Vancomicin-Belpharm 1 000 mg

Trade name of the drug: Vancomycin-Belpharm
Active ingredient (INN): Vancomycin
Dosage form: Powder for the preparation of infusion solution 500 mg or 1000 mg
Composition for 1 bottle:
Active substance:
Vancomycin (as vancomycin hydrochloride) – 500 mg or 1000 mg.
Description: Powder of white or white with a pinkish or yellowish or brownish tint color
Pharmacotherapeutic group: Antibacterial agents for systemic use. Glycopeptide antibacterial agents.
ATX code: J01XA01

Pharmacological properties
Pharmacodynamics
Mechanism of action
Vancomycin is a tricyclic glycopeptide antibiotic that inhibits the synthesis of the cell wall of sensitive bacteria by high-affinity binding to
D-alanyl-D-alanine residues of cell wall precursors have a bactericidal effect on dividing microorganisms, and also reduce the permeability of the cell membrane and inhibit RNA synthesis.

Pharmacokinetics/pharmacodynamics (PK/PD) relationship
Vancomycin exhibits concentration-independent activity. The main PK/PD parameter that determines the effectiveness of an antibiotic is the ratio between the area under the pharmacokinetic curve (AUC) and the minimum inhibitory concentration (MIC) of vancomycin for the target pathogen. Based on data from in vitro studies, data from vancomycin in animals, and limited data from its use in humans, an AUC/MIC ratio of 400 has been established as the target PK/PD ratio for achieving clinical efficacy of vancomycin. Achieving a target MIC > 1.0 mg/L requires dosing in the upper range and achieving high serum concentrations (15-20 mg/l).

Mechanism of resistance
Acquired resistance to glycopeptides is most typical for enterococci and is based on the use of Van gene complexes that modify the D-alanyl-D-alanine target to D-alanyl-D-lactate or D-alanyl-D-serine that poorly binds vancomycin. In some countries, there are increasing cases of resistance, particularly for enterococci. Multiresistant strains of Enterococcus faecium are especially dangerous.
Van genes are rare in Staphylococcus aureus, in which changes in cell wall structure lead to “intermediate” susceptibility, which is most often heterogeneous. Methicillin-resistant strains of staphylococcus with reduced susceptibility to vancomycin have also been reported. Reduced susceptibility or resistance to vancomycin in Staphylococcus has not been well studied.
There is no cross-resistance between vancomycin and antibiotics of other classes. It is possible to develop cross-resistance to other glycopeptide antibiotics, such as teicoplanin. Secondary development of resistance during therapy is rare.

Synergistic action
The combination of vancomycin with aminoglycosides is synergistic against many strains of Staphylococcus aureus, non-enterococcal group D streptococci, enterococci and Viridans group streptococci. Combination of vancomycin with cephalosporin has a synergistic effect on some oxacillin-resistant strains of Staphylococcus epidermidis. The combination of vancomycin with rifampicin also has a synergistic effect against Staphylococcus epidermidis and a partial synergistic effect against some strains of Staphylococcus aureus.
Since vancomycin in combination with a cephalosporin may have an antagonistic effect on some strains of Staphylococcus epidermidis, and in combination with rifampicin on some strains of Staphylococcus aureus, a preliminary analysis for synergy is advisable.
Bacterial culture samples must be obtained to isolate and identify pathogens and determine their sensitivity to vancomycin.

Borderline concentrations
Vancomycin is active against gram-positive bacteria such as staphylococci, streptococci, enterococci, pneumococci and clostridia. Gram-negative bacteria are resistant to vancomycin. The prevalence of acquired resistance of individual species may vary in different geographical regions and at different times, so it is recommended to have local information on resistance, especially when treating severe infections. If the pattern of local resistance is such that the use of a particular drug for at least some types of infection is questionable, expert advice should be sought.
European Committee on Antimicrobial Susceptibility Testing (EUCAST) has established vancomycin MIC breakpoints for the determination of susceptible and resistant pathogens.

Minimum inhibitory concentration (MIC) limit values*

¹ S. aureus at a vancomycin MIC of 2 mg/L is at the edge of the wild-type distribution and may therefore result in impaired clinical response.
Vancomycin is active against the following microorganisms:
Gram-positive microorganisms: Enterococcus faecalis, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, coagulase-negative staphylococci, Staphylococcus spp., Streptococcus spp., Streptococcus pneumoniae, Enterococcus spp., anaerobic microorganisms: Eubacterium spp., Peptostreptococcus spp., Clostridium spp., with exception of Clostridium innocuum.
Microorganisms that can acquire resistance: Enterococcus faecium.
Species with natural resistance:
All gram-negative bacteria are resistant to vancomycin, as well as gram-positive aerobic microorganisms: Erysipelothrix rhusiopathiae, heterofermentative Lactobacillus spp., Leuconostoc spp., Pediococcus spp., anaerobic microorganisms: Clostridium innocuum.


Pharmacokinetics
To treat systemic infections, vancomycin is administered intravenously.
With normal renal function, multiple-dose infusion of 1 g of vancomycin (15 mg/kg) over 60 minutes gives approximate mean plasma concentrations of 50-60 mg/L immediately, 20-25 mg/L over 2 hours and 5- 10 mg/l within 11 hours after infusion. Plasma concentrations after repeated administration are similar to those achieved after a single administration.

