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

1 bottle of the drug Verklav 500 mg + 100 mg contains the active substances: amoxicillin sodium (in terms of amoxicillin) - 500 mg and potassium clavulanate (in terms of clavulanic acid) - 100 mg;

1 bottle of the drug Verklav 1000 mg + 200 mg contains the active substances: amoxicillin sodium (in terms of amoxicillin) - 1000 mg potassium clavulanate (in terms of clavulanic acid) - 200 mg.

Description:Powder from white to light yellow color.

Pharmacotherapeutic group:Antibiotic-penicillin semisynthetic + beta-lactamase inhibitor

ATX: & nbsp

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

Pharmacodynamics:

Mechanism of action

Amoxicillin - a semisynthetic broad-spectrum antibiotic with activity against many Gram-positive and Gram-negative 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 these enzymes.

Clavulanic acid - 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 less effective against chromosomal beta-lactamases of type 1.

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

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

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

Gram-positive aerobes:

Bacillus anthracis

Enterococcus faecalis

Gardnerella vaginalis

Listeria monocytogenes

Nocardia asteroides

Streptococcus pneumoniae^1,2

Streptococcus pyogenes^1,2

Streptococcus agalactiae^1,2

Group streptococci Viridans ²

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

Staphylococcus aureus (sensitive to methicillin)¹

Staphylococcus saprophyticus (sensitive to methicillin)

Coagulase-negative staphylococci (sensitive to methicillin)

Gram-positive anaerobes:

Clostridium spp.

Peptococcus niger

Peptostreptococcus magnus

Peptostreptococcus micros

Peptostreptococcus spp.

Gram-negative aerobes:

Bordetella pertussis

Haemophilus influenzae ¹

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

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

Bacteria, possessing natural sustainability to combinations amoxicillin from clavulanate 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 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:

Suction

The mean values of the main pharmacokinetic parameters for intravenous bolus administration to healthy volunteers of the preparation containing amoxicillin and clavulanic acid in a dosage of 500 mg + 100 mg or 1000 mg + 200 mg.

Active substances in the preparation	Mean values of pharmacokinetic parameters
Active substances in the preparation	Dose (mg)	FROM_mOh(μg / ml)	T_1/2(clock)	AUC (h x mg / l)	Excretion in urine,% 0-6 h
Amoxicillin	500	32,2	1,07	25,5	66,5
Amoxicillin	1000	105,4	0,9	76,3	77,4
Clavulanic acid	100	10,5	1,12	9,2	46,0
Clavulanic acid	200	28,5	0,9	27,9	63,8

FROM_max - maximum concentration in blood plasma

T_1/2 - half-life

AUC - the area under the pharmacokinetic curve of the concentration-time relationship.

Distribution

When administered intravenously, the combination of amoxicillin with clavulanic acid, therapeutic concentrations of amoxicillin and clavulanic acid are found in various tissues and interstitial fluid (in the gall bladder, abdominal tissue, skin, fat and muscle tissues, synovial and peritoneal fluids, bile, purulent).

Amoxicillin and clavulanic acid have a weak degree of binding to blood plasma proteins (about 13-20% of each component of the drug).

In animal studies, no cumulation of the components of the drug in any organ was detected.

Amoxicillin, like most penicillins, penetrates into breast milk. Traces of clavulanic acid can also be detected in breast milk. With the exception of the possibility of developing diarrhea or candidiasis of the oral mucosa, no other adverse effects of amoxicillin and clavulanic acid on the health of infants breast-fed are known.Studies of reproductive function in animals have shown that amoxicillin and clavulanic acid penetrates the placental barrier. However, there was no adverse effect on the fetus.

Metabolism

10-25% of the initial dose of amoxicillin is excreted by the kidneys in the form of an inactive metabolite (penicillic acid).

Clavulanic acid undergoes intensive metabolism to 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 (GIT), as well as with exhaled air in the form of carbon dioxide.

Excretion

Like other penicillins, amoxicillin is excreted mainly by the kidneys, whereas clavulanic acid - by means of both renal and extrarenal mechanisms.

Approximately 60-70% of amoxicillin and 40-65% of clavulanic acid are excreted by the kidneys unchanged in the first 6 hours after a single bolus injection of the drug at a dosage of 500 mg + 100 mg and 1000 mg + 200 mg.

