Ekoklav® (Amoxicillin + Clavulanic acid) powder 250 mg + 62.5 mg / 5 ml

Instructions for use of Ekoklav® (Amoxicillin + Clavulanic acid) powder 250 mg + 62.5 mg / 5 ml

Brand name: Ekoklav^®

International nonproprietary or grouping name: Amoxicillin + Clavulanic acid

Dosage form: Powder for preparation of oral suspension

Composition

Composition of components in 5 ml of the prepared suspension (one dosing spoon):

Active substances: Amoxicillin trihydrate 144 mg / 287 mg (equivalent to amoxicillin) 125 mg / 250 mg; Potassium clavulanate + Silicon dioxide (1:1) 74.85 mg / 149.70 mg (equivalent to clavulanic acid) 31.25 mg / 62.5 mg

Excipients:  Aspartame 5.5 mg / 5.5 mg, Xanthan gum 10.0 mg / 10.0 mg, Crospovidone (Kollidon CL-M) 28.1 mg / 28.1 mg, Anhydrous citric acid 2.165 mg / 2.165 mg, Sodium citrate dihydrate 8.335 mg / 8.335 mg, Sodium benzoate 2.085 mg / 2.085 mg, Talc  25.0 mg / 25.0 mg, Strawberry flavor 40.0 mg / 40.0 mg,  Mannitol (Mannite) - up to the powder weight of 1.25 g / 1.25 g

Description

Powder from white to almost white with a slight fruity odor. After reconstitution with water, it forms a suspension from almost white to light yellow with a fruity odor.

Pharmacotherapeutic group:

Antibiotic - penicillin semi-synthetic + beta-lactamase inhibitor.

ATC Code: J01CR02

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Amoxicillin is a broad-spectrum semi-synthetic antibiotic active against many gram-positive and gram-negative microorganisms. However, amoxicillin is susceptible to degradation by beta-lactamases, and therefore its spectrum of activity does not extend to microorganisms that produce this enzyme.

Clavulanic acid is a beta-lactamase inhibitor, structurally related to penicillins,  capable of inactivating a wide spectrum of beta-lactamases found in microorganisms resistant to penicillins and cephalosporins. Clavulanic acid is sufficiently effective against plasmid beta-lactamases, which most often cause bacterial resistance, and is not effective against chromosomal type 1 beta-lactamases, which are not inhibited by clavulanic acid.

The presence of clavulanic acid in Ekoklav®  protects amoxicillin from degradation by beta-lactamase enzymes, thereby expanding the antibacterial spectrum of amoxicillin.

The following represents the activity of the amoxicillin and clavulanic acid combination in vitro:

Bacteria usually susceptible to the amoxicillin/clavulanic acid combination

Gram-positive aerobes

• Bacillus anthracis
• Enterococcus faecalis
• Listeria monocytogenes
• Nocardia asteroides
• Streptococcus pyogenes^1,2
• Streptococcus agalactiae^1,2
• Streptococcus spp. (other beta-hemolytic streptococci)^1,2
• Staphylococcus aureus (methicillin-susceptible)¹
• Staphylococcus saprophyticus (methicillin-susceptible)
• Coagulase-negative staphylococci (methicillin-susceptible)

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
• Bacteroides 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 may be a problem

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 pneumoniae^1,2
• Streptococcus group Viridans

Bacteria possessing natural resistance to the amoxicillin/clavulanic acid combination

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 the amoxicillin/clavulanic acid combination has been demonstrated in clinical studies.

² – Strains of these bacterial species do not produce beta-lactamases. Susceptibility to amoxicillin monotherapy suggests analogous susceptibility to the amoxicillin/clavulanic acid combination.

Pharmacokinetics

Absorption

Both active substances of Ekoklav®  amoxicillin and clavulanic acid, are rapidly and completely absorbed from the gastrointestinal tract (GIT) after oral administration. Absorption of the active substances of Ekoklav® is optimal when the drug is taken at the start of a meal.

The table below shows pharmacokinetic parameters of amoxicillin and clavulanic acid obtained in various studies where healthy volunteers aged 2-12 years, fasting, received the amoxicillin/clavulanic acid combination powder for oral suspension, 125 mg/31.25 mg in 5 ml, three times a day at a dose of 40 mg/10 mg/kg/day.

Main pharmacokinetic parameters

Dose (mg/kg)

Cmax (mg/l)

Tmax (hours)

AUC (mg×h/l)

T1/2 (hours)

Amoxicillin

40

7.3 ± 1.7

2.1 (1.2-3.0)

18.6 ± 2.6

1.0 ± 0.33

Clavulanic acid

10

2.7 ± 1.6

1.6 (1.0-2.0)

5.5 ± 3.1

0.94 ± 0.05

C_max – maximum plasma concentration.

