Description
Pharmacological action of
Pharmacotherapeutic group: semisynthetic antibiotic-penicillin + beta-lactamase
ATX inhibitor:
J.01.CR02 Amoxicillin in combination with enzyme inhibitors
Pharmacodynamic activity s: against many gram-positive and gram-negative microorganisms. At the same time, amoxicillin is susceptible to destruction by beta-lactamases, and therefore the activity spectrum of amoxicillin does not extend to the microorganisms that produce this enzyme.
Clavulanic acid, a beta-lactamase inhibitor structurally related to penicillins, has the ability to inactivate a wide range of beta-lactamases found in penicillin and cephalosporin resistant microorganisms. Clavulanic acid has sufficient efficacy against plasmid beta-lactamases, which most often cause bacterial resistance, and is not effective against type 1 chromosomal beta-lactamases that are not inhibited by clavulanic acid.
The presence of clavulanic acid in Betaclav ® protects amoxicillin from destruction by enzymes – beta-lactamases, which allows you to expand the antibacterial spectrum of amoxicillin.
The following is the in vitro combination activity of amoxicillin with clavulanic acid.
Bacteria commonly susceptible to the combination of amoxicillin with clavulanic acid
Gram-positive aerobes
Bacillus anthracis
Enterococcus faecalis
Listeria monocytogenes
socrdocpocptocpocptoc. Streptococcus streptococcus streptococci (other beta-hemolytic streptococci) 1.2
Staphylococcus aureus (methicillin-sensitive) 1
Staphylococcus saprophyticus (methicillin-sensitive)
Coagulase-negative staphylococci (methicillin-sensitive) srdlprd
Peptococcus niger
Peptostreptococcus magnus
Peptostreptococcus micros
Peptostreptococcus spp.
Gram-negative aerobes
Bordetella pertussis
Haemophilus influenzae1
Helicobacter pylori
Moraxella catarrhalis1
Neisseria gonorrhoeae
Pasteurella multocida srdlrd srdlrd
Capnocytophaga spp.
Eikenella corrodens
Fusobacterium nucleatum
Fusobacterium spp.
Porphyromonas spp.
Prevotella spp.
Other
Borrelia burgdorferi
Leptospira icterohaemorrhagiae
Treponema pallidum
Bacteria, for which acquired resistance to the combination of amoxicillin with clavulanic acid is likely
Gram-negative aerobes
Escherichia coli1
Klebsiella oxytoca
Klebsiella pneumoniae1
Klebsiella spp.
Proteus mirabilis
Proteus vulgaris
Proteus spp.
Salmonella spp.
Shigella spp.
Gram-positive aerobes
Corynebacterium spp.
Enterococcus faecium
Streptococcus pneumoniae1,2
Streptococcus group Viridans
Bacteria that are naturally resistant to the combination of amoxicillin with clavulanic acid
Gram-negative aerobes
Acinetobacter spp.
Citrobacter freundii
Enterobacter spp.
Hafnia alvei
Legionella pneumophila
Morganella morganii
Providencia spp.
Pseudomonas spp.
Serratia spp.
Stenotrophomonas maltophilia
Yersinia enterocolitica
Other
Chlamydia pneumoniae
Chlamydia psittaci
Chlamydia spp.
Coxiella burnetii
Mycoplasma spp.
1 – for these bacteria, the clinical efficacy of a combination of amoxncillin with clavulanic acid has been demonstrated in clinical studies.
2 – strains of these types of bacteria do not produce beta-lactamases. Sensitivity with amoxicillin monotherapy suggests a similar sensitivity to the combination of amoxicillin with clavulanic acid.
Pharmacokinetics:
Absorption
Both active ingredients of Betaclav ®, amoxicillin and clavulanic acid, are rapidly and completely absorbed from the gastrointestinal tract (GIT) after oral administration. The absorption of the active ingredients of Betaclav ® is optimal when taking the drug at the beginning of a meal.
The following shows the pharmacokinetic parameters of amoxicillin and clavulanic acid obtained in separate studies when healthy fasting volunteers took:
– 1 tablet containing amoxicillin and clavulanic acid, 500 mg + 125 mg (625 mg)
– 500 mg of amoxicillin srdl 125 mg clavulanic acid
– 2 tablets of the drug containing amoxicillin and clavulanic acid, 875 mg + 125 mg (1000 mg).
