Amoxiclav - instructions for use, dose, side effects, contraindications

Active substances (core): Each 250mg + 125mg tablet contains 250 mg of amoxicillin in the form of trihydrate and 125 mg of clavulanic acid in the form of a potassium salt; each 500mg + 125mg tablet contains 500 mg of amoxicillin in the form of trihydrate and 125 mg of clavulanic acid in the form of a potassium salt; Each tablet of 875 mg + 125 mg contains 875 mg of amoxicillin in the form of trihydrate and 125 mg of clavulanic acid in the form of potassium salt.

Excipients (for each dosage, respectively): silicon dioxide colloid 5,40 mg / 9,00 mg / 12,00 mg, crospovidone 27,40 mg / 45,00 mg / 61,00 mg, croscarmellose sodium 27,40 mg / 35,00 mg / 47,00, magnesium stearate 12.00 mg / 20.00 mg / 17.22 mg, talc 13.40 mg (for a dosage of 250 mg + 125 mg), microcrystalline cellulose up to 650 mg / d to 1060 mg / 1435 mg; film coating tablets 250mg + 125mg hypromellose 14,378 mg, ethylcellulose 0,702, mg, polysorbate 80 - 0,780 mg, triethyl citrate 0,793 mg, titanium dioxide 7.605 mg, talc 1.742 mg; film coating tablets 500mg + 125mg - hypromellose 17,696 mg, ethylcellulose 0,864 mg, polysorbate 80 - 0.960 mg, triethyl citrate 0.976 mg, titanium dioxide 9.360 mg, talc 2.144 mg; film coating tablets 875mg + 125mg - Hypromellose 23.226 mg, 1.134 mg ethylcellulose, polysorbate 80 - 1,260 mg triethyl citrate 1.280 mg 12.286 mg titanium dioxide, talc 2.814 mg.

Description:

Tablets 250 mg + 125 mg: White or almost white, oblong, octagonal, biconvex tablets, film-coated, stamped with "250/125" on one side and "AMC" on the other side.

Tablets 500 mg + 125 mg: white or almost white, oval, biconvex tablets, covered with a film membrane.

Tablets 875 mg + 125 mg: White or almost white, oblong, biconvex tablets, film-coated, with a notch and a print of "875/125" on one side and "AMC" on the other side.

View of the fracture: a mass of yellowish color.

Pharmacotherapeutic group:Antibiotic - penicillin semisynthetic + beta-lactamase

ATX: & nbsp

J.01.C.R.02 Amoxicillin in combination with enzyme inhibitors

Pharmacodynamics:

Mechanism of action

Amoxicillin is a semi-synthetic penicillin, which has activity against many gram-positive and gram-negative microorganisms. Amoxicillin violates the biosynthesis of peptidoglycan, which is a structural component of the bacterial cell wall.Violation of the synthesis of peptidoglycan leads to loss of strength of the cell wall, which causes lysis and death of cells of microorganisms. In the same time, amoxicillin is subject to destruction by beta-lactamases, and therefore the spectrum of amoxicillin activity does not extend to microorganisms that produce this enzyme.

Clavulanic acid, a beta-lactamase inhibitor structurally related to penicillins, has the ability to inactivate a wide spectrum of beta-lactamases found in microorganisms resistant to penicillins and cephalosporins. Clavulanic acid has sufficient efficacy against plasmid beta-lactamases, which most often determine the resistance of bacteria, and is not effective against type I chromosomal beta-lactamases that are not inhibited by clavulanic acid.

The presence of clavulanic acid in the preparation protects amoxicillin from destruction by enzymes - beta-lactamases, which allows to expand antibacterial spectrum of amoxicillin.

The activity of a combination of amoxicillin with clavulanic acid in vitro is given below.

Bacteria, usually sensitive to a combination of amoxicillin and clavulanic acid

Gram-positive aerobes: Bacillus anthracis, Enterococcus faecalis, Listeria monocytogenes, Nocardia asteroides, Streptococcus pyogenes and other beta-hemolytic streptococci^1,2, Streptococcus agalactiae^1,2, Staphylococcus aureus (sensitive to methicillin)¹, Staphylococcus saprophyticus (sensitive to methicillin), coagulase-negative staphylococci (sensitive to methicillin).

