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

Active substances: Amoxicillin - 250,00 mg in the form of amoxicillin sodium - 265,00 mg; clavulanic acid - 50,00 mg, in the form of potassium clavulanate - 59,55 mg.

Dosage 500 mg + 100 mg

Active substances: amoxicillin - 500,00 mg in the form of amoxicillin sodium - 530,00 mg; clavulanic acid - 100.00 mg, in the form of potassium clavulanate - 119.10 mg.

Dosage of 1000 mg + 200 mg

Active substances: Amoxicillin - 1000,00 mg in the form of amoxicillin sodium - 1060,00 mg; clavulanic acid - 200.00 mg, in the form of potassium clavulanate - 238.20 mg.

Description:PThe powder is white or white with a yellowish hue.

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 antibiotic with a broad spectrum of action, which has 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 cause bacterial resistance, and is less effective against type I chromosomal beta-lactamases.

The presence of clavulanic acid in the preparation Novaklav 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

Staphylococcus aureus (sensitive to methicillin)¹

Streptococcus pneumoniae^1,2

Streptococcus pyogenes^1,2

Streptococcus agalactiae^1,2

Group streptococci Viridans²

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 influenzae¹

Helicobacter pylori

Moraxella catarrhal is¹

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

Treponema pallidum

Leptospira icterohaemorrhagiae

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

Gram-negative aerobes:

Escherichia coli¹

Klebsiella pneumoniae¹

Klebsiella oxytoca

Klebsiella spp.

Proteus mirabilis

Proteus vulgaris

Proteus spp.

Salmonella spp.

Shigella spp.

Gram-positive aerobes:

Corynebacterium spp.

Enterococcus faecium

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

Gram-negative aerobes:

Acinetobacter spp.

Citrobacter freundii

Enterobacter spp.

Hafnia alvei

Legionella pneumophila

Morganella morganii

Providencia spp.

Pseudomonas spp.

Serratia spp.

Stenotrophomonas maltophilia

Yersinia enterocolitica.

Other:

Chlamydia pneumoniae

Chlamydia psittaci

Chlamydia spp.

Coxiella burnetii

Mycoplasma spp.

1 - for these bacteria, the clinical efficacy of a combination of 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

Amoxicillin and clavulanic acid in combination do not affect the pharmacokinetics of each other.The maximum concentration in the plasm after the bolus intravenous injection of amoxicillin + clavulanic acid (1000 mg + 200 mg) is 105 μg / ml for amoxicillin and 28 μg / ml for clavulanic acid, with 500 mg of amoxicillin and 100 mg of clavulanic acid 32 μg / ml and 10 μg / ml, respectively. Area under the pharmacokinetic curve "concentration-time" (AUC) Amoxicillin (dose 1000 mg) is 76.3 h * mg / l, clavulanic acid (200 mg dose) is 27.9 h * mg / l. AUC when 500 mg of amoxicillin and 100 mg of clavulanic acid were administered, 25.5 and 9.2 hours * mg / L, respectively.

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 plasma proteins. Both components are characterized by low binding to plasma proteins (about 13-20%).

In animal studies, no cumulation of amoxicillin and clavulanic acid 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 mucous membranes of the oral cavity, 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 penetrate 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 - through both renal and extrarenal mechanisms.Approximately 60-70% of amoxicillin and about 40-65% of clavulanic acid is 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 or 1000 mg + 200 mg. The half-life (T_1/2) amoxicillin (dose 1000 mg) is 0.9 hours, clavulanic acid (200 mg dose) is 0.9 hours. T_1/2when 500 mg amoxicillin and 100 mg clavulanic acid are administered, 1 hour for both components.

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 catarrhalis 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, prolonged therapy.

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

- The drug Novaklav in the dosage of 1000 mg + 200 mg is also indicated for the prevention of postoperative infections, with surgical interventions on the gastrointestinal tract, pelvic organs, head and neck, heart, kidneys, bile ducts, and implantation of artificial joints.

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

Infections caused by microorganisms sensitive to amoxicillin can be treated with Novaklave, because amoxicillin is one of its active substances.

Novaklave 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, other beta-lactam antibiotics, incl. to 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:

Violation of liver function, impaired renal function (creatinine clearance (CK) less than 30 ml / min).

Pregnancy and lactation:

In studies of reproductive function in animals, oral and parenteral administration of the drug amoxicillin+ [clavulanic acid] did not cause teratogenic effects. In a single study in women with premature rupture of membranes, it was found that preventive therapy with a combination of amoxicillin with clavulanic acid may be associated with an increased risk of developing necrotizing enterocolitis in newborns. The drug is not recommended for use during pregnancy, except when the benefit to the mother exceeds the potential risk to the fetus.

The drug can be used during breastfeeding. With the exception of the possibility of developing sensitization, diarrhea, or candidiasis of the oral mucosa associated with the penetration of trace amounts of active substances 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, kidney function, 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 administration (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 weighing more than 40 kg

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

In severe infections: a dose of 1000 mg + 200 mg every 4-6 hours.

