Amoxicillin+Clavulanic acid EXPRESS, 500 mg+125 mg 14 pcs

The antibiotic is a semisynthetic penicillin + beta-lactamase inhibitor.

The ATC code: J01CR02

Pharmacological properties

Pharmacodynamics

The mechanism of action

Amoxicillin is a broad spectrum semi-synthetic antibiotic with activity against many Gram-positive and Gram-negative microorganisms. At the same time, amoxicillin is subject to degradation by beta-lactamases, and therefore the spectrum of activity of amoxicillin 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 range of beta-lactamases found in microorganisms that are resistant to penicillins and cephalosporins.

Clavulanic acid is sufficiently effective against plasmid beta-lactamases that 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 the drug Amoxicillin + Clavulanic acid EXPRESS protects amoxicillin from degradation by enzymes – beta-lactamases, which allows to expand the antibacterial spectrum of amoxicillin.

The in vitro activity of the combination of amoxicillin with clavulanic acid is shown below.

Bacteria generally sensitive to the combination of amoxicillin with clavulanic acid

Gram-positive aerobes:

Bacillus anthracis

Enterococcus faecalis

Listeria monocytogenes

Nocardia asteroides

Streptococcus pyogenes1,2

Streptococcus agalactiae1,2

Streptococcus spp. (other beta-haemolytic streptococci)1,2

Staphylococcus aureus (sensitive to methicillin)1

Staphylococcus saprophyticus (sensitive to methicillin)

Coagulazonegative staphylococci (sensitive to methicillin).

Gram-positive anaerobes:

Clostridium spp.

Peptococcus niger

Peptostreptococcus magnus

Peptostreptococcus micros

Peptostreptococcus spp.

Gram-negative aerobes:

Bordetella pertussis

Haemophilus influenzae1

Helicobacter pylori

Moraxella catarrhalis1

Neisseria gonorrhoeae

Pasteurella multocida

Vibrio cholerae.

Gram-negative anaerobes:

Bacteroides fragilis

Basteroides spp.

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 and 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 Viridans2.

Bacteria with natural resistance 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 burnetti

Mycoplasma spp.

1 – For these types of microorganisms, the clinical effectiveness of the combination of amoxicillin with clavulanic acid has been demonstrated in clinical trials.

2 – strains of these bacterial species do not produce β-lactamases. The sensitivity with amoxicillin monotherapy suggests similar sensitivity to a combination of amoxicillin and clavulanic acid.

Pharmacokinetics

Amoxicillin and clavulanic acid dissociate completely in aqueous solution at physiological pH values. Both active ingredients of the drug, amoxicillin and clavulanic acid, are rapidly and well absorbed from the gastrointestinal tract (GIT) after oral administration. Absorption of active ingredients is optimal at the beginning of meals. Bioavailability of amoxicillin and clavulanic acid when taken orally is high. After a single dose of fixed combination of amoxicillin and clavulanic acid (500 mg + 125 mg) maximum concentration of amoxicillin in blood plasma is in 1.5 hours (1.0-2.5 hours), and it is 7.19±2.26 µg/ml (Cmax), clavulanic acid – in 1.5 hours (1.0-2.0 hours), it is 2.4±0.83 µg/ml. The PFC (area under the pharmacokinetic curve) of amoxicillin and clavulanic acid was 53.5±8.87 µg*h/L and 15.72±3.86 µg*h/L, respectively. Plasma concentrations of amoxicillin and clavulanic acid achieved with amoxicillin/clavulanate are similar to those achieved with oral administration of equivalent doses of amoxicillin and clavulanic acid alone.

Distribution

Approximately about 18% of amoxicillin and 25% of clavulanic acid binds to plasma proteins. The apparent volume of distribution is 0.3-0.4 l/kg for amoxicillin and about 0.2 l/kg for clavulanic acid. Amoxicillin is poorly distributed in the cerebrospinal fluid.

In animal studies no cumulation of the drug components in the body tissues was found.