Gram-negative aerobes: Bordetella pertussis, Haemophilus influenzae¹, Helicobacter pylori, Moraxella catarrhalis¹, Neisseria gonorrhoeae , Pasteurella multocida, Vibrio cholerae.

Other: Borrelia burgdorferi, Leptospira icterohaemorrhagiae, Treponema pallidum.

Gram-positive anaerobes: species of the genus Clostridium, Peptococcus niger, Peptostreptococcus magnus, Peptostreptococcus micros, species of the genus Peptostreptococcus.

Gram-negative anaerobes: Bacteroides fragilis, species of the genus Bacteroides, species of the genus Capnocytophaga, Eikenella corrodens, Fusobacterium nucleatum, species of the genus Fusobacterium, species of the genus Porphyromonas, species of the genus Prevotella.

Bacteria for which the acquired resistance to a combination of amoxicillin and clavulanic acid is probable

Gram-negative aerobes: Escherichia coli¹, Klebsiella oxytoca, Klebsiella pneumoniae, species of the genus Klebsiella, Proteus mirabilis, Proteus vulgaris, species of the genus Proteus, species of the genus Salmonella, species of the genus Shigella.

Gram-positive aerobes: species of the genus Corynebacterium, Enterococcus faecium, Streptococcus pneumoniae^1,2, streptococcus group Viridans.

Bacteria that have natural resistance to a combination of amoxicillin and clavulanic acid

Gram-negative aerobes: species of the genus Acinetobacter, Citrobacter freundii, species of the genus Enterobacter, Hafnia alvei, Legionella pneumophila, Morganella morganii, species of the genus Providencia, species of the genus Pseudomonas, species of the genus Serratia, Stenotrophomonas maltophilia, Yersinia enterocolitica.Other: Chlamydophila pneumoniae, Chlamydophila psittaci, species of the genus Chlamydia, Coxiella burnetii, species of the genus Mycoplasma.

¹ for these bacteria, the clinical efficacy of the combination of amoxicillin with clavulanic acid has been demonstrated in clinical studies.

² strains of these bacteria do not produce beta-lactamases.

Sensitivity to monotherapy with amoxicillin suggests a similar sensitivity to the combination of amoxicillin and clavulanic acid.

Pharmacokinetics:

The main pharmacokinetic parameters of amoxicillin and clavulanic acid are similar. Amoxicillin and clavulanic acid are readily soluble in aqueous solutions with a physiological pH value and after absorption of Amoxiclav® are rapidly and completely absorbed from the gastrointestinal tract (GIT). Absorption of active substances amoxicillin and clavulanic acid is optimal in case of its intake at the beginning of the meal.

Bioavailability of amoxicillin and clavulanic acid after oral administration is about 70%.

The following pharmacokinetic parameters of amoxicillin and clavulanic acid after taking in a dose of 875 mg / 125 mg and 500 mg / 125 mg twice daily, 250 mg / 125 mg three times a day by healthy volunteers

The mean (± SD) F			ermakinetic parameters
Active substances Amoxicillin / clavulanic acid	One-time dose (mg)		FROMmOh (μg / ml)	Tmax (hour)	AUC (0-24h) (μg.h. s / ml)	T_1/2 (hour)
Amoxicillin
875 mg / 125 mg	875	11,64±2,78		1.50(1.0-2.5)	53,52±12,31	1.19±0.21
500mg / 125mg	500	7,19±2,26		1.50(1.0-2.5)	53,5±8,87	1.15±0.20
250mg / 125mg	250	3,3±1,12		1,5(1,0-2,0)	26,7±4,56	1,36±0,56
Clavulanic acid
875 mg / 125 mg	125	2,18±0,99		1.25(1.0-2.0)	10,16±3,04	0.96±0.12
500mg / 125mg	125	2,40±0,83		1.5(1.0-2.0)	15,72±3,86	0.98±0.12
250mg / 125mg	125	1,5±0,70		1,2(1,0-2,0)	12,6±3,25	1.01±0,11

Сmах - the maximum concentration in blood plasma;

Tmax - the time to reach the maximum concentration in the blood plasma;

AUC is the area under the concentration-time curve;

T_1/2 - half-life

Distribution

Both components are characterized by a good volume of distribution in different organs, tissues and body fluids (including pulmonary, abdominal, fat, bone and muscle tissue, pleural, peritoneal and synovial fluids, in the skin, bile, urine, purulent detachable, sputum, in the interstitial fluid).