Prophylaxis in surgery

Interventions lasting less than 1 h: a dose of 1000 mg + 200 mg during anesthesia. Interventions lasting more than 1 h: a 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 should be injected 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

Dosage adjustment, dosing as in adult patients is not required.

Application for renal dysfunction

Correction of doses is based on the maximum recommended dose of amoxicillin and is performed taking into account the values of CC.

Adults

Creatinine clearance	Dosing regimen
> 30 ml / min	Correction of the dosing regimen is not required
10-30 ml / min	The initial dose of 1000 mg + 200 mg and further 500 mg + 100 mg 2 times a day.
<10 ml / min	The initial dose of 1000 mg + 200 mg and further 500 mg + 100 mg every 24 hours.

Children

Creatinine clearance	Dosing regimen
> 30 ml / min	Correction of the dosing regimen is not required
10-30 ml / min	25 mg + 5 mg per 1 kg 2 times a day.
<10 ml / min	25 mg + 5 mg per 1 kg every 24 hours.

Patients on hemodialysis

Dose adjustment is based on the maximum recommended dose of amoxicillin.

Adults

Initially, 1 dose of 1000 mg + 200 mg, followed by 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 mg of amoxicillin and 5 mg of clavulanic acid per 1 kg of body weight per day.

Patients with hepatic impairment

Treat with caution; regularly monitor liver function.

There is insufficient data to change the recommendation of the dosing regimen in such patients.

Mode of application

Bolus injection

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

Proportion / solvent ratio
Bottle	Solvent (ml)
1000 mg / 200 mg	20
500 mg / 100 mg	10
250 mg / 50 mg	5

During the preparation, the solution may acquire a pink color that disappears afterwards. The finished solution can have a color from colorless to light-straw.

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

Infusion introduction

The drug Novaklav is administered intravenously drip for 30-40 minutes.

The solution prepared as described above for bolus administration is added without delay to 100 ml of one of the infusion solutions listed in the table below.

Infusion solutions	Stability period
Infusion solutions	At a temperature of 25 ° C (hours)	At a temperature of 5 ° C (hours)
Water for injections	4	8
A solution of sodium chloride 0.9%	4	8
Sodium lactate solution for intravenous administration	4
Ringer's solution	3
Ringer's lactate solution according to Hartman	3

Side effects:

The undesirable reactions presented below are listed depending on the anatomophysiological classification and frequency of occurrence. Frequency of occurrence is defined as follows: very often (≥1 / 10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1000 and <1/100); rarely (≥1 / 10000 and <1/1000), very rarely (<10,000, including individual cases).

Infectious and parasitic diseases

Often: Candidiasis of the skin and mucous membranes.

Violations of the blood and lymphatic system

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

Rarely: reversible agranulocytosis and reversible hemolytic anemia, prolongation of prothrombin time and bleeding time, anemia, eosinophilia, thrombocytosis.

Immune system disorders

Rarely: angioedema, anaphylactic reactions; a syndrome similar to serum sickness, allergic vasculitis.

Disturbances from the skin and subcutaneous tissues

Infrequently: skin rash, itching, hives.

Rarely: erythema multiforme.

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

With the development of any skin allergic reactions should stop using the drug.

Disturbances from the nervous system

Infrequently: dizziness, headache.

Rarely: convulsions (can occur in patients with impaired renal function when taking high doses of the drug), insomnia, agitation, anxiety, behavior change, reversible hyperactivity.

Disorders from the gastrointestinal tract

Often: diarrhea.

Infrequently: nausea, vomiting, dyspeptic disorders.

Rarely: antibiotic-associated colitis (including pseudomembranous and hemorrhagic (see section "Special instructions")), is less common with parenteral administration of amoxicillin + clavulanic acid.

Disturbances from the liver and bile ducts

Infrequently: a moderate increase in aspartate aminotransferase and / or alanine aminotransferase (ACT and / or ALT), but the clinical significance of this phenomenon is unknown.

Rarely: hepatitis and cholestatic jaundice (noted when combined with other penicillins and cephalosporins), increased activity of alkaline phosphatase and / or bilirubin concentrations.

Side effects from the liver occur mainly in men and in elderly patients and can be associated with long-term therapy, usually occur during or shortly after treatment, but in some patients they develop only a few weeks after the end of treatment. Usually, side effects from the liver are reversible.It is extremely rare in patients with serious previous diseases or in those who have received potentially hepatotoxic drugs, they can be quite severe up to a lethal outcome.

Disorders from the kidneys and urinary tract

Rarely: interstitial nephritis, crystalluria, hematuria.

Vascular disorders

Rarely: thrombophlebitis in the injection area.