T_max – time to reach maximum plasma concentration.

AUC – area under the concentration-time curve.

T_1/2 – half-life

Distribution

As with intravenous administration of the amoxicillin/clavulanic acid combination, 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, bile, purulent discharge).

Amoxicillin and clavulanic acid have a low degree of binding to plasma proteins. Studies have shown that approximately 25% of the total amount of clavulanic acid and 18% of amoxicillin in plasma are bound to plasma proteins.

Animal studies have not revealed accumulation of the components of the amoxicillin/clavulanic acid combination in any organ. Amoxicillin, like most penicillins, passes into breast milk. Trace amounts of clavulanic acid may also be detected in breast milk. Apart from the possibility of sensitization, diarrhea, and candidiasis of the oral mucosa, no other negative effects of amoxicillin and clavulanic acid on the health of breastfed infants are known.

Reproductive studies in animals have shown that amoxicillin and clavulanic acid cross the placental barrier. However, no negative effects on the fetus were identified.

Metabolism

10-25% of the initial dose of amoxicillin is excreted by the kidneys as an inactive metabolite (penicilloic acid). Clavulanic acid undergoes extensive metabolism to 2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid and 1-amino-4-hydroxy-butan-2-one and is excreted by the kidneys, through the gastrointestinal tract, and also in exhaled air as carbon dioxide.

Excretion

Like other penicillins, amoxicillin is excreted mainly by the kidneys, whereas clavulanic acid is eliminated by both renal and extrarenal mechanisms. Approximately 60-70% of amoxicillin and about 40-65% of clavulanic acid are excreted unchanged by the kidneys within the first 6 hours after administration of one 250 mg/125 mg tablet or one 500 mg/125 mg tablet. Concurrent administration of probenecid slows the excretion of amoxicillin but not clavulanic acid (see section "Interaction with other medicinal products").

Indications for use

The amoxicillin/clavulanic acid combination is indicated for the treatment of bacterial infections of the following localizations, caused by microorganisms susceptible to the amoxicillin/clavulanic acid combination:

• Infections of the upper respiratory tract (including ENT infections), e.g., recurrent tonsillitis, sinusitis, otitis media, usually caused by Streptococcus pneumoniae, Haemophilus influenzae*, Moraxella catarrhalis* and Streptococcus pyogenes.
• Infections of the lower respiratory tract, e.g., exacerbations of chronic bronchitis, lobar pneumonia and bronchopneumonia, usually caused by Streptococcus pneumoniae, Haemophilus influenzae*, Moraxella catarrhalis*.
• Infections of the genitourinary tract, e.g., cystitis, urethritis, pyelonephritis, female genital infections, usually caused by members of the Enterobacteriaceae* family (primarily Escherichia coli*), Staphylococcus saprophyticus and Enterococcus species, as well as gonorrhea caused by Neisseria gonorrhoeae*.
• Infections of the skin and soft tissues, usually caused by Staphylococcus aureus*, Streptococcus pyogenes and Bacteroides* species.

• Infections of bones and joints, e.g., osteomyelitis, usually caused by Staphylococcus aureus*; long-term therapy may be necessary.

*Individual representatives of these genera of microorganisms produce beta-lactamase, making them insensitive to amoxicillin (see also section "Pharmacological Properties").

Infections caused by amoxicillin-susceptible microorganisms can be treated with Ekoklav®, as amoxicillin is one of its active ingredients.

Ekoklav® is also indicated for the treatment of mixed infections caused by amoxicillin-susceptible microorganisms and beta-lactamase-producing microorganisms susceptible to the amoxicillin/clavulanic acid combination.

Bacterial susceptibility to the amoxicillin/clavulanic acid combination varies by region and over time. Where possible, local susceptibility data should be considered. If necessary, microbiological samples should be collected and tested for bacteriological susceptibility.

Contraindications

• Hypersensitivity to amoxicillin, clavulanic acid, other components of the drug, beta-lactam antibiotics (e.g., penicillins and cephalosporins)  in history;
• Previous episodes of jaundice or impaired liver function associated with the use of the amoxicillin/clavulanic acid combination in history;
• Phenylketonuria.

With caution

Ekoklav® should be used with caution in patients with impaired liver function.

Use during pregnancy and breastfeeding

Pregnancy

Studies of reproductive function in animals with oral and parenteral administration of the amoxicillin/clavulanic acid combination did not reveal teratogenic effects.