Plasma protein binding moderate: 25% for the clavulanic acid and 18% for amoxycillin. The volume of distribution is about 0.3-0.4 liters / kg amoxycillin and about 0.2 l / kg for clavulanic acid. Amoxicillin and clavulanic acid do not penetrate the blood-brain barrier in non-inflamed meninges. Amoxicillin (like most penicillins) is excreted in breast milk. Trace amounts of clavulanic acid have also been found in breast milk. Amoxicillin and clavulanic acid penetrate the placental barrier.

Metabolism

About 10-25% of the initial dose of amoxicillin is excreted by the kidneys in the form of inactive penicillic acid. Clavulanic acid in the human body undergoes intensive metabolism with the formation of 2,5-dihydro-4- (2-hydroxyethyl) -5-oxo-1H-pyrrole-3-carboxylic acid and 1-amino-4-hydroxybutan-2-one and is excreted by the kidneys through the gastrointestinal tract, exhaled air, in the form of carbon dioxide.

Excretion

Amoxicillin is excreted mainly by the kidneys, whereas clavulanic acid is through both renal and extrarenal mechanisms. After a single dose of 250 mg / 125 mg or 500 mg / 125 mg of approximately 60-70% amoxicillin and 40-65% clavulanic acid within the first 6 hours is excreted unchanged in the first 6 hours.

Mean half-life (T_1/2) amoxicillin / clavulanic acid is approximately one hour, the average total clearance is approximately 25 l / h in healthy patients.

The greatest amount of clavulanic acid is excreted within the first 2 hours after administration.

Patients with impaired renal function

General information the 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, because most of the amoxicillin is excreted by the kidneys. Doses of the drug for renal failure should be selected taking into account the undesirability of cumulation of amoxicillin against the background of maintaining a normal level of clavulanic acid.

Patients with impaired hepatic function

In patients with impaired liver function, the drug is used with caution, it is necessary to carry out constant monitoring of liver function.

Both components are removed by hemodialysis and minor amounts by peritoneal dialysis.

Indications:

Infections caused by sensitive strains of microorganisms:

- infections of the upper respiratory tract and ENT organs (including acute and chronic sinusitis, acute and chronic otitis media, zaglugal abscess, tonsillitis, pharyngitis);

- infections of the lower respiratory tract (including acute bronchitis with bacterial superinfection, chronic bronchitis, pneumonia);

- urinary tract infections;

- infections in gynecology;

- skin and soft tissue infections, as well as wounds from human and animal bites;

- infections of bone and connective tissues;

- biliary tract infections (cholecystitis, cholangitis);

odontogenic infections.

Contraindications:

- Hypersensitivity to the components of the drug;

- increased sensitivity in the anamnesis to penicillins, cephalosporins and other beta-lactam antibiotics;

- Cholestatic jaundice and / or other liver function disorders caused by taking amoxicillin / clavulanic acid in a history;

- infectious mononucleosis and lymphocytic leukemia;

- Children under 12 years of age or weighing less than 40 kg.

Carefully:Pseudomembranous colitis in history, diseases of the gastrointestinal tract, hepatic insufficiency, severe renal dysfunction, pregnancy, lactation, with simultaneous use with anticoagulants.

Pregnancy and lactation:

Studies in animals have not revealed data on the dangers of taking the drug during pregnancy and its effect on embryonic development of the fetus.