Overdose:

Symptoms: mainly from the gastrointestinal tract and the disturbance of the water-electrolyte balance. Amoxicillin crystalluria is described, in some cases leading to the development of renal failure. Cramps can occur in patients with impaired renal function, as well as in those who receive 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: carrying out symptomatic therapy, normalization of water-electrolyte balance. Amoxicillin and clavulanic acid are removed from the blood by hemodialysis.

Interaction:

Simultaneous use of the drug and probenecid is not recommended. Probenecid reduces the tubular secretion of amoxicillin, and therefore simultaneous use of the drug and probenecid can lead to an increase in the concentration and persistence in the blood of amoxicillin, 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 and methotrexate may increase the toxicity of methotrexate.

The combination of amoxicillin with clavulanic acid, affecting the intestinal microflora, can lead to a decrease in the absorption of estrogens from the gastrointestinal tract, resulting in a decrease in the effectiveness of oral contraceptives.

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 simultaneous use of the drug with indirect anticoagulants is necessary, prothrombin time or INR should be carefully monitored during treatment and when the drug is withdrawn; may require correction of the dose of indirect anticoagulants.

In patients receiving 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.

Clavulanic acid can lead to nonspecific binding of immunoglobulin G and albumin with a cell membrane of erythrocytes, which can lead to a false positive reaction with a Coombs sample.

Pharmaceutical incompatibility

The drug 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.

The drug solution can not be mixed with solutions containing dextrose, dextran or sodium hydrogen carbonate.

Special instructions:

Before starting treatment with the drug, you need to collect a detailed history of previous hypersensitivity reactions to penicillins, cephalosporins or other allergens. Serious and sometimes lethal reactions (hypersensitivity reactions (anaphylactic reactions) to penicillins are described.) The risk of occurrence of such reactions is highest in patients who have a history of hypersensitivity reaction to penicillins.

In case of an allergic reaction, it is necessary to stop treatment with the drug and begin the appropriate alternative therapy. In severe reactions of hypersensitivity, you should immediately enter epinephrine. Oxygen therapy, intravenous glucocorticosteroids, and airway patency, including intubation, may also be required.

In the case of suspected infectious mononucleosis, the drug should not be used because patients with this disease amoxicillin can cause a skinlike skin rash, which makes it difficult to diagnose the disease.

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

During prolonged therapy with the drug it is recommended to periodically evaluate the function of the kidneys, liver and hematopoiesis.

Cases of pseudomembranous colitis occur when antibacterial drugs are used, the severity of which can range from mild to life-threatening. Therefore, it is important to consider the possibility of developing pseudomembranous colitis in patients with diarrhea during or after using antibacterial drugs. If diarrhea is long and severe, or the patient experiences abdominal cramps, treatment should be discontinued and the patient should be examined. Contraindicated use of drugs that inhibit intestinal peristalsis.

If simultaneous use of the drug with indirect anticoagulants is necessary, prothrombin time or INR should be carefully monitored; may require correction of the dose of indirect anticoagulants.

In patients with impaired renal function, the dose of the drug should be reduced, respectively, the degree of impairment (see Section "Method of administration and dose" Application for renal dysfunction).

In patients with reduced diuresis, crystalluria is very rare, mainly with parenteral therapy. During the administration of high doses of amoxicillin, it is recommended to take a sufficient amount of fluid and maintain an adequate diuresis to reduce the likelihood of amoxicillin crystals.

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

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

The drug should be used with caution in patients with impaired liver function.

The severity of side effects from the gastrointestinal tract can be reduced by taking the drug at the beginning of the meal.

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

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

Since the combination of amoxicillin with clavulanic acid can cause dizziness, caution should be exercised when administering the drug while driving or other mechanisms.

Form release / dosage:

Powder for the preparation of a solution for intravenous administration, 250 mg + 50 mg; 500 mg + 100 mg and 1000 mg + 200 mg.

Packaging:

250 mg amoxicillin + 50 mg clavulanic acid, or 500 mg amoxicillin + 100 mg clavulanic acid, or 1000 mg amoxicillin + 200 mg clavulanic acid in a bottle of colorless transparent glass (hydrolytic class I), sealed with a plug of bromobutyl rubber and aluminum cap with protective plastic cover. Each label is labeled.

1 bottle is placed in a cardboard box together with instructions for use.

For hospitals. For 5,10,100 vials, together with an equal number of instructions for use are placed in a cardboard box.

Storage conditions:In dry, dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 of the year.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004113

Date of registration:31.01.2017

Expiration Date:31.01.2022

The owner of the registration certificate:JODAS EKSPOIM, LLC JODAS EKSPOIM, LLC Russia

Manufacturer: & nbsp

NOVALEK PHARMACEITICAL, Pvt. Ltd. India

Representation: & nbspJodas Expoim, Open CompanyJodas Expoim, Open Company

Information update date: & nbsp24.02.2017

Illustrated instructions

Instructions

Novaklav (Novaclav)