients with reduced diuresis, very rarely, mainly during therapy, crystalluria (crystallization of salts in urine) has been observed, which can lead to acute renal failure. When taking high doses of amoxicillin, it is recommended to consume sufficient fluids and maintain adequate urine output to reduce the likelihood of crystalluria. Patients with a urinary catheter in place must have its patency regularly monitored. If it is necessary to assess glucose levels in the urine, enzymatic methods using glucose oxidase should be used, as non-enzymatic methods sometimes give false-positive results. The presence of clavulanic acid in amoksiklav can cause non-specific binding of IgG and albumin to erythrocyte membranes, which can lead to false-positive Coombs test results. False-positive results of immunofluorometric assay (IFA) for Aspergillus have been reported in some patients taking the drug. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses have been observed within the scope of Aspergillus IFA tests. Positive test results in patients taking amoksiklav should be interpreted with caution and confirmed by other diagnostic methods. Pregnancy and lactation Limited data on the use of the drug during pregnancy do not indicate an increased risk of congenital anomalies. In women with premature rupture of fetal membranes, a potential association has been found between prophylactic treatment with amoxicillin/clavulanic acid and an increased risk of necrotizing enterocolitis in newborns. The drug should be avoided during pregnancy unless considered essential by the physician. Both active substances are excreted into breast milk. Diarrhea and fungal infections of mucous membranes may develop in breastfed infants, which may require discontinuation of breastfeeding. Sensitization may develop. Treatment with the drug during breastfeeding is possible only after assessment of the benefit-risk ratio by the treating physician. Effects on ability to drive and operate machinery Effects on ability to drive and operate machinery have not been studied. Adverse reactions (e.g., allergic reactions, dizziness, seizures) may develop, which can potentially affect the performance of these functions. Dosage and administration Doses reflect the composition of amoxicillin and clavulanic acid. When selecting the dose for the treatment of specific infections, the following factors are taken into account: · Suspected pathogens and their potential susceptibility to antibacterial agents; · Severity and localization of the infection; · Age, body weight, and renal function, as indicated below. When taking this drug twice daily at the recommended minimum doses, adults and children weighing 40 kg or more will receive a total recommended daily dose of 1750 mg of amoxicillin and 250 mg of clavulanic acid, and when taken three times daily, 2625 mg of amoxicillin and 375 mg of clavulanic acid. When taking this drug at the recommended minimum doses, the maximum daily dose for children weighing less than 40 kg is 1000-2800 mg of amoxicillin and 143-400 mg of clavulanic acid. If a higher daily dose of amoxicillin is required, it is recommended to select another form of the drug to avoid excessively high daily doses of clavulanic acid. The duration of treatment should not exceed 14 days without review (see "Special Precautions and Warnings" section for information on long-term treatment). Adults and children weighing 40 kg or more Recommended doses: - Standard dose: one tablet twice daily. - Relatively high dose: one tablet three times daily. Children weighing less than 40 kg Children weighing less than 40 kg can take amoksiklav tablets only on the recommendation of a doctor. Recommended doses: - From 25mg/3.6mg/kg/day to 45mg/6.4mg/kg/day, divided into two doses; - For the treatment of some infections (e.g., otitis media, sinusitis, and lower respiratory tract infections), a dose of 70mg/10mg/kg/day, divided into two doses, may be used; For the treatment of children aged 6 years and younger or weighing less than 25 kg, it is recommended to use amoxicillin/clavulanic acid in suspension form. Elderly patients Dose adjustment is not required. Patients with impaired renal function Patients with a creatinine clearance greater than 30 ml/min do not require dose adjustment. The use of this form of amoksiklav is not recommended for patients with a creatinine clearance less than 30 ml/min, as there is no dose adjustment recommendation for them. Patients with impaired liver function Use with caution. Liver function should be monitored regularly (see "Contraindications" and "Special Precautions and Warnings"). Method of administration For oral administration. Take at the beginning of a meal, with a glass of water. The tablet can be broken at the score line to facilitate swallowing. Treatment can be initiated parenterally, according to the drug's dosing recommendations, by intravenous administration, and continued with the oral preparation. If a scheduled dose is missed, take it as soon as you remember. At least 4 hours should pass before taking the next dose. Do not double the dose to compensate