Simultaneous administration of probenecid slows the excretion of amoxicillin, but does not slow the renal excretion of clavulanic acid (see section "Interaction with other drugs").

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 a combination of amoxicillin and clavulanic acid:

- Upper respiratory tract infections (including ENT diseases), for example, relapsing tonsillitis, sinusitis, otitis media, usually caused by Streptococcus pneumoniae, Haemophilus influenzae^#, Moraxella catarrhallis^# and Streptococcus pyogenes.

- Infections of the lower respiratory tract, for example, exacerbation of chronic bronchitis, lobar pneumonia and bronchopneumonia, usually caused Streptococcus pneumoniae, Haemophilus influenzae^#and Moraxella catarrhalis^#.

- Urinary tract infections, for example, cystitis, urethritis, pyelonephritis, infections of female genitalia, usually caused by species of the family Enterobacteriaceae (mainly Escherichia coli^#), Staphylococcus saprophyticus and species Enterococcus, as well as gonorrhea caused by Neisseria gonorrhoeae^#.

- Infections of the skin and soft tissues, usually caused Staphylococcus aureus^#, Streptococcus pyogenes and species Bacteroides^#.

- Infections of bones and joints, for example, osteomyelitis, usually caused by Staphylococcus aureus^#, if necessary, long-term therapy is possible.

- Other mixed infections (eg, septic abortion, postpartum sepsis, intra-abdominal sepsis, sepsis, peritonitis, postoperative infections) in the framework of stepwise therapy.

The drug Verklav at a dosage of 1000 mg + 200 mg is also indicated for the prevention of postoperative infections, for surgical interventions on the gastrointestinal tract, pelvic organs, head and neck, heart, kidneys, biliary tract, and implantation of artificial joints.

^#Individual representatives of this kind of microorganisms produce beta-lactamase, which makes them insensitive to amoxicillin (see section "Pharmacological properties").

Infections caused by microorganisms sensitive to amoxicillin can be treated with Verklav preparation, since amoxicillin is one of its active substances. The drug Verklav is also indicated for the treatment of mixed infections caused by microorganisms sensitive to amoxicillin, as well as by microorganisms producing beta-lactamases that are sensitive to a combination of amoxicillin and clavulanic acid.

The sensitivity of bacteria to the combination of amoxicillin and clavulanic acid varies depending on the region and over time. Wherever possible, local sensitivity data should be taken into account.If necessary, the collection of microbiological samples and analysis for bacteriological sensitivity should be carried out.

Contraindications:

- Hypersensitivity to amoxicillin, clavulanic acid, other components of the drug; beta-lactam antibiotics (for example, penicillins and cephalosporins) in the anamnesis;

- previous episodes of jaundice or impaired liver function when using a combination of amoxicillin with clavulanic acid in the anamnesis.

Carefully:

The drug Verklav should be used with caution in patients with impaired liver function and impaired renal function (creatinine clearance <30 mL / min).

Pregnancy and lactation:

Pregnancy

In studies of reproductive function in animals, parenteral and oral administration of a combination of amoxicillin and clavulanic acid did not reveal teratogenic effects. In a single study in women with premature rupture of membranes, it was found that preventive therapy with this combination may be associated with an increased risk of developing necrotizing enterocolitis in newborns.

The drug Verklav is not recommended for use during pregnancy, except when the expected benefit to the mother exceeds the potential risk to the fetus.

Breastfeeding period

The drug Verklav can be used during breastfeeding. With the exception of the possibility of developing diarrhea or candidiasis of the oral mucosa associated with the penetration of trace amounts of the active ingredients of this preparation into breast milk, no other adverse effects were observed in infants fed breastfeeding. In case of adverse effects in infants who are breastfeeding, it is necessary to stop it.

Dosing and Administration:

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.

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

The drug is not intended for intramuscular injection (due to instability at a concentration that could be administered intramuscularly).

Doses are given in terms of the active ingredients: amoxicillin and clavulanic acid.

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

Infections of mild to moderate severity: a dose of 1000 mg + 200 mg every 8 hours.

Severe infections: dose of 1000 mg + 200 mg every 4-6 hours.

Prophylaxis in surgery

Surgical interventions of less than 1 h: dose of 1000 mg + 200 mg during the initial anesthesia.