Like most penicillins, amoxicillin penetrates into breast milk. Clavulanic acid is also found in breast milk in trace concentrations. Amoxicillin and clavulanic acid penetrate the placental barrier.

Metabolism

10-25% of the initial dose of amoxicillin is excreted by the kidneys as an inactive metabolite (penicillic acid). Clavulanic acid is extensively metabolized and excreted by the kidneys, intestines and exhaled air as carbon dioxide.

After a single administration of fixed combination of amoxicillin and clavulanic acid (500 mg + 125 mg) the half-life of amoxicillin is 1.15±0.20 h, clavulanic acid – 0.98±0.12 h, total clearance – about 25 l/h. Approximately 60-70% of amoxicillin and about 40-65% of clavulanic acid is excreted unchanged by the kidneys during the first 6 hours after taking 1 tablet of the drug 500/125 mg. The greatest amount of clavulanic acid is excreted within the first 2 hours after intake. In various studies it has been shown that within 24 hours up to 50-85% of amoxicillin and up to 27-60% of clavulanic acid are excreted through the kidneys.

Concomitant administration of probenecid delays excretion of amoxicillin, but does not affect renal excretion of clavulanic acid (see section “Interaction with other medicinal products”).

Pharmacokinetics in special cases

Age specificities

The half-life of amoxicillin in children from 3 months to 2 years does not differ from that of older children and adults. Children of the first week of life (including premature infants) should not prescribe the drug more than 2 times a day because of the immaturity of the renal elimination pathway. Because of the possible decrease of renal function, the drug dose for elderly patients should be selected with caution. Renal function monitoring may be necessary.

Gender specificities

When oral administration of amoxicillin/clavulanic acid in healthy males and females there is no significant effect of patient’s gender on the pharmacokinetics of the active ingredients of the drug.

Renal dysfunction

The total clearance of amoxicillin/clavulanic acid decreases in proportion to decreased renal function. Clearance of amoxicillin is particularly impaired because the kidneys excrete most of it. Thus, in case of impaired renal function the dose of the drug should be adjusted to avoid excessive concentration of amoxicillin and to maintain the necessary level of clavulanic acid.

Hepatic impairment

In patients with hepatic impairment the drug should be prescribed with caution. Liver function should be monitored regularly.

Indications

The combination of amoxicillin with clavulanic acid is indicated for the treatment of bacterial infections of the following localizations caused by microorganisms sensitive to the combination of amoxicillin and clavulanic acid:

– Upper respiratory tract infections (including ENT organ infections), such as: recurrent tonsillitis, sinusitis, otitis media, usually caused by Streptococcus pneumoniae1,2, Haemophilus influenzae1, Moraxella catarrhalis1, and Streptococcus pyogenes1,2;

– Lower respiratory tract infections, such as: exacerbations of chronic bronchitis, lobular pneumonia, and bronchopneumonia, usually caused by Streptococcus pneumoniae1,2, Haemophilus influenzae1, and Moraxella catarrhalis1;

– Genitourinary tract infections, such as cystitis, urethritis, pyelonephritis, infections of the female genitalia, usually caused by species of the family Enterobacteriaceae (mainly Escherichia coli1), Staphylococcus saprophyticus and species of the genus Enterococcus, and gonorrhea caused by Neisseria gonorrhoeae;

– skin and soft tissue infections, usually caused by Staphylococcus aureus1, Streptococcus pyogenes1,2 and species of the genus Bacteroides;

– bone and joint infections, such as osteomyelitis, usually caused by Staphylococcus aureus1, with long-term therapy if necessary;

– odontogenic infections, such as: periodontitis, odontogenic maxillary sinusitis, severe dental abscesses with spreading cellulitis;

– other mixed infections (e.g.: septic abortion, postpartum sepsis, intra-abdominal sepsis) as part of step therapy.