for a missed dose. Adverse reactions The following categories are used to classify the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), unknown frequency (cannot be estimated from available data). The most common adverse reactions when taking the drug are: diarrhea, nausea, and vomiting. Infections and parasitic diseases Common: Candidiasis of the skin and mucous membranes. Unknown frequency: Overgrowth of non-susceptible microorganisms. Disorders of the blood and lymphatic system Rare: Reversible leukopenia (including neutropenia), thrombocytopenia. Unknown frequency: Reversible agranulocytosis, hemolytic anemia, prolonged bleeding time and prothrombin time. Cardiac disorders Unknown frequency: Stevens-Johnson syndrome. Immune system disorders Unknown frequency: Angioneurotic edema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis. Nervous system disorders Uncommon: Dizziness, headache. Unknown frequency: Reversible hyperactivity, convulsions, aseptic meningitis. Gastrointestinal disorders Very common: Diarrhea. Common: Nausea (more often associated with high oral doses; gastrointestinal reactions can be minimized if the drug is taken at the beginning of a meal), vomiting. Uncommon: Indigestion. Unknown frequency: Antibiotic-associated colitis (including pseudomembranous colitis and hemorrhagic colitis, see "Special Precautions and Warnings" section), "black hairy" tongue, drug-induced enterocolitis syndrome, acute pancreatitis. Hepatic and biliary disorders Uncommon: Elevated AST and/or ALT levels (moderate elevations are observed in patients treated with beta-lactam antibiotics, but the significance of these observations is unknown). Unknown frequency: Hepatitis, cholestatic jaundice (these adverse events have been observed with the use of other penicillins and cephalosporins, see "Special Precautions and Warnings"). Skin and subcutaneous tissue disorders In case of any allergic skin reaction, treatment should be discontinued. Uncommon: Rash, pruritus, urticaria. Rare: Erythema multiforme. Unknown frequency: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms, so-called DRESS syndrome, presenting as flu-like symptoms with rash, fever, enlarged lymph nodes, and abnormal blood test results (including increased eosinophils and liver enzymes), linear IgA-dependent bullous dermatosis (rash with vesicles and bullae with crusts in the center, tending to group in a linear or "string of pearls" pattern). Kidney and urinary tract disorders Unknown frequency: Interstitial nephritis, crystalluria (including acute renal failure). Overdose Gastrointestinal symptoms and disturbances of water-electrolyte balance may develop. Cases of amoxicillin-associated crystalluria, sometimes complicated by acute renal failure, have been reported. Amoxicillin precipitates in urinary catheters, mainly after intravenous administration of high doses. Regular monitoring of catheter patency is necessary. Symptomatic treatment may be carried out for gastrointestinal symptoms, along with restoration of water-electrolyte balance. Seizures may develop in patients with impaired renal function or those receiving high-dose therapy. Amoxicillin and potassium clavulanate can be removed from the body by hemodialysis. Interactions with other medicinal products and other types of interactions Oral anticoagulants Increased international normalized ratio (INR) has been reported in patients receiving maintenance therapy with acenocoumarol or warfarin during a prescribed course of amoxicillin. If these drugs are used concurrently, prothrombin time or INR should be carefully monitored at the start and end of amoxicillin treatment. Dose adjustment of oral anticoagulants may be necessary. Methotrexate Penicillins can reduce the excretion of methotrexate and may cause increased toxicity. Probenecid Concomitant use of probenecid is not recommended. It reduces the renal tubular secretion of amoxicillin, which can lead to increased blood levels of amoxicillin (but not clavulanic acid) and their prolonged maintenance. Mycophenolate mofetil Patients taking mycophenolate mofetil have experienced a 50% decrease in the concentration of the active metabolite, mycophenolic acid (MPA), before the next dose of mycophenolate mofetil after starting oral amoxicillin and clavulanic acid. This change in MPA concentration does not necessarily indicate a change in overall MPA exposure. Therefore, dose adjustment of mycophenolate mofetil is not necessary in the absence of clinical signs of graft dysfunction. Close medical observation is necessary during such combination therapy and for some time after the completion of antibiotic therapy. Packaging Blisters (aluminum/aluminum foil) of 10 (2x5) or 14 (2x7) tablets in a carton. Storage conditions Keep out of reach of children. Store in the original packaging, protected from moisture, at a temperature not exceeding 30°C. Shelf life 2 years. Do not use after the expiry date indicated on the packaging. Dispensing conditions. Pharmaceutical product group II, dispensed by prescription №3. See also: Amoksiklav 2X - Amoksiklav 2X 1000mg 10 tablets