Surgical interventions of more than 1 h: 1 dose of 1000 mg + 200 mg during anesthesia and then up to 4 doses of 1000 mg + 200 mg for 24 hours.

Special patient groups

Children

For children weighing less than 40 kg, the dose is calculated depending on the body weight. In children younger than 3 months, the drug Verklav should be administered only slowly infusion for 30-40 minutes.

Less than 3 months with a body weight of less than 4 kg

25 mg of amoxicillin and 5 mg of clavulanic acid per 1 kg of body weight every 12 hours.

Less than 3 months with a body weight of more than 4 kg

25 mg of amoxicillin and 5 mg of clavulanic acid per 1 kg of body weight every 8 hours.

From 3 months to 12 years with a body weight of less than 40 kg

25 mg of amoxicillin and 5 mg of clavulanic acid per 1 kg of body weight every 6-8 hours, depending on the severity of the infection.

Elderly patients

Correction of the dosing regimen is not required, dosing as in adult patients.

Patients with impaired renal function

Correction of the dosing regimen is based on the maximum recommended dose of amoxicillin and the clearance of creatinine (CK).

Adults

CK> 30 ml / min	Correction of the dosing regimen is not required.
KK 10-30 ml / min	The initial dose is 1000 mg + 200 mg and then 500 mg + 100 mg twice a day.
CK <10 ml / min	The initial dose of 1000 mg + 200 mg and further 500 mg + 100 mg every 24 hours.

Children

CK> 30 ml / min	Correction of the dosing regimen is not required.
KK 10-30 ml / min	(25 mg + 5 mg) / kg 2 times a day.
CK <10 ml / min	(25 mg + 5 mg) / kg every 24 hours.

Patients, on hemodialysis

Correction of the dosing regimen is based on the maximum recommended dose of amoxicillin.

Adults

The initial dose is 1000 mg + 200 mg, then 500 mg + 100 mg every 24 hours and an additional 500 mg + 100 mg at the end of the hemodialysis session (to compensate for the decrease in amoxicillin and clavulanic acid levels in the blood plasma).

Children

25 mg of amoxicillin and 5 mg of clavulanic acid per kg of body weight every 24 hours and an additional 12.5 mg of amoxicillin and 2.5 mg of clavulanic acid per kg of body weight at the end of the hemodialysis session (to compensate for the decrease in amoxicillin and clavulanic acid in plasma blood) and then 25 amoxicillin and 5 mg clavulanic acid per 1 kg of body weight per day.

Patients with impaired hepatic function

Treat with caution; regularly monitor liver function.

At present, there is insufficient data to correct the dose in such patients.

Mode of application

Bolus injection

The drug Verklav can be administered in the form of a slow intravenous injection of 3-4 minutes duration directly into the vein or through the catheter.

Dissolve the contents of the vial in water for injection - 600 mg (500 mg + 100 mg) in 10 ml of water for injection or 1.2 g (1000 mg + 200 mg) - in 20 ml of water for injection.

The resulting solution should be introduced within 20 minutes after dilution.

Infusion introduction

The drug Verklav injected intravenously drip for 30-40 minutes.

For the infusion of the drug, Verklav needs further dilution: the prepared solutions for bolus administration containing 600 mg (500 mg + 100 mg) or 1.2 g (1000 mg + 200 mg) of the drug should be diluted in 50 ml or 100 ml infusion solution respectively (sodium chloride solution 0.9%, sodium lactate solution for intravenous administration, Ringer's solution, Hartman's solution, water for injections).

Side effects:

The adverse events presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence.

Frequency of occurrence is defined as follows: Often (≥1/10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1000 and <1/100), rarely (≥1 / 10,000 and <1/1000), rarely (<1/10 000, including individual cases). Frequency categories were formed on the basis of clinical studies of the drug and post-registration surveillance.

Frequency of occurrence of undesirable phenomena

Infectious and parasitic diseases:

Often: candidiasis of skin and mucous membranes.

On the part of the blood and lymphatic system:

Rarely: reversible leukopenia (including neutropenia), reversible thrombocytopenia.

Very rarely: reversible agranulocytosis and reversible hemolytic anemia, lengthening prothrombin time and bleeding time, eosinophilia, thrombocytosis, anemia.

