Amoxiclav powder for suspension Forte for oral administration (250mg + 62.5mg) / 5ml 100ml No. 1

Name:
Amoxiclav por d/prig.susp. forte d / vnutr. approx. (250mg+62.5mg)/5ml per vial 100ml in pack. No. 1
Description:
Crystalline powder of white or yellowish-white color. The main active ingredient Amoxicillin + clavulanic acid Release form Powder Dosage 5 ml of suspension for internal use contain 250 mg of amoxicillin in the form of trihydrate and 62.5 mg of clavulanic acid in the form of potassium salt. Pharmacological properties Pharmacodynamics Amoxicillin is a semi-synthetic penicillin, a beta-lactam antibiotic that inhibits one or more enzymes (often called penicillin-binding proteins) in the biosynthesis of peptidoglycan, a structural component of the bacterial cell wall. Suppression of peptidoglycan synthesis leads to a loss of cell wall strength, which usually leads to cell death. Amoxicillin is destroyed by the action of beta-lactamases produced by resistant bacteria, so it is inactive against microorganisms that produce these enzymes. Clavulanic acid is a beta-lactam structurally similar to penicillins. It inhibits some beta-lactamases and thus prevents the inactivation of amoxicillin. By itself, clavulanic acid does not have a clinically useful antibacterial effect. The time to maintain the concentration above the minimum inhibitory (T>MIC) is recognized as the main determining factor in the effectiveness of amoxicillin. The two main mechanisms for the development of resistance to amoxicillin/clavulanic acid are: inactivation by bacterial beta-lactamases that are insensitive to the inhibitory effect of clavulanic acid, including class B, C, and D beta-lactamases; and a change in penicillin-binding proteins that causes a decrease in the affinity of the antibacterial drug for the target. Bacterial impermeability or active drug transport mechanisms out of the bacterial cell can directly cause or contribute to resistance, especially in Gram-negative bacteria. The minimum inhibitory concentrations (MICs) for amoxicillin/clavulanic acid correspond to the detection limits established by the European Committee for the Evaluation of Antibiotic Susceptibility (EUCAST) Organism Detection Limits (µg/ml) Sensitivity Intermediate Sensitivity Resistance Haemophilus influenzae1 1->1 Moraxella catarrhalis1 ? 1->1 Staphylococcus aureus2 ? 2 – > 2 Coagulase-negative staphylococcus aureus2 ? 0.25 > 0.25 Enterococcus1? 4 8 > 8 Streptococcus A, B, C, G5 ? 0.25 – > 0.25 Streptococcus pneumoniae3 ? 0.5 1-2 > 2 Enterobacteria1.4 – – > 8 Gram-negative anaerobes1 ? 4 8 > 8 Gram-positive anaerobes1 ? 4 8 > 8 Non-species-specific limits1 ? 2 4-8 > 8 1 The obtained values correspond to the concentrations of amoxicillin. For the purpose of sensitivity assessment, a fixed concentration of clavulanic acid is used – 2 mg / l. 2 The values obtained correspond to the concentrations of oxacillin. 3 Limit values in the table are based on ampicillin susceptibility limits. 4 The resistance limit R > 8 mg/l guarantees the antibiotic resistance of all isolated strains with resistance mechanisms. 5 Limit values in the table are based on sensitivity limits for benzylpenicillin. The prevalence of resistance in individual species is geographically and temporally dependent, and therefore it is desirable to obtain local information on antibiotic resistance before starting therapy, especially in the case of severe infections. If local indicators of antibiotic resistance cast doubt on the effectiveness of the drug in at least some types of infections, you should seek the help of appropriate expert specialists. Generally susceptible species Gram-positive aerobes: Enterococcus faecalis, Gardnerella vaginalis, Staphylococcus aureus (methicillin-susceptible)?, Coagulase-negative staphylococci (methicillin-susceptible)?, Streptococcus agalactiae, Streptococcus pneumoniae1, Streptococcus pyogenes and other beta-hemolytic streptococci, group Streptococcus viridians . Gram-negative aerobes: Capnocytophaga spp., Eikenella corrodens, Haemophilus influenzae2, Moraxella catarrhalis, Pasteurella multocida. Anaerobes: Bacteroides fragilis, Fusobacterium nucleatum, Prevotella spp. Species with possible development of acquired resistance Gram-positive aerobes: Enterococcus faecium$ Gram-negative aerobes: Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris. Species with natural resistance Gram-negative aerobes: Acinetobacter sp., Citrobacter freundii, Enterobacter sp., Legionella pneumophila, Morganela morganii, Providencia spp., Pseudomonas sp., Serratia sp., Stenotrophomonas maltophilia. Other microorganisms: Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetti, Mycoplasma pneumonia. $ Natural intermediate susceptibility in the absence of an acquired resistance mechanism. ? All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid. 1 Infections caused by Streptococcus pneumoniae fully sensitive to penicillin can be treated with this formulation. Infections caused by microorganisms with any degree of resistance to penicillin should not be treated with this dosage