Basic pharmacokinetic parameters
Drugs
Dose
(mg)
Cmax
(mg / l)
Tmax
(hours)
AUC
(mhh / l) srdlrd ppm acid / 2
clkp1 / 2 500 mg + 125 mg
500
6.5
1.5
23.2
1.3
Amoxicillin / Clavulanic acid, 875 mg + 125 mg
1750
11.64 ± 2.78
1.50
( 1.0-2.5)
53.52 ± 12.31
1.19 ± 0.21
Amoxicillin, 500 mg
500
6.5
1.3
19.5
1.1
Clavulanic acid
Clavulanic acid, 125 mg
125
3.4
0.9
7.8
0.7
Amoxicillin / Clavulanic acid, 500 mg + 125 mg
125
2.8
1.3
7.3
0.8
Amoxicillin / Clavulanic acid, 875 mg + 125 mg
250
2.18 ± 0.99
1.25
(1.0-2.0)
10.16 ± 3.04
0.96 ± 0.12
Cmax – maximum plasma concentration.
Tmax – time to reach maximum plasma concentration.
AUC – area under the concentration-time curve.
T1 / 2 – elimination half-life.
Distribution of
As with the intravenous combination of amoxicillin with clavulanic acid, therapeutic concentrations of amoxicillin and clavulanic acid are found in various tissues and interstitial fluid (in the gallbladder, abdominal tissues, skin, adipose and muscle tissues, synovial and peritoneal fluids purulent discharge).
Amoxicillin and clavulanic acid have a weak degree of binding to plasma proteins. Studies have shown that about 25% of the total amount of clavulanic acid and 18% of amoxicillin in blood plasma binds to plasma proteins.
In animal studies, no cumulation of the components of Betaclav ® in any organ was found. Amoxicillin, like most penicillins, passes into breast milk. Traces of clavulanic acid may also be found in breast milk. With the exception of the possibility of sensitization, diarrhea, or candidiasis of the oral mucosa, no other negative effects of amoxicillin and clavulanic acid on the health of breast-fed children are known.
Animal reproductive studies have shown that amoxicillin and clavulanic acid cross the placental barrier. However, no adverse effects on the fetus were detected.
Metabolism
10-25% of the initial dose of amoxicillin is excreted by the kidneys as an inactive metabolite (penicilloic acid). Clavulanic acid is extensively metabolized to 2, 5-dihydro-4- (2-hydroxyethyl) -5-oxo-1H-pyrrole-3-carboxylic acid and 1-amino-4-hydroxy-butan-2-one is excreted by the kidneys, through the gastrointestinal tract, as well as with exhaled air in the form of carbon dioxide.
Excretion
Like other penicillins, amoxicillin is excreted mainly by the kidneys, while clavulanic acid is excreted by both the renal and extrarenal mechanisms. About 60-70% of amoxicillin and about 40-65% of clavulanic acid are excreted by the kidneys unchanged in the first 6 hours after application.
The simultaneous administration of probenecid slows the excretion of amoxicillin, but not clavulanic acid (see Interaction with other drugs).
Contraindications
Hypersensitivity to amoxicillin, clavulanic acid, other components of the drug, beta-lactam antibiotics (eg, penicillins, cephalosporins) in history.
Previous episodes of jaundice or impaired liver function with a history of amoxicillin and clavulanic acid.
Children under 12 years old or body weight less than 40 kg.
Severe renal impairment (creatinine clearance <30 ml / min) (for a dosage of 875 mg + 125 mg). Caution: Betaclav ® should be used with caution in patients with impaired liver function. Use during pregnancy and lactation Pregnancy In studies of reproductive function in animals, oral and parenteral administration of the combination of amoxicillin + clavulanic acid did not cause teratogenic effects. In a single study in women with premature rupture of membranes, it was found that preventive therapy may be associated with an increased risk of necrotizing enterocolitis in newborns. Like all medicines, Betaclav ® is not recommended for use during pregnancy, unless the expected benefit to the mother outweighs the potential risk to the fetus. Breastfeeding period Betaclav ® can be used during breastfeeding. Except for the possibility of sensitization, diarrhea, or candidiasis of the oral mucous membranes associated with the penetration of trace amounts of the active ingredients of this drug into breast milk, no other adverse effects were observed in breast-fed infants. In case of adverse effects in breast-fed infants, it is necessary to stop breastfeeding. Special instructions Before starting treatment with Betaclav ®, a detailed history should be collected regarding previous hypersensitivity reactions to penicillins, cephalosporins or other substances that cause an allergic reaction in the patient. Serious and sometimes fatal hypersensitivity reactions (including anaphylactoid and severe skin adverse reactions) to penicillins are described. The risk of such reactions is highest in patients with a history of hypersensitivity reactions to penicillins. In case of an allergic reaction, it is necessary to discontinue treatment with Betaclav ® and begin appropriate alternative therapy. In case of severe anaphylactic reactions, epinephrine should be administered to the patient immediately. Oxygen therapy, intravenous administration of glucocorticosteroids, and airway management, including intubation, may also be required. In case of skin allergic reactions, treatment with Betaclav ® should be discontinued. In the case of suspected infectious mononucleosis, Betaclav ® should not be used, since in patients with this disease, amoxicillin can cause a measles-like skin rash, which makes it difficult to diagnose the disease. Long-term treatment with Betaclav ® may lead to excessive proliferation