From the immune system:

Very rarely: angioedema, anaphylactic reactions, a syndrome similar to serum sickness, allergic vasculitis.

From the nervous system:

Infrequent: dizziness, headache.

Very rarely: convulsions. Seizures 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.

From the side of the vessels:

Rarely: thrombophlebitis in the area of injection.

From the gastrointestinal tract:

Often: diarrhea.

Infrequently: nausea, vomiting, dyspeptic disorders.

Very rarely: antibiotic-associated colitis, incl. pseudomembranous and hemorrhagic (see section "Special instructions and precautions for use").

From the liver and biliary tract:

Infrequent: moderate increase in activity of aspartate aminotransferase (ACT) and / or alanine aminotransferase (ALT). This phenomenon is observed in patients receiving therapy with any antibiotic of the penicillin series, but its effect on the clinical condition of the patient is unknown.

Very rarely: hepatitis and cholestatic jaundice. These phenomena are observed in patients receiving penicillin antibiotics and cephalosporins. Increased activity of alkaline phosphatase, hyperbilirubinemia. Undesirable liver side effects were observed predominantly in men and in elderly patients and may be associated with long-term therapy.

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 phenomena are usually reversible.

Undesirable phenomena from the liver can be severe, in extremely rare cases there have been reports of lethal outcomes. In almost all cases, these were patients with serious concomitant pathologies or patients who were simultaneously receiving potentially hepatotoxic drugs.

From the skin and subcutaneous tissues:

Infrequent: skin rash, itching, hives.

Rarely: erythema polyforma.

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

In case of skin allergic reactions, treatment with Verklav should be stopped.

From the side of the kidneys and urinary tract:

Very rarely: interstitial nephritis, crystalluria (see section "Overdose").

Overdose:

Symptoms

Symptoms on the part of the gastrointestinal tract and violations of the water-electrolyte balance can be observed.

Amoxicillin crystalluria is described, in some cases leading to the development of renal failure (see section "Special instructions and precautions for use").

Seizures may occur in patients with impaired renal function or in patients receiving high doses of the drug.

After intravenous administration of large doses of amoxicillin, it can precipitate in urinary catheters. Therefore, a regular check of the permeability of urinary catheters should be carried out.

Treatment

Symptoms from the gastrointestinal tract are symptomatic therapy, paying special attention to the normalization of the water-electrolyte balance. Amoxicillin and clavulanic acid can be removed from the bloodstream by hemodialysis.

Interaction:

The simultaneous use of the drug Verklav and probenecid is not recommended. Probenecid reduces the tubular secretion of amoxicillin, and therefore simultaneous use of the drug Verklav and probenecid can lead to an increase and persistence of the concentration of amoxicillin in the blood (but not clavulanic acid).

The simultaneous use of allopurinol and amoxicillin may increase the risk of skin allergic reactions. Currently, there is no data in the literature on the simultaneous use of a combination of amoxicillin with clavulanic acid and allopurinol.

Penicillins can slow the excretion of methotrexate from the body by inhibiting its tubular secretion, so the simultaneous use of the drug Verklav and methotrexate may increase the toxicity of methotrexate.

Like other antibacterial drugs, the drug may have an effect on the intestinal microflora, leading to a reduction in absorption of estrogens from the gastrointestinal tract and a decrease in the effectiveness of combined oral contraceptives.

The presence of clavulanic acid in the preparation of Verklav may lead to nonspecific binding of the immunoglobulin G and albumin with a cell membrane of erythrocytes, which can lead to a false positive reaction with a Coombs sample.

In the literature, rare cases of an increase in the international normalized ratio (INR) in patients with simultaneous use of acenocoumarol or warfarin and amoxicillin are described. If it is necessary to simultaneously use the drug Verklav with anticoagulants, prothrombin time or INR should be carefully monitored with the appointment or with the cancellation of the drug Verklav, it may be necessary to adjust the dose of anticoagulants for oral administration.

In patients receiving mycophenolate mofetil, when the use of amoxicillin and clavulanic acid was started, 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 concentration observed before the administration of the drug can not accurately reflect the overall changes in the concentration of mycophenolic acid.

Pharmaceutical incompatibility

The drug Verklav should not be mixed with blood products, other protein-containing fluids, such as protein hydrolysates, or with intravenous lipid emulsions.