In one study, in women with premature rupture of amniotic membranes, it was found that preventive use amoxicillin / clavulanic acid may be associated with an increased risk of developing necrotizing enterocolitis in newborns. During pregnancy and lactation, the drug is used only if the intended benefit to the mother exceeds the potential risk to the fetus and the baby. Amoxicillin and clavulanic acid penetrate into breast milk in small amounts. In infants receiving breastfeeding, it is possible to develop sensitization, diarrhea, candidiasis of the mucous membranes of the oral cavity. When taking Amoxiclav®, it is necessary to resolve the issue of stopping breastfeeding.

Dosing and Administration:

Inside.

The dosage regimen is set individually depending on the age, body weight, function of the patient's kidneys, and also on the severity of the infection.

The drug Amoxiclav® is recommended to be taken at the beginning of the meal for optimal absorption and to reduce possible side effects from the digestive system.

A course of treatment is 5-14 days. The duration of the course of treatment is determined by the attending physician. Treatment should not last more than 14 days without a second medical examination.

Adults and children 12 years of age or older or with a body weight of 40 kg or more:

For the treatment of infections of mild and moderate severity - 1 tablet 250 mg + 125 mg every 8 hours (3 times a day).

For the treatment of severe infections and infections of the respiratory system - 1 tablet of 500 mg + 125 mg every 8 hours (3 times a day) or 1 tablet of 875 mg + 125 mg every 12 hours (2 times a day).

Since the pills of the combination of amoxicillin and clavulanic acid of 250 mg + 125 mg and 500 mg + 125 mg contain the same amount of clavulanic acid-125 mg, 2 tablets of 250 mg + 125 mg are not equivalent to 1 tablet of 500 mg + 125 mg.

Patients with impaired renal function

Correction of doses is based on the maximum recommended dose of amoxicillin and is carried out taking into account the values of creatinine clearance (CK).

QC	Dosing regimen Amoxiclav®
> 30 ml / min	Correction of the dosing regimen is not required
10-30 ml / min	1 tablet 500 mg + 125 mg 2 times / day or 1 tablet 250 mg + 125 mg 2 times / day (depending on the severity of the disease).
<10 ml / min	1 tablet 500 mg + 125 mg 1 time / day or 1 tablet 250 mg + 125 mg 1 time / day (depending on the severity of the disease).
Hemodialysis	1 tablet 500 mg + 125 mg in one dose every 24 hours. During the dialysis session, 1 additional dose (one tablet) and one more tablet at the end of the dialysis session (to compensate for the decrease in serum concentrations of amoxicillin and clavulanic acid).Or 2 tablets 250 mg + 125 mg in a single dose every 24 hours. During the dialysis session, 1 additional dose (one tablet) and one more tablet at the end of the dialysis session (to compensate for the decrease in serum concentrations of amoxicillin and clavulanic acid).

Tablets 875 mg + 125 mg should be used only in patients with CK> 30 ml / min.

Patients with impaired hepatic function

Take Amoxiclav® with caution. It is necessary to carry out regular monitoring of liver function.

It does not require correction of the dosing regimen for elderly patients. In elderly patients with impaired renal function, the dose should be adjusted as for adult patients with impaired renal function.

Side effects:

According to the World Health Organization (WHO), undesirable effects are classified according to their frequency of development as follows: very often (≥1/10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, < 1/100), rarely (≥1 / 10000, <1/1000) and very rarely (<1/10000); frequency is unknown (the frequency of occurrence of phenomena can not be determined on the basis of available data).

From the gastrointestinal tract: very often: diarrhea; often: nausea, vomiting. Nausea is most often observed with ingestion of high doses.If violations of the GI tract are confirmed, they can be eliminated if you take the drug at the beginning of the meal. Infrequently: indigestion; very rarely: antibiotic-associated colitis (including hemorrhagic colitis and pseudomembranous colitis), black hairy tongue, gastritis, stomatitis.

From the liver and biliary tract: infrequently: increased activity of alanine aminotransferase (ALT) and / or aspartate aminotransferase (ACT). These reactions are observed in patients receiving beta-lactam antibiotic therapy, but its clinical significance is unknown. Very rarely: cholestatic jaundice, hepatitis, increased activity of alkaline phosphatase, increased activity of bilirubin in the blood plasma.