Particular representatives of the mentioned microorganisms produce beta-lactamase, which makes them insensitive to amoxicillin (see also section “Pharmacological properties”). Infections caused by microorganisms sensitive to amoxicillin can be treated with Amoxicillin + Clavulanic acid EXPRESS because amoxicillin is one of its active ingredients. Amoxicillin + Clavulanic acid EXPRESS is also indicated for the treatment of mixed infections caused by microorganisms sensitive to amoxicillin as well as by beta-lactamase-producing microorganisms sensitive to the combination of amoxicillin and clavulanic acid.

The sensitivity of bacteria to the combination of amoxicillin and clavulanic acid varies by region and over time. Where possible, local sensitivity data should be taken into account. If necessary, microbiologic samples should be collected and bacteriologic sensitivity testing should be performed.

1 – For these types of microorganisms, the clinical efficacy of the combination of amoxicillin with clavulanic acid has been demonstrated in clinical trials.

2 – strains of these bacterial species do not produce β-lactamases. The sensitivity with amoxicillin monotherapy suggests similar sensitivity to the combination of amoxicillin with clavulanic acid.

Active ingredient

Composition

One tablet 500 mg + 125 mg contains:

The active ingredients:

amoxicillin trihydrate in terms of amoxicillin – 573.89 mg (500.00 mg);

potassium clavulanate + microcrystalline cellulose (1:1) in terms of clavulanic acid – 297.82 mg (125.00 mg).

Excipients:

Microcrystalline cellulose 302 – 87.09 mg;

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crospovidone – 201.20 mg;

vanillin – 1.00 mg;

saccharin – 9.00 mg;

magnesium stearate – 5.00 mg;

apricot flavoring – 9.00 mg.

How to take, the dosage

For oral administration.

The dosing regimen is adjusted individually depending on the patient’s age, body weight, renal function, and the severity of the infection. In order to reduce the potential gastrointestinal disorders and to optimize absorption, the drug should be taken at the beginning of meals. The tablet should be swallowed as a whole with a glass of water, or dissolved in half a glass of water (30 ml minimum), stirring thoroughly before drinking.

The minimum course of antibiotic therapy is 5 days.

The treatment should not continue for more than 14 days without a review of the clinical situation. If necessary, staggered therapy (parenteral administration of amoxicillin + clavulanic acid first, followed by switch to oral administration) is possible.

Adults and children over 12 years of age with body weight ≥ 40 kg are indicated with 500 mg/125 mg 3 times daily or 875 mg/125 mg 2 times daily.

The maximum daily dose should not exceed 2400 mg/600 mg daily.

In children aged 1 to 12 years with a body weight of 10 to 40 kg, the dosing regimen is adjusted individually based on the clinical situation and the severity of infection.

The recommended daily dose is from 20 mg/5mg/kg/day to 60 mg/15mg/kg/day and divided into 2-3 doses. There are no clinical data on the use of amoxicillin/clavulanic acid in a 4:1 ratio in doses > 40 mg/10mg/kg/day in children younger than two years. The maximum daily dose for children is 60 mg/15 mg/kg/day.

Low doses of the drug are recommended for the treatment of skin and soft tissue infections and recurrent tonsillitis; high doses of the drug are recommended for the treatment of conditions such as otitis media, sinusitis, lower respiratory and urinary tract infections, bone and joint infections.

There is insufficient clinical data to recommend the use of the drug at a dose greater than 40 mg/10 mg/kg/day in 3 doses (4:1 ratio) in children younger than 2 years. The approximate dosing schedule of the drug in pediatric patients is presented in the table below:

Child’s weight, kg Age (approximately) Use of low doses of the drug Use of high doses of the drug:

10-12 10-12 1-2 years 2 times daily 1 tablet 125 mg/ 31.25 mg 3 times daily 1 tablet 125 mg/ 31.25 mg*

12-15 2-4 years 3 times daily 1 tablet 125 mg/ 31.25 mg 3 times daily 1 tablet 250 mg/62.5 mg

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15-20 4-6 years old 3 times a day 1 tablet 250 mg/62.5 mg 3 times a day 1 tablet 250 mg/62.5 mg or 2 times a day 500 mg/125 mg

20-30 6-10 years old 3 times daily 1 tablet 250 mg/62.5 mg 2 times daily 1 tablet 500 mg/125 mg

30-40 10-12 years old 2 times daily 1 tablet 500 mg/125 mg 3 times daily 1 tablet 500 mg/125 mg

≥40 ≥12 years old 3 times daily 1 tablet 500 mg/125 mg 3 times daily 1 tablet 500 mg/125 mg

*Not enough clinical data to recommend use of the drug at a dose greater than 40 mg/10 mg/kg/day in 3 doses (ratio 4:1) in children younger than 2 years of age.