In a single study in women with premature rupture of membranes, it was found that prophylactic therapy with the drug may be associated with an increased risk of necrotizing enterocolitis in newborns. Like all medicines, Ekoklav® is not recommended during pregnancy, except when the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period

Ekoklav® can be used during breastfeeding. Except for the possibility of sensitization, diarrhea, or candidiasis of the oral mucosa associated with the passage of trace amounts of the active substances of this drug into breast milk, no other adverse effects have been observed in breastfed infants. If adverse effects occur in breastfed infants, breastfeeding should be discontinued.

Dosage and administration

For oral administration.

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

To reduce potential gastrointestinal disturbances and to optimize absorption, the drug should be taken at the start of a meal.

Treatment should not continue for more than 14 days without reviewing the clinical situation.

If necessary, stepwise therapy is possible (parenteral administration of the amoxicillin/clavulanic acid combination in the form of a powder for solution for intravenous administration followed by a switch to Ekoklav®  in oral dosage forms).

Adults and children aged 12 years and older or with body weight 40 kg and more

It is recommended to use other dosage forms of Ekoklav® or a suspension with an amoxicillin to clavulanic acid ratio of 7:1 (400 mg/57 mg in 5 ml).

Children aged 3 months to 12 years with body weight less than 40 kg

The dose is calculated depending on age and body weight, indicated in mg/kg of body weight per day, or in ml of suspension. The daily dose is divided into 3 doses every 8 hours. The recommended dosing regimen and frequency of administration are presented in the table below.

Table of dosing regimen for Ekoklav® (dose calculated based on amoxicillin)

	Suspension 4:1 (125 mg/31.25 mg in 5 ml or 250 mg/62.5 mg in 5 ml) in 3 doses every 8 hours
Low doses	20 mg/kg/day
High doses	40 mg/kg/day

Low doses of Ekoklav® are recommended for the treatment of skin and soft tissue infections, as well as recurrent tonsillitis.

High doses of Ekoklav® are recommended for the treatment of conditions such as otitis media, sinusitis, lower respiratory tract and urinary tract infections, and bone and joint infections.

There is insufficient clinical data to recommend the use of Ekoklav® at a dose exceeding 40 mg/10 mg/kg/day in 3 doses (suspension 4:1) in children under 2 years of age.

Children from birth to 3 months

Due to the immaturity of renal excretory function, the recommended dose of Ekoklav® (calculated based on amoxicillin) is 30 mg/kg/day in 2 doses as a suspension 4:1.

Children born prematurely

There are no recommendations regarding the dosing regimen 

Special patient groups

Patients with impaired renal function

Dosage adjustment is based on the maximum recommended dose of amoxicillin and the creatinine clearance value.

Creatinine clearance	Dosing regimen of Ekoklav® suspension 4:1 (125 mg/31.25 mg in 5 ml or 250 mg/62.5 mg in 5 ml )
> 30 ml/min	No dosage adjustment required
10-30 ml/min	15 mg/3.75 mg/kg twice daily maximum daily dose 500 mg/125 mg twice daily
< 10 ml/min	15 mg/3.75 mg/kg once daily maximum daily dose 500 mg/125 mg once daily

In most cases, parenteral therapy should be preferred whenever possible.

Patients on hemodialysis

Recommended dosing regimen:

15 mg/3.75 mg/kg once daily.

Before  a hemodialysis session, one additional dose of  15 mg/3.75 mg/kg should be administered. To restore blood concentrations of the active components of Ekoklav®, a second additional dose of 15 mg/3.75 mg/kg should be administered after the hemodialysis session.

Patients with impaired liver function

Treatment should be carried out with caution,  with regular monitoring of liver function. There is insufficient data to change dose recommendations in such patients.

Method of suspension preparation

The suspension should be prepared immediately before first use.

Add approximately 60 ml of boiled water, cooled to room temperature, to the bottle with the powder. Then close the bottle with the cap and shake until the powder is completely dissolved. Let the bottle stand for 5 minutes to ensure complete dissolution. Then add water up to the mark on the bottle and shake the bottle again. In total, about 92 ml of water is required to prepare the suspension.

The bottle should be shaken well before each use. For accurate dosing of the drug, use the double-sided dosing spoon provided, which should be rinsed well with water after each use. After reconstitution, the suspension should be stored for no more than 7 days in a refrigerator, but not frozen.

For children under 2 years of age, the measured single dose of Ekoklav® suspension can be diluted in half with water.