Undesirable reactions from the liver have been observed mainly in men and elderly patients and can be associated with long-term therapy. These undesirable reactions are very rare in children. These signs and symptoms usually occur in the process or immediately after the end of therapy, but in some cases may not appear for several weeks after the completion of therapy.Undesirable reactions, as a rule, are reversible. Undesirable reactions from the liver can be severe, in extremely rare cases there have been reports of lethal outcomes. In almost all cases, these were persons with serious concomitant pathology or persons receiving potentially hepatotoxic drugs at the same time.

From the immune system: very rarely: angioedema, anaphylactic reactions, allergic vasculitis.

On the part of the blood and lymphatic system: rarely: reversible leukopenia (including neutropenia), thrombocytopenia; very rarely: reversible agranulocytosis, hemolytic anemia, reversible increase in prothrombin time, reversible increase in bleeding time (see Section "Special instructions"), eosinophilia, thrombocytosis.

From the nervous system: infrequently: dizziness, headache; very rarely: convulsions (can occur in patients with impaired renal function, as well as when taking high doses of the drug), reversible hyperactivity, aseptic meningitis, anxiety, insomnia, behavioral change, agitation.

From the skin and subcutaneous tissues: infrequently: skin rash, itching, hives; rarely: multiforme exudative erythema; very rarely: exfoliative dermatitis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, a syndrome similar to serum sickness, toxic epidermal necrolysis.

From the side of the kidneys and urinary tract: very rarely: interstitial nephritis, crystalluria (see Section "Overdose"), hematuria.

Infectious and parasitic diseases: often: candidiasis of the skin and mucous membranes.

Other: frequency unknown: growth of insensitive microorganisms.

Overdose:

There are no reports of death or the occurrence of life-threatening side effects due to an overdose of the drug.

In most cases, the symptoms of an overdose include gastrointestinal disorders (abdominal pain, diarrhea, vomiting) and disturbances of the water-electrolyte balance.

Reports on the development of crystalluria caused by the use of amoxicillin have been reported, which in some cases led to the development of renal insufficiency. Possible development of seizures in patients with renal insufficiency or in patients receiving high doses of the drug.

In case of an overdose, the patient should be under the supervision of a physician, the treatment is symptomatic.

In the case of a recent intake (less than 4 hours), it is necessary to wash the stomach and prescribe Activated carbon to reduce suction. Amoxicillin / clavulanic acid is removed by hemodialysis.

Interaction:

Antacids, glucosamine, laxative drugs, aminoglycosides slow absorption, ascorbic acid - increases absorption.

Diuretics, allopurinol, phenylbutazone, non-steroidal anti-inflammatory drugs (NSAIDs) and other drugs that block tubular secretion (probenecid), increase the concentration of amoxicillin (clavulanic acid is excreted mainly by glomerular filtration). The simultaneous use of Amoxiclav® and probenecid can lead to an increase and persistence in the blood of the level of amoxicillin, but not clavulanic acid, therefore simultaneous use with probenecid is not recommended.

The simultaneous use of Amoxiclav® and methotrexate raises the toxicity of methotrexate. The use of the drug together with allopurinol can lead to the development of skin allergic reactions.

Currently, there is no data on the simultaneous use of a combination of amoxicillin with clavulanic acid and allopurinol. Do not use concomitantly with disulfiram.

Reduces the effectiveness of drugs, in the process of metabolism of which forms para-aminobenzoic acid, ethinyl estradiol - risk of bleeding "breakthrough".

In the literature, rare cases of an increase in the international normalized ratio (INR) in patients with joint use of acenocoumarol or warfarin and amoxicillin are described. If it is necessary to simultaneously use anticoagulants, it is necessary to regularly monitor prothrombin time or INR when prescribing or canceling the drug, it may be necessary to adjust the dose of anticoagulants for oral administration.

With simultaneous use with rifampicin, a mutual weakening of the antibacterial effect is possible.