form of the drug. 2 In some EU countries, strains with reduced sensitivity have been identified, occurring at a frequency above 10%. Pharmacokinetics Amoxicillin and clavulanic acid are completely soluble in water at physiological pH. Both components are rapidly and well absorbed after oral administration. Their absorption improves if the drug is taken immediately before meals. When administered orally, the bioavailability of amoxicillin and clavulanic acid reaches approximately 70%. The plasma concentration profiles of both components are similar and the time to peak concentration (Tmax) for each substance is approximately one hour. In a group of healthy volunteers, when taking the combined drug at a dose of 875 mg / 125 mg in the form of tablets twice a day on an empty stomach, the maximum serum concentrations were 11.64 ± 2.78 μg / ml for amoxicillin and 2.18 ± 0.99 μg / ml for clavulanic acid. The time to peak concentration was 1.5 hours (range 1.0–2.5) for amoxicillin and 1.25 hours (range 1.0–2.0) for clavulanic acid. AUC(0-24) values were 53.52 ± 12.31 μg h/mL for amoxicillin and 10.16 ± 3.04 μg h/mL for clavulanic acid. The half-life (T?) was 1.19 ± 0.21 h for amoxicillin and 0.96 ± 0.12 h for clavulanic acid. Serum concentrations of amoxicillin and clavulanic acid achieved by oral administration are similar to those obtained by oral administration of equivalent doses of amoxicillin or clavulanic acid alone. Approximately 25% of the total content of clavulanic acid and 18% of the total content of amoxicillin in plasma is in a protein-bound state. The apparent volume of distribution is about 0.3 – 0.4 l / kg for amoxicillin and about 0.2 l / kg for clavulanic acid. 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 weakly into the cerebrospinal fluid. In animal studies, there was no evidence of a significant retention of drug components in tissues. Amoxicillin passes into breast milk. Trace amounts of clavulanic acid are also found in breast milk. Amoxicillin and clavulanic acid cross the placental barrier. Amoxicillin is partially excreted in the urine in the form of inactive penicillic acid in amounts equivalent to no more than 10-25% of the original dose. Clavulanic acid is extensively metabolized, excreted in urine and feces, and also in the form of carbon dioxide with exhaled air. Amoxicillin is excreted mainly by the kidneys, while clavulanic acid is excreted from the body through both renal and extrarenal mechanisms. The amoxicillin/clavulanic acid combination in healthy individuals has a mean half-life of about one hour and a mean total clearance of about 25 L/h. Approximately 60-70% of amoxicillin and approximately 40-65% of clavulanic acid are excreted unchanged in the urine in the first 6 hours after a single dose of amoxicillin / clavulanic acid in the form of tablets with a dose of 250 mg / 125 mg or 500 mg / 125 mg. Removal in the urine within a 24-hour period is 50-85% for amoxicillin and 27-60% for clavulanic acid. The maximum amount of clavulanic acid is excreted in the first two hours after taking the drug. Concomitant use of probenecid causes a delay in the excretion of amoxicillin, however, does not affect the excretion of clavulanic acid by the kidneys. Age The half-life of amoxicillin in children aged 3 months to 2 years, older children and adults is similar. In very young children (including premature newborns) in the first week of life, the drug should not be used more than twice a day due to the immaturity of the renal excretion pathway. Since the elderly are more likely to have decreased renal function, caution should be exercised in the selection of doses, and monitoring of renal function may also be required. Gender The pharmacokinetics of amoxicillin or clavulanic acid does not depend on the gender of the patient. Impaired renal function The total plasma clearance of amoxicillin / clavulanic acid decreases in proportion to the decrease in renal function. The decrease in clearance is more pronounced for amoxicillin than for clavulanic acid, since the proportion of amoxicillin excreted by the kidneys is higher. In renal insufficiency, doses are selected so as to avoid excessive accumulation of amoxicillin while maintaining sufficient levels of clavulanic acid. Liver failure Treatment of patients with liver failure is carried out with caution, regular monitoring of liver function is required. Amoxiclav is indicated for the treatment of the following infections in adults and children: acute bacterial sinusitis; acute otitis media; acute bronchitis, exacerbation of chronic bronchitis; community-acquired pneumonia; cystitis; pyelonephritis; infections of the skin and soft tissues, in particular inflammation of the subcutaneous tissue, wounds from animal bites, severe tooth abscess with widespread phlegmon; infections of bones and joints, in particular osteomyelitis. Consideration should be given to official guidelines on the appropriate use of antibacterial drugs. Route of administration and dosesDoses reflect the content of amoxicillin / clavulanic acid, unless indicated that the dose corresponds to the content of the individual component. When choosing a dose for the treatment of specific infections, the following factors should be considered: suspected pathogens and their possible susceptibility to antibacterial drugs; the severity and location of the infection; age, weight, and kidney function, as listed below. The use of other dosage forms of Amoxiclav (for example, with higher doses of amoxicillin and / or with a different dose ratio of amoxicillin / clavulanic acid) is considered as necessary. When taking Amoxiclav in accordance with the recommendations below, the total daily dose for adults and children weighing ? 