Side effects

The adverse reactions listed below are presented by organ system and frequency.  Frequency is defined as: Very common (>1/10), Common (>1/100 to <1/10), Uncommon (>1/1,000 to <1/100), Rare (>1/10,000 to <1/1,000), Very rare (<1/10,000), Frequency unknown.

Infections and infestations

Common: Candidiasis of the skin and mucous membranes.

Blood and lymphatic system disorders:

Rare: Reversible leukopenia (including neutropenia) and reversible thrombocytopenia.

Very rare: Reversible agranulocytosis and reversible hemolytic anemia, prolongation of prothrombin time and bleeding time, anemia, eosinophilia, thrombocytosis.

Immune system disorders:

Very rare: Angioedema, anaphylactic reactions;  serum sickness-like syndrome, allergic vasculitis.

Skin and subcutaneous tissue disorders:

Uncommon: Skin rash, pruritus, urticaria.

Rare: Erythema multiforme.

Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis.

If any skin allergic reactions occur, use of the drug should be discontinued.

Nervous system disorders:

Uncommon: Dizziness, headache.

Very rare: Convulsions (may occur in patients with impaired renal function and those receiving high doses of the drug), insomnia, agitation, anxiety, behavior changes, reversible hyperactivity.

Gastrointestinal disorders:

Adults:

Very common: Diarrhea.

Common: Nausea, vomiting.

Children:

Common: Diarrhea, nausea, vomiting.

Entire population: Nausea occurred most frequently with high doses of the drug. If GI adverse reactions are observed after starting the drug, they can be mitigated by taking Ekoklav® at the start of a meal.

Uncommon: Indigestion.

Very rare: Antibiotic-associated colitis (including pseudomembranous and hemorrhagic colitis), gastritis, stomatitis, black "hairy" tongue, change in color of the surface layer of tooth enamel in children.

Hepatobiliary disorders:

Uncommon: Moderate increase in aspartate aminotransferase activity. This reaction is observed in patients receiving therapy with beta-lactam antibiotics, but its clinical significance is unknown.

Very rare: Hepatitis and cholestatic jaundice (these reactions have been observed in patients receiving therapy with penicillin and cephalosporin antibiotics), increased activity of alkaline phosphatase and/or bilirubin concentration.

Hepatic adverse reactions were observed mainly in men and elderly patients and may be associated with long-term therapy. These adverse reactions are very rare in children. The listed signs and symptoms occur very rarely during or immediately after therapy, but in some cases may not appear until several weeks after completion of therapy. Adverse reactions are generally reversible. Hepatic adverse reactions can be severe; in extremely rare cases, fatalities have been reported. In almost all cases, these were patients with serious concomitant pathology or patients receiving potentially hepatotoxic drugs concurrently.

Renal and urinary disorders:

Very rare: Interstitial nephritis, crystalluria, hematuria.

Overdose

Symptoms

Symptoms from the gastrointestinal tract and disturbances in water-electrolyte balance may be observed.

Amoxicillin crystalluria has been described, which in some cases has led to renal failure (see section "Special Instructions").

Convulsions may occur in patients with impaired renal function and those receiving high doses of the drug.

Treatment

Gastrointestinal symptoms – symptomatic therapy, paying attention to the normalization of water-electrolyte balance. Amoxicillin and clavulanic acid can be removed from the bloodstream by hemodialysis.

Results from a prospective study involving 51 children at a poison control center showed that administration of amoxicillin at a dose of less than  250 mg/kg did not cause significant clinical symptoms and did not require gastric lavage.

Interaction with other medicinal products

Concomitant use of Ekoklav®  and probenecid is not recommended. Probenecid reduces the tubular secretion of amoxicillin, so concomitant use of Ekoklav® and probenecid may lead to an increase and persistence of amoxicillin levels in the blood, but not clavulanic acid.

Concomitant use of allopurinol and amoxicillin may increase the risk of skin allergic reactions. Currently, there are no data in the literature on the simultaneous use of the amoxicillin/clavulanic acid combination and allopurinol.

Penicillins can slow the elimination of methotrexate from the body by inhibiting its tubular secretion, so concomitant use of Ekoklav® and methotrexate may increase the toxicity of methotrexate.

Like other antibacterial drugs, Ekoklav® may affect the intestinal flora, leading to reduced absorption of estrogens from the gastrointestinal tract and reduced effectiveness of combined  oral contraceptives.