Amoxiclav® should not be used concomitantly in combination with bacteriostatic antibiotics (macrolides, tetracyclines), sulfonamides, because of the possible decrease in the effectiveness of Amoxiclav®.

The drug Amoxiclav8 reduces effectiveness of oral contraceptives.

In patients who received mycophenolate mofetil, after the start of the combination of amoxicillin with clavulanic acid, a decrease in the concentration of the active metabolite, mycophenolic acid, was observed, before taking the next dose of the drug by approximately 50%. Changes in this concentration can not accurately reflect the overall changes in the exposure of mycophenolic acid.

Special instructions:

Before starting treatment, it is necessary to interview the patient to identify in a history of hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam antibiotics. Patients who are hypersensitive to penicillins may have cross-allergic reactions with cephalosporin antibiotics. In course treatment it is necessary to monitor the status of the function of the organs of hematopoiesis, liver, kidneys. Patients with severe renal dysfunction require adequate dose adjustment or an increase in the intervals between doses. To reduce the risk of side effects from the gastrointestinal tract, you should take the drug while eating.

Perhaps the development of superinfection due to the growth of microflora insensitive to amoxicillin, which requires a corresponding change in antibacterial therapy.

In patients with impaired renal function, as well as when taking high doses of the drug, cramps may appear.

It is not recommended to use the drug in patients with suspected infectious mononucleosis.

If antibiotic-associated colitis occurs, immediately stop taking Amoxiclav®, consult a doctor and begin appropriate treatment. Drugs that inhibit peristalsis are contraindicated in such situations.

In patients with reduced diuresis, crystalluria is very rare. During the application of large doses of amoxicillin, it is recommended to take a sufficient amount of fluid and maintain an adequate diuresis in order to reduce the probability of formation of amoxicillin crystals.

Laboratory tests: high concentrations of amoxicillin give a false positive reaction to urine glucose when using a Benedict reagent or Fehling solution.

It is recommended to use enzymatic reactions with glucosidase.

Clavulanic acid can induce non-specific binding of immunoglobulin G (IgG) and albumin to erythrocyte membranes, which leads to false positive results of Coombs test.

Effect on the ability to drive transp. cf. and fur:

If unwanted reactions from the nervous system develop (for example, dizziness, convulsions), one should refrain from driving and doing other activities, requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, film-coated 250 mg + 125 mg; 500 mg + 125 mg; 875 mg + 125 mg.

Packaging:

Primary packaging:

Film-coated tablets, 250 mg + 125 mg: 15, 20 or 21 tablets and 2 desiccants (silica gel) placed in a round red container with the inscription "inedible" in a dark glass bottle sealed with a metal screw cap with a control ring with perforations and a low density polyethylene liner inside.

Tablets, film-coated, 500 mg + 125 mg: 15 or 21 tablets and 2 desiccants (silicagel) placed in a round red container with the inscription "inedible" in a dark glass bottle sealed with a metal screw cap with a check ring with perforations and a low density polyethylene liner inside or 5, 6 , 7 or 8 tablets in a blister of lacquered hard aluminum / soft aluminum foil.

Tablets, film-coated, 875 mg + 125 mg: 2, 5, 6, 7 or 8 tablets in a blister of lacquered hard aluminum / soft aluminum foil.

Secondary packaging:

Film-coated tablets, 250 mg + 125 mg: one vial in a cardboard pack together with the instruction on medical application.

Tablets, film-coated, 500 mg + 125 mg: one vial or one, two, three, four or ten blisters for 5, 6, 7 or 8 tablets in a cardboard box, along with instructions for medical use.

Tablets, film-coated, 875 mg + 125 mg: one, two, three, four or ten blisters for 2, 5, 6, 7 or 8 tablets in a cardboard box together with instructions for medical use.

Storage conditions:

In a dry place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the product after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N012124 / 01

Date of registration:22.07.2011 / 05.05.2015

Expiration Date:Unlimited

The owner of the registration certificate: Lek dd Lek dd Slovenia

Manufacturer: & nbsp

LEK d.d. Slovenia

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp19.08.2017

Illustrated instructions

Instructions

Amoxiclav® (Amoksiklav®)