40 kg will be 1500 mg amoxicillin / 375 mg clavulanic acid; Children weighing < 40 kg will receive doses ranging from 20 mg/5 mg/kg/day to 60 mg/15 mg/kg/day, with a maximum daily dose of 2400 mg amoxicillin/600 mg clavulanic acid. If it is necessary to use a higher daily dose of amoxicillin, it is recommended to use a different form of the drug in order to avoid taking an excessively high daily dose of clavulanic acid. The duration of therapy is determined by the effectiveness of treatment. Some infections (eg, osteomyelitis) require longer therapy. The duration of treatment should not exceed 14 days without revision. Adults and children weighing ? 40 kg 500 mg/125 mg three times a day. Children weighing < 40 kg Children can take the drug in the form of a suspension or tablets. Dose from 20 mg/5 mg/kg/day to 60 mg/15 mg/kg/day divided into three doses. For the treatment of children, you can use the drug in the form of a suspension or tablets. For the treatment of children aged 6 years and younger, it is preferable to use a suspension. Clinical data on the use of dosage forms of the drug with a ratio of active ingredients 4:1 in doses above 40 mg / 10 mg / kg / day for the treatment of children under the age of 2 years are not available. Elderly patients Dose adjustment is not required. Patients with impaired renal function The dose should be adjusted based on the maximum recommended dose of amoxicillin. Patients with creatinine clearance above 30 ml / min dose adjustment is not required. Adults and children weighing ? 40 kg QC: 10-30 ml/min 500 mg/125 mg twice daily QC: < 10 ml/min 500 mg/125 mg once daily Hemodialysis 500 mg/125 mg every 24 hours plus 500 mg/125 mg during dialysis and another dose at the end of dialysis (because serum concentrations of amoxicillin and clavulanic acid are reduced). Children weighing < 40 kg CC: 10-30 ml / min 15 mg / 3.75 mg / kg twice a day (no more than 500 mg / 125 mg twice a day) CC: < 10 ml / min 15 mg /3.75 mg/kg once a day (not more than 500 mg/125 mg) Hemodialysis 15 mg/3.75 mg/kg once a day. Before hemodialysis 15 mg/3.75 mg/kg. To restore the appropriate concentrations of the drug in the blood, it is necessary to take another dose of 15 mg / 3.75 mg / kg after hemodialysis. Patients with impaired liver function Use with caution. It is necessary to regularly monitor liver function. Method of application For oral administration. Take immediately before meals to minimize possible gastrointestinal side effects. Treatment can be started with parenteral forms of the drug, following the instructions attached to them, and continue with the oral dosage form. Suspension preparation Before use, check that the sealing of the cap is not broken. Shake the bottle to loosen the powder. Add water (86 ml - for Amoxiclav (125mg + 31.25mg) / 5ml, 85 ml - for Amoxiclav (250mg + 62.5mg) / 5ml) in two portions (first 2/3, then up to the mark), and each time shake the suspension well. Shake well before each use! Dispose of unused product in accordance with local regulations. Use during pregnancy and lactation In animal studies, neither direct nor indirect harmful effects on the course of pregnancy, development of the embryo / fetus, the process of childbirth and the development of the newborn have been shown. Limited data on the use of the drug during pregnancy do not indicate an increased risk of congenital anomalies. In women with preterm preterm rupture of membranes, prophylactic treatment with amoxicillin/clavulanic acid has been potentially associated with an increased risk of neonatal necrotizing enterocolitis. The use of the drug during pregnancy should be avoided unless the doctor considers treatment necessary. Both active ingredients are excreted in breast milk (data on the effect of clavulanic acid on breastfed children are not available). Breastfed babies may develop diarrhea and fungal infections of the mucous membranes, which may require stopping breastfeeding. Possible sensitization should be considered. Taking the drug during breastfeeding is possible only after assessing the benefits and risks by the attending physician. Precautions Before starting therapy with the drug, it is necessary to conduct a thorough history taking for hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam drugs. Serious and sometimes fatal hypersensitivity reactions (including anaphylactoid and severe skin adverse reactions) have been observed during penicillin