Rare cases of increased International Normalized Ratio (INR) have been described in the literature in patients with simultaneous use of acenocoumarol or warfarin and amoxicillin. If it is necessary to prescribe Ekoklav®  concurrently with  anticoagulants, prothrombin time or INR should be carefully monitored when prescribing or  discontinuing Ekoklav®; adjustment of the dose of oral anticoagulants may be required.

In patients taking mycophenolate mofetil, after starting the amoxicillin/clavulanic acid combination, a decrease in the concentration of the active metabolite – mycophenolic acid, by approximately 50% before the next dose of the drug was observed. This change in concentration may not accurately reflect the overall changes in mycophenolic acid exposure.

Special instructions

Before starting treatment with Ekoklav®  it is necessary to collect a detailed history regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other substances causing an allergic reaction in the patient.

Serious, and sometimes fatal, hypersensitivity reactions (anaphylactic 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 an allergic reaction, treatment with Ekoklav® should be discontinued and appropriate alternative therapy initiated. In severe anaphylactic reactions, epinephrine should be administered immediately to the patient. Oxygen therapy, intravenous glucocorticosteroids  and securing the airway, including intubation, may also be required.

If infectious mononucleosis is suspected, Ekoklav®  should not be used, as in patients with this disease, amoxicillin can cause a measles-like skin rash, which complicates the diagnosis of the disease.

Long-term treatment with Ekoklav® may lead to overgrowth of non-susceptible microorganisms.

In general, Ekoklav® is well tolerated and has the low toxicity characteristic of all penicillins. During long-term therapy with Ekoklav®, it is recommended to periodically evaluate renal, hepatic, and hematopoietic function.

Cases of pseudomembranous colitis have been described with the use of 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 diarrhea is prolonged or severe, or the patient experiences abdominal cramps, treatment should be stopped immediately and the patient should be examined.

In patients receiving the amoxicillin/clavulanic acid combination concurrently with indirect (oral) anticoagulants, cases of increased prothrombin time (increased INR) have been rarely reported. When prescribing indirect (oral) anticoagulants concurrently with the amoxicillin/clavulanic acid combination, monitoring of relevant indicators is necessary. Adjustment of the dose of oral anticoagulants may be required to maintain the desired effect.

In patients with impaired renal function, the dose of Ekoklav® should be reduced according to the degree of impairment (see section "Dosage and Administration" - Patients with impaired renal function).

In patients with reduced diuresis, crystalluria occurs very rarely, mainly during parenteral therapy. When administering high doses of amoxicillin, it is recommended to take sufficient fluids and maintain adequate diuresis to reduce the likelihood of amoxicillin crystal formation. (see section "Overdose")

Oral administration of Ekoklav® leads to high levels of amoxicillin in the urine, which may cause false-positive results when testing for glucose in urine (e.g., Benedict's test, Fehling's test). In this case, it is recommended to use the glucose oxidase method for determining urine glucose concentration.

Clavulanic acid may cause nonspecific binding of immunoglobulin G and albumin to red blood cell membranes, leading to false-positive  Coombs test results.

Oral care helps prevent discoloration of teeth associated with taking Ekoklav®, as brushing teeth is sufficient.

Drug abuse and dependence

No drug dependence, addiction, or euphoric reactions associated with the use of Ekoklav® have been observed.

Effects on ability to drive and use machines

Since Ekoklav®  may cause dizziness, patients should be cautioned about precautions when driving vehicles or operating machinery. 

Dosage form

Powder for preparation of oral suspension 125 mg + 31.25 mg / 5 ml and 250 mg + 62.5 mg / 5 ml.

25 g in brown glass bottles of 125 ml volume with a mark and a screw-on plastic cap.

Each bottle, together with a double-sided dosing spoon (small capacity 2.5 ml, large – 5 ml) and instructions for use, is placed in a cardboard box.

Storage conditions

In a dry, light-protected place  at a temperature not exceeding 25 °C.

The prepared suspension should be stored at a temperature of 2 ºC to 8 ºC in a tightly closed bottle.

Keep out of reach of children.

Shelf life

2 years.

Prepared suspension – 7 days.

Do not use after the expiration date.

Pharmacy supply terms

By prescription.

Name and address of the legal entity in whose name the registration certificate is issued / Organization accepting claims:

JSC "AVVA RUS", Russia,

121614, Moscow, Krylatskie Kholmy st., 30, bld. 9.

Tel/Fax: +7 (495) 956-75-54

Address of the production site:

JSC "AVVA RUS", Russia,

610044,  Kirov region, Kirov, Luganskaya st., 53a.

Tel.: +7 (8332) 25-12-29, +7 (495) 956-75-54

avva.com.ru

ecoantibiotic.ru