In children aged ≤6 years, it is preferable to take the drug in dissolved form.

Interaction

Directions for use

Before starting treatment with Amoxicillin + Clavulanic Acid EXPRESS, a detailed history of previous hypersensitivity reactions to penicillins, cephalosporins or other substances causing an allergic reaction in the patient should be collected.

Serious, and sometimes fatal, hypersensitivity reactions (including anaphylactic and severe skin adverse reactions) to penicillins have been described. The risk of such reactions is highest in patients with a history of hypersensitivity reactions to penicillins. In case of allergic reactions it is necessary to discontinue treatment with Amoxicillin + Clavulanic acid EXPRESS and initiate appropriate alternative therapy.

In the event that the infection is proven to be caused by amoxicillin-sensitive organisms, amoxicillin/clavulanic acid combination should be considered for replacement with amoxicillin in accordance with official clinical guidelines.

Amoxicillin/clavulanic acid is not appropriate for use in cases where there is a high risk that the suspected pathogens are hypersensitive or resistant to beta-lactam drugs that are not due to beta-lactamases susceptible to inhibition by clavulanic acid.

Amoxicillin/clavulanic acid should not be used for therapy of infections caused by penicillin-resistant strains of S. pneumoniae.

Acute coronary syndrome associated with hypersensitivity (Coneys syndrome)

In rare cases hypersensitivity reactions have been reported during treatment with amoxicillin (acute coronary syndrome associated with hypersensitivity), in these cases the drug should be withdrawn and appropriate treatment should be prescribed.

In patients with impaired renal function, as well as when taking high doses of the drug, seizures may be observed (see section “Side effects”).

In case of suspected infectious mononucleosis Amoxicillin + Clavulanic acid EXPRESS should not be used because in patients with this disease amoxicillin may cause exanthema (crust-like skin rash).

The concomitant use of allopurinol during treatment with amoxicillin may increase the likelihood of skin allergic reactions.

Long-term treatment with Amoxicillin + Clavulanic acid EXPRESS may lead to overgrowth of insensitive microorganisms.

The occurrence of generalized erythema with fever accompanied by pustules at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis (GEEP). This reaction requires discontinuation of the drug containing amoxicillin/clavulanic acid and is a contraindication to the subsequent use of amoxicillin drugs.

The drugs containing amoxicillin/clavulanic acid should be used with caution in patients with impaired liver function.

Hepatic adverse events have been observed mainly in men and elderly patients and may be associated with prolonged therapy. These adverse events are very rarely seen in children. In all populations, the listed signs and symptoms usually occur during or shortly after completion of therapy, but in some cases may not appear for several weeks after completion of therapy. They are generally reversible. Liver adverse events can be severe, with exceptionally rare reported fatalities. In almost all cases, these were patients with serious comorbidities or patients concomitantly receiving drugs that potentially affect the liver.

Pseudomembranous colitis has been described when taking antibiotics, the severity of which can range from mild to life-threatening. Therefore, it is important to consider the possibility of pseudomembranous colitis in patients with diarrhea during or after antibiotic use. If antibiotic-associated colitis occurs, the treatment with amoxicillin/clavulanic acid combination should be stopped immediately, a physician should be consulted and appropriate treatment should be started. Drugs that inhibit peristalsis are contraindicated in this situation. During prolonged therapy with the drug Amoxicillin + Clavulanic acid EXPRESS it is recommended to periodically assess renal function, liver and hematopoiesis.