therapy. They are most likely to develop in patients with hypersensitivity reactions to penicillins in the past and in individuals prone to developing allergic reactions. In the event of an allergic reaction, Amoxiclav therapy should be discontinued and other suitable antibacterial drugs prescribed. In cases of proven susceptibility of infectious agents to amoxicillin, a switch from Amoxiclav to amoxicillin should be considered in accordance with official guidelines. This dosage form of the drug is not suitable for use if there is a high risk that the suspected pathogens have reduced sensitivity or resistance to beta-lactam drugs due to non-beta-lactamases sensitive to clavulanic acid suppression. The drug should not be used to treat infections caused by penicillin-resistant strains of S.pneumoniae. Seizures may develop in patients with impaired renal function or receiving high-dose therapy. Amoxiclav should not be taken if infectious mononucleosis is suspected, since after the use of amoxicillin against the background of this disease, a measles-like rash was observed. The concomitant use of allopurinol during treatment with amoxicillin may increase the likelihood of allergic skin reactions. Prolonged use of the drug can sometimes lead to excessive reproduction 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 Amoxiclav therapy and is a contraindication to the subsequent use of amoxicillin. Treatment of patients with hepatic insufficiency should be carried out with caution. Adverse events from the liver were observed mainly in men and elderly patients and are potentially associated with long-term treatment. These adverse events in very rare cases were observed in children. In all groups of patients, signs and symptoms usually develop during or shortly after treatment, but in some cases they do not appear until a few weeks after stopping therapy. They are usually reversible. Serious adverse events from the liver can develop, extremely rarely with a fatal outcome. They have almost always been observed in patients with serious underlying diseases or in people taking drugs that can damage the liver. Cases of antibiotic-associated colitis observed during therapy with almost all antibacterial drugs can vary in severity from mild to life-threatening. It is important to consider this diagnosis in patients with diarrhea during or after completion of any course of antibiotic therapy. In the event of the development of antibiotic-associated colitis, Amoxiclav therapy should be stopped immediately, consult a doctor and start appropriate treatment. In this situation, the use of drugs that depress peristalsis is contraindicated. During long-term therapy, periodic evaluation of the functions of various organ systems, including the kidneys, liver, and hematopoietic organs, is recommended. In rare cases, while taking the drug, prolongation of prothrombin time was noted. When taking anticoagulants at the same time, proper monitoring must be carried out. Dose adjustment of oral anticoagulants may be required to achieve the desired level of anticoagulation. In patients with renal insufficiency, dose adjustment is mandatory in accordance with the level of insufficiency. In patients with reduced diuresis, crystalluria was observed in rare cases, mainly against the background of parenteral therapy. During high-dose amoxicillin therapy, adequate fluid intake and diuresis control are recommended to reduce the likelihood of amoxicillin-associated crystalluria. In patients with a catheter installed in the bladder, it is imperative to regularly monitor its patency. If it is necessary to assess the level of glucose in the urine during treatment with amoxicillin, it is necessary to use enzymatic methods with glucose oxidase, since non-enzymatic methods sometimes give false positive results. The presence of clavulanic acid in Amoxiclav can cause non-specific binding of IgG and albumin to erythrocyte membranes, which can cause false positive Coombs test results. There have been cases of positive results of enzyme-linked immunosorbent assay (ELISA) for Aspergillus in patients treated with the drug, in whom the absence of infections caused by Aspergillus was subsequently determined. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses have been noted in the ELISA test for Aspergillus. Positive test results in patients taking Amoxiclav should be interpreted with caution and confirmed by other diagnostic methods. Interactions with other drugs Oral anticoagulants Oral anticoagulants and penicillin antibiotics have been widely used together, and no drug interactions have been reported. However, literature sources describe cases of an increase in the international normalized ratio (INR) in patients receiving maintenance therapy with acenocoumarol or warfarin against the background of the prescribed course of amoxicillin. If necessary, simultaneous appointment should be carefully monitored prothrombin time or INR during the initiation of treatment and withdrawal of amoxicillin. Dose adjustment of oral anticoagulants may be required. Methotrexate