of insensitive microorganisms. Cases of the occurrence of pseudomembranous colitis when taking antibiotics are described, the severity of which can vary from mild to life-threatening. Therefore, it is important to consider the possibility of developing pseudomembranous colitis in patients with diarrhea during or after the use of antibiotics. If diarrhea is prolonged or severe, or the patient experiences abdominal cramps, treatment should be stopped immediately and the patient should be examined. In general, Betaclav ® is well tolerated and has a low toxicity characteristic of all penicillins. During long-term therapy with Betaclav ®, it is recommended to periodically evaluate the function of the kidneys, liver and hematopoiesis. In patients receiving a combination of amoxicillin with clavulanic acid simultaneously with indirect (for oral administration) anticoagulants, in rare cases, an increase in prothrombin time (increased INR) has been reported. With the simultaneous use of indirect (for oral administration) anticoagulants with a combination of amoxicillin with clavulanic acid, monitoring of the relevant indicators is necessary. To maintain the desired effect of anticoagulants for oral administration, dosage adjustment may be required. In patients with impaired renal function, the dose of Betaclav ® should be reduced accordingly to the degree of impairment (see section Dosage and Administration, subsection Patients with impaired renal function). Crystalluria is very rare in patients with reduced diuresis, mainly with parenteral therapy. During the administration of high doses of amoxicillin, it is recommended to take a sufficient amount of liquid and maintain adequate diuresis to reduce the likelihood of the formation of amoxicillin crystals (see section Overdose). Ingestion of Betaclav ® leads to a high content of amoxicillin in the urine, which can lead to false-positive results in the determination of glucose in the urine (for example, a Benedict test, a Feling test). In this case, it is recommended to use the glucose oxidase method for determining the concentration of glucose in the urine. Clavulanic acid can cause nonspecific binding of immunoglobulin G and albumin to red blood cell membranes, which leads to false positive Coombs test results. Abuse and drug dependence No drug dependence, addiction and euphoria reactions associated with the use of Betaclav ®. Impact on the ability to drive transp. Wed and fur.: Since the use of Betaclav ® may cause dizziness, it is necessary to warn patients about precautions when driving or working with moving machinery. Composition For 1 film-coated tablet, 500 mg + 125 mg / 875 mg +125 mg: Core Active ingredients: Amoxicillin trihydrate 573.892 mg / 1004.310 mg, equivalent to amoxicillin 500,000 mg / 875,000 mg clavulkp Microcrystalline cellulose (1: 1) 303.834 mg / 303.834 mg, equivalent to potassium clavulanate 151.915 mg / 151.915 mg, equivalent to clavulanic acid 125,000 mg / 125,000 mg Excipients: microcrystalline cellulose, magnesium stearate, silicon dioxide colloidal carbamide Opadry white Y-1-7000 * * Opadry white Y-1-7000: hypromellose 5 cP (E464), titanium dioxide (E171), macrogol-400 Dosage and administration For oral administration. The dosage regimen is set individually depending on the age, body weight, patient’s kidney function, as well as the severity of the infection. To reduce potential gastrointestinal disturbances and to optimize absorption, the drug should be taken at the beginning of a meal. The minimum course of antibiotic therapy is 5 days. Treatment should not be continued for more than 14 days without a review of the clinical situation. If necessary, it is possible to carry out step-by-step therapy (first, intravenous administration of a drug containing amoxicillin and clavulanic acid, in powder form, to prepare a solution for intravenous administration, followed by switching to a preparation containing amoxicillin and clavulanic acid, in oral dosage forms). Adults and children 12 years of age or older or weighing 40 kg or more 1 tablet 500 mg + 125 mg 3 times a day. 1 tablet 875 mg + 125 mg 2 times a day. Special patient groups Children under 12 years of age or weighing less than 40 kg Other dosage forms of the drug containing amoxicillin and clavulanic acid are recommended. Elderly patients Dosage adjustment not required. In elderly patients with impaired renal function, the dose should be adjusted as described below for adults with impaired renal function. Patients with impaired renal function Dosage adjustment is based on the maximum recommended dose of amoxicillin and creatinine clearance (QC). Creatinine clearance Dosage regimen Betaclav ® > 30 ml / min
Dosage adjustment not required
10-30 ml / min
1 tablet 500 mg + 125 mg (for moderate and severe infections) 2 times a day
< 10 ml / min 1 tablet 500 mg + 1 25 mg (for moderate and severe infections) 1 time per day Patients on hemodialysis Dosage adjustment based on the maximum recommended dose of amoxicillin. 1 tablet 500 mg + 125 mg in one dose every 24 hours. During the dialysis session, an additional 1 dose (1 tablet) and another 1 tablet at the end of the dialysis session (to compensate for the decrease in serum concentrations of amoxicillin and clavulanic acid). 875 mg + 125 mg tablets should be used only in patients with CC> 30 ml / min. however, correction of the dosage regimen is not required.