When used simultaneously with aminoglycosides, antibiotics should not be mixed in a single syringe or in one vial for intravenous fluids, because aminoglycosides lose activity in such conditions.

Solution of the drug Verklav should not be mixed with solutions containing dextrose, dextran or sodium hydrogen carbonate.

Special instructions:

Before starting treatment with Verklav, you need to collect a detailed history of previous hypersensitivity reactions to penicillins, cephalosporins, or other substances that cause an allergic reaction in the patient. Serious and sometimes lethal hypersensitivity reactions (anaphylactic reactions) are described with the use of penicillins. The risk of occurrence of such reactions is highest in patients who have a history of hypersensitivity reactions to penicillins.In case of an allergic reaction, it is necessary to stop treatment with Verklav and start the appropriate alternative therapy.

Serious anaphylactic reactions should be promptly administered to the patient epinephrine. Oxygen therapy, intravenous glucocorticosteroids, and airway patency, including intubation, may also be required.

In case of suspected infectious mononucleosis, the drug Verklav should not be used, since in patients with such a disease amoxicillin can cause a skinlike skin rash that makes it difficult to diagnose the disease.

Long-term treatment with the drug Verklav may lead to excessive reproduction of insensitive microorganisms.

There are cases of pseudomembranous colitis occurring when taking antibiotics, the severity of which can range from mild to life-threatening. Thus, it is important to diagnose it in patients who develop diarrhea during or after the administration of antibiotics. If diarrhea is prolonged or the patient experiences abdominal cramps, treatment should be stopped immediately and the patient should be examined.

In general, the drug Verklav is well tolerated, has a characteristic of all penicillins, low toxicity. During prolonged therapy with the drug Verklav it is recommended to periodically evaluate the function of the kidneys, liver and hematopoiesis.

In patients who received a combination of amoxicillin with clavulanic acid in conjunction with indirect (oral) anticoagulants, in rare cases, increased prothrombin time (increased INR) was reported. When co-administration of indirect (oral) anticoagulants with a combination of amoxicillin and clavulanic acid, monitoring of the relevant indicators is necessary. To maintain the necessary effect of oral anticoagulants, their dose may need to be adjusted.

In patients with impaired renal function, the dose of the drug should be reduced depending on the QC values (see the section "Dosing and Administration").

If parenteral administration of high doses of Verklav preparation is necessary, patients on a low-salt diet should take into account the presence of sodium ion in the preparation.

In patients with reduced diuresis, crystalluria is very rare, mainly with parenteral therapy with a combination of amoxicillin and clavulanic acid. When large doses of amoxicillin are administered, it is recommended to take a sufficient amount of fluid and maintain an adequate diuresis to reduce the likelihood of amoxicillin crystals (see "Overdose" section).

The use of the drug Verklav leads to a high content of amoxicillin in the urine, which can cause false positive results in the determination of glucose in the urine (for example, the Benedict test, Feeling's test). In this case, it is recommended to use a glucose oxidant method for determining the concentration of glucose in the urine.

Abuse and drug dependence

There was no drug dependence, addiction and reactions of euphoria associated with the use of the drug Verklav.

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

Since the drug may cause dizziness, it is necessary to warn patients about precautions when driving a vehicle or working with moving machinery.

Form release / dosage:

Powder for the preparation of a solution for intravenous administration, 500 mg + 100 mg and 1000 mg + 200 mg.

Packaging:

For 500 mg + 100 mg, 1000 mg + 200 mg of active substances in a vial of colorless glass, corked with brown bromobutyl rubber stopper and crimped with an aluminum cap.

1 A vial with instructions for use in a cardboard box.

For hospitals: 50 bottles together with an equal number of instructions for use in a cardboard box.

Storage conditions:

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

Keep out of the reach of children.

Shelf life:2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001206

Date of registration:15.11.2011 / 14.12.2016

Expiration Date:Unlimited

The owner of the registration certificate:RUSYUROFARM, LLC RUSYUROFARM, LLC Russia

Manufacturer: & nbsp

KARNATAKA ANTIBIOTICS & PHARMACEUTICALS, Limited India

Representation: & nbspRusyurofarm, Open CompanyRusyurofarm, Open Company

Information update date: & nbsp02.02.2017

Illustrated instructions

Instructions

Verklav (Verklav)