In patients receiving a combination of amoxicillin and clavulanic acid in rare cases it was reported an increase in prothrombin time (INR). When co-administration of indirect (oral) anticoagulants with the combination of amoxicillin with clavulanic acid it is necessary to monitor the corresponding indicators. To maintain the desired effect of oral anticoagulants may require adjustment of their dose.

In patients with impaired renal function the dose of the drug Amoxicillin + clavulanic acid EXPRESS should be reduced according to the degree of impairment (see section “Dosage and administration” – Patients with impaired renal function).

In patients with decreased diuresis, crystalluria is very rare, mainly during parenteral therapy. During the management of high doses of amoxicillin it is recommended to take sufficient fluids and maintain adequate diuresis to reduce the likelihood of formation of amoxicillin crystals (see section “Overdose”). In patients with bladder catheters, their patency should be regularly checked. Intake of Amoxicillin + Clavulanic acid EXPRESS leads to high content of amoxicillin in the urine, which may lead to false positive results in determining glucose in the urine (e.g., Benedict test, Felling test). In this case it is recommended to use glucose-oxidant method of determining the concentration of glucose in urine.

Clavulanic acid may cause non-specific binding of immunoglobulin G and albumin to erythrocyte membranes, leading to false positive Coombs test results.

The Bio-Rad Laboratories Platelia Aspergillus ELISA test has been reported positive in patients treated with the amoxicillin/clavulanic acid combination who were not subsequently found to have Aspergillus infection. Cross-reactions with polysaccharides and polyfurans not characteristic of the genus Aspergillus have been reported in the Platelia Aspergillus ELISA test. Therefore, positive results of the Platelia Aspergillus ELISA test in patients receiving the amoxicillin/clavulanic acid combination should be interpreted with caution and confirmed by other diagnostic methods.

One dispersible tablet of Amoxicillin + Clavulanic acid 125 mg/31.25 mg contains 0.16 mmol (6.13 mg) of potassium, 250 mg/62.5 mg contains 0.32 mmol (12.3 mg), 500 mg/125 mg contains 0.64 mmol (24.53 mg), 875 mg/125 mg contains 0.64 mmol (25 mg).

Potassium intake greater than 1 mmol per day requires special attention in patients with reduced renal function and those on a controlled potassium diet.

Impact on driving and operating ability

There have been no studies to study the effect on the ability to drive and operate machinery. Since the drug may cause side effects (e.g., allergic reactions, dizziness, seizures) (see section “Side effects”), patients should be warned about the precautions to take when driving or operating moving machinery.

Special Instructions

Contraindications

– hypersensitivity to amoxicillin, clavulanic acid, other penicillins or any other component of the drug;

– history of severe immediate-type hypersensitivity reactions (eg, anaphylaxis) to other beta-lactam antibiotics (eg, cephalosporins, carbapenems or monobactams);

– history of jaundice or hepatic failure due to administration of amoxicillin/clavulanic acid;

– childhood age under 1 year and/or body weight under 10 kg (due to the impossibility of dosing the dosage form in this category of patients).

The drug is contraindicated at a dose of 875 mg + 125 mg for children under 12 years of age with CK≤30 ml/min.

With caution

Severe hepatic impairment, gastrointestinal diseases (including a history of colitis associated with penicillin use), chronic renal failure.

Side effects

Overdose

Pregnancy use

Pregnancy

In animal studies of reproduction, oral and parenteral administration of amoxicillin + clavulanic acid did not cause teratogenic effects.

In a single study in women with premature rupture of fetal membranes, it was found that prophylactic therapy with the drug may be associated with an increased risk of necrotizing enterocolitis in newborns.

The drug is not recommended for use during pregnancy unless the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period

The drug Amoxicillin + Clavulanic acid EXPRESS can be used during breastfeeding.

With the exception of possible sensitization, diarrhea, or oral candidiasis associated with penetration into breast milk of trace amounts of the active ingredients of this drug, no other adverse effects have been observed in breastfed infants.

Breastfeeding should be stopped if adverse effects occur in breastfed infants.

Similarities