Penicillins may reduce the excretion of methotrexate, which is accompanied by an increase in toxicity. Probenecid Concomitant use of probenecid is not recommended. It reduces the secretion of amoxicillin in the renal tubules. Simultaneous use of probenecid with Amoxiclav may lead to an increase in the levels of amoxicillin (but not clavulanic acid) in the blood and their longer maintenance. Mycophenolate mofetil In patients taking mycophenolate mofetil, after initiation of oral amoxicillin and clavulanic acid, an approximately 50% decrease in the concentration of the active metabolite of mycophenolic acid (MPA) was observed before taking the next dose of mycophenolate mofetil. Such a change in concentration before taking the next dose may not indicate a change in the overall exposure of the MPA. Therefore, in the absence of clinical signs of graft dysfunction, there is usually no need to change the dose of mycophenolate mofetil. However, during such combination therapy and for some time after the end of antibiotic therapy, close medical supervision is necessary. Contraindications Hypersensitivity to the active or excipients of the drug, as well as to any penicillins. History of severe immediate hypersensitivity reactions (eg, anaphylaxis) to other beta-lactam drugs (eg, cephalosporins, carbapenems, or monobactams). History of jaundice or other liver damage associated with the use of amoxicillin / clavulanic acid. Amoxiclav (250mg + 62.5mg)/5ml 5ml oral suspension contains 250mg amoxicillin trihydrate and 62.5mg clavulanic acid potassium salt. Excipients: anhydrous crushed citric acid, anhydrous crushed sodium citrate, dried microcrystalline cellulose and sodium carboxymethylcellulose, xanthan gum, anhydrous colloidal silicon dioxide, silicon dioxide, wild cherry flavor, sodium benzoate, dried sodium saccharin, mannitol. Overdose Development of gastrointestinal symptoms and disturbance of water and electrolytic balance is possible. There have been cases of amoxicillin-associated crystalluria, sometimes leading to renal failure. Convulsions may occur in patients with impaired renal function or in those receiving high-dose therapy. Amoxicillin precipitates in urinary catheters, predominantly after intravenous administration of large doses. It is necessary to regularly monitor the patency of catheters. For gastrointestinal symptoms, symptomatic treatment can be carried out along with the restoration of fluid and electrolyte balance. Amoxicillin and clavulanic acid can be excreted from the body by hemodialysis. Side effects The most common adverse reactions are diarrhea, nausea and vomiting. The following categories were used to classify the incidence of adverse effects: very common (? 1/10), frequent (from ? 1/100 to < 1/10), infrequent (from ? 1/1000 to < 1/100), rare (from ? 1/10,000 to < 1/1000), very rare (< 1/10,000), unknown frequency (estimation from the available data is not possible). Infectious and parasitic diseases Frequent: candidiasis of the skin and mucous membranes. Unknown frequency: overgrowth of non-susceptible microorganisms. Blood and lymphatic system disorders Rare: reversible leukopenia (including neutropenia), thrombocytopenia. Unknown frequency: reversible agranulocytosis, hemolytic anemia, prolongation of bleeding time and prothrombin time. Immune system disorders Unknown frequency: angioedema, anaphylaxis, serum-like syndrome, allergic vasculitis. Nervous system disorders Uncommon: dizziness, headache. Unknown frequency: reversible hyperactivity, convulsions, aseptic meningitis. Gastrointestinal disorders Common: Nausea (often due to high oral doses; gastrointestinal reactions can be minimized if the drug is taken immediately before meals), vomiting, diarrhea. Uncommon: indigestion. Unknown frequency: Antibiotic-associated colitis (including pseudomembranous and hemorrhagic colitis), black hairy tongue, discoloration of teeth (very rare discoloration of the surface of the teeth has been observed in children. Proper oral hygiene can help prevent discoloration of the teeth, as plaque forms can usually be removed with a toothbrush). Liver and biliary tract disorders Uncommon: Elevated AST and/or ALT levels (moderate increases have been reported in patients treated with beta-lactam antibiotics, but the significance of these observations is unknown). Unknown frequency: hepatitis, cholestatic jaundice (these adverse events were observed against the background of the use of other penicillins and cephalosporins). Skin and subcutaneous tissue disorders Treatment should be discontinued if any allergic skin reaction develops. Uncommon: skin rash, itching, urticaria. Rare: erythema multiforme. Frequency unknown: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Renal and urinary disorders Unknown frequency: interstitial nephritis, crystalluria. Storage conditionsKeep out of the reach of children. Store in a dry place at a temperature not exceeding 25°C. Store the finished suspension in a tightly closed vial at a temperature of 2-8 ° C for no more than 7 days. oral administration (250mg+62.5mg)/5ml 100ml №1