In most cases, parenteral therapy should be preferred if possible.
Patients with impaired liver function
Treatment is carried out with caution, liver function monitoring is carried out regularly.
There is not enough data to change the recommendation of the dosing regimen in such patients.
Side effects
The adverse reactions presented below are listed in accordance with the damage to organs and organ systems and the frequency of occurrence.
Frequency is defined as follows: very often (? 1/10), often (? 1/100 and <1/10), infrequently (? 1/1000 and <1/100), rarely (? 1/10000 and <1/1000), very rarely (<1/10000, including some cases ) Frequency categories were formed on the basis of clinical studies of the drug and post-registration observation. Frequency of occurrence of adverse reactions Infectious and parasitic diseases: often: candidiasis of the skin and mucous membranes. Disorders of the blood and lymphatic system: rare: reversible leukopenia (including neutropenia), reversible thrombocytopenia very rare: reversible agranulocytosis and reversible hemolytic anemia, prolonged bleeding time and prothrombin time, anemia, eosinophilia, thrombocytosis. Immune system disorders: very rare: angioedema, anaphylactic reactions, syndrome, similar to serum sickness, allergic vasculitis. Disorders of the nervous system: infrequently: dizziness, headache very rare: reversible hyperactivity, cramps (cramps can occur in patients with impaired renal function, as well as in those who receive high doses of the drug), insomnia, agitation, anxiety, behavior change. Disorders of the gastrointestinal tract: Adults very often: diarrhea often: nausea, vomiting. Children often: diarrhea, nausea, vomiting. The entire population of Nausea was most often associated with the use of high doses of the drug. If after the start of taking the drug there are undesirable reactions from the gastrointestinal tract, they can be eliminated if you take Betaclav® at the beginning of the meal. Infrequently: digestion disorder is very rare: antibiotic-associated colitis (including pseudomembranous colitis and hemorrhagic colitis) (see Special instructions), black hairy tongue, gastritis, stomatitis. Disorders of the liver and biliary tract: infrequently: moderate increase in the activity of aspartate aminotransferase and / or alanine aminotransferase (ACT and / or ALT). This reaction is observed in patients receiving beta-lactam antibiotic therapy, but is rarely known for its clinical significance: hepatitis and cholestatic jaundice (these reactions are observed in patients receiving other penicillin antibiotics and cephalosporins), an increase in the concentration of bilirubin and alkaline phosphatase. Adverse reactions from the liver were observed mainly in men and elderly patients and may be associated with long-term therapy. These adverse reactions are very rarely observed in children. The listed signs and symptoms usually occur during or immediately after the end of therapy, but in some cases they may not appear for several weeks after completion of therapy. Adverse reactions are usually reversible. Adverse reactions from the liver can be severe, in extremely rare cases there have been reports of fatal outcomes. In almost all cases, these were patients with serious concomitant pathology or patients receiving potentially hepatotoxic drugs. Disorders of the skin and subcutaneous tissue: infrequently: skin rash, itching, urticaria rare: erythema multiforme very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis frequency unknown: drug rash with eosinophilia and systemic manifestations (DRESS syndrome). Disorders from the kidneys and urinary tract: very rare: interstitial nephritis, crystalluria (see section Overdose), hematuria. Overdose of Symptoms of Gastrointestinal symptoms and disturbances in water-electrolyte balance may be observed. Amoxicillin crystalluria has been described, in some cases leading to the development of renal failure (see section Special instructions). Seizures may occur in patients with impaired renal function, as well as in those who receive high doses of the drug. Treatment Gastrointestinal symptoms are symptomatic therapy, with particular attention to normalizing the water-electrolyte balance. Amoxicillin and clavulanic acid can be removed from the bloodstream by hemodialysis. A prospective study of 51 children at a poison center showed that administration of amoxicillin at a dose of less than 250 mg / kg did not lead to significant clinical symptoms and did not require gastric lavage. Storage conditions At a temperature not exceeding 25 ° C (in the strip). At a temperature not exceeding 25 ° C, in the original packaging (in a blister pack). Keep out of the reach of children. Expiration 3 years (in strip). 2 years (in blister). Do not use after the expiry date. Deystvuyuschee substances Amoxicillin, clavulanic acid pharmacy terms for prescription Form of Treatment tablets Appointment Detyam to doctor appointments, Adult prescription Indications Cholecystitis, Tonsillitis, Angina, Inflammation of the urinary tract, Urinary tract infections, Urinary tract infections, Urinary tract infections, Urinary tract infections skin, Sinusitis