* EUCAST, version 9.0 on 01.01.2019, www.eucast.org

With normal renal function, multiple-dose infusion of 1 g of vancomycin (15 mg/kg) over 60 minutes gives approximate mean plasma concentrations of 50-60 mg/L immediately, 20-25 mg/L over 2 hours and 5- 10 mg/l within 11 hours after infusion. Plasma concentrations after repeated administration are similar to those achieved after a single administration.
When administered orally, vancomycin is usually not absorbed. However, absorption may occur after oral administration in patients with pseudomembranous colitis. This may lead to accumulation of vancomycin in patients with concomitant renal failure.

Distribution
The volume of distribution of vancomycin is approximately 60 L/1.73 m2 of body surface. Serum concentrations of vancomycin range from 10 mg/L to 100 mg/L. Plasma protein binding is 30-55%.
Vancomycin easily penetrates the placenta into the umbilical cord blood. In the absence of inflammation of the meninges, vancomycin practically does not penetrate the blood-brain barrier.

Metabolism and excretion
Vancomycin is practically not metabolized. After parenteral administration, it is excreted almost completely as a microbiologically active substance (about 75-90% within 24 hours) by glomerular filtration through the kidneys.
The half-life of vancomycin is 4 to 6 hours in adults with normal renal function and 2.2 to 3 hours in children. Plasma clearance is about 0.058 l/kg/h, renal clearance is about 0.048 l/kg/h. In the first 24 hours, approximately 80% of the administered dose of vancomycin is excreted in the urine by glomerular filtration. With renal dysfunction, the release of vancomycin slows down. In patients with a removed kidney, the half-life of vancomycin is 7.5 days. In the case of adjuvant therapy, due to the risk of ototoxicity, it is necessary to monitor plasma concentrations of vancomycin.
Excretion with bile is insignificant (less than 5% of the dose).
Although vancomycin is not effectively removed by hemodialysis or peritoneal dialysis, increased clearance of vancomycin by hemoperfusion and hemofiltration has been reported.
After oral administration, only a portion of the administered dose is found in the urine. High concentrations of vancomycin are found in feces (> 3100 mg/kg at a dose of 2 g/day).

Linearity
Vancomycin concentrations usually increase proportionally with increasing doses. Plasma concentrations following multiple doses are similar to plasma concentrations following a single dose.

Pharmacokinetics in special clinical situations
Vancomycin is eliminated primarily by glomerular filtration. In patients with impaired renal function, the half-life of vancomycin is prolonged and the overall clearance is reduced.
In patients with hepatic impairment, the pharmacokinetics of vancomycin do not change.
To achieve therapeutic serum concentrations in pregnant women, a significant dose increase may be required.
In overweight patients, the distribution of vancomycin may be altered due to an increased volume of distribution. Renal clearance and percentage of plasma protein binding may also vary. In this group of patients, an increased concentration of vancomycin in the blood serum was recorded compared to healthy adult male patients.
Children
The pharmacokinetics of vancomycin shows wide interindividual variability in term and preterm neonates. After intravenous administration to newborns, the volume of distribution of vancomycin, as in adults, varies from 0.38 to 0.97 l/kg, while clearance ranges from 0.63 to 1.4 ml/kg/min. The half-life varies from 3.5 to 10 hours, indicating lower clearance values in neonates.
In infants and older children, the volume of distribution is 0.26-1.05 l/kg, and clearance ranges between 0.33-1.87 ml/kg/min.

Indications for use
Intravenous use
Vancomycin-Belpharm is indicated for use in patients of all age groups for the following indications:
- complicated infections of the skin and soft tissues;
- infections of bones and joints;
- community-acquired pneumonia;
- nosocomial pneumonia, including pneumonia associated with artificial lung ventilation (ventilator-associated);
- infective endocarditis.
Vancomycin-Belpharm is also indicated in all age groups for perioperative antibacterial prophylaxis in patients at high risk of developing bacterial endocarditis during major surgical procedures.

Oral use
Treatment of infection caused by Clostridium difficile in patients of all age groups. Official recommendations for the proper use of antibacterial agents should be taken into account.

Directions for use and doses
If necessary, Vancomycin-Belpharm should be used in combination with other antibacterial agents.
Vancomycin-Belpharm cannot be administered intramuscularly or intravenously as a bolus!
Intravenous use
Intravenous Vancomycin-Belpharm is administered as intermittent infusions slowly over at least 60 minutes or at a rate of no more than 10 mg/min (whichever is longer). In this case, the dose of Vancomycin-Belpharm must be diluted in a sufficient amount of solvent (at least 100 ml per 500 mg or at least 200 ml per 1000 mg). The concentration of the prepared Vancomycin-Belpharm solution should not exceed 5 mg/ml.
When administered over a shorter period of time or at higher concentrations, there is a risk of severe hypotension and thrombophlebitis. Also, rapid administration of Vancomycin-Belpharm can cause flushing of the face and upper half of the body and a short-term rash on the neck and shoulders.
In patients with limited fluid intake, a 500 mg/50 mL or 1000 mg/100 mL solution may be used, although this increases the risk of infusion-related adverse effects.
The initial dose of vancomycin should be based on the patient's body weight.
Subsequent dose adjustments should be based on vancomycin serum concentrations to achieve target therapeutic concentrations. When calculating subsequent doses and administration intervals, the state of renal function should be taken into account.
Adults and children from 12 years old
The initial dose is 15 to 20 mg/kg every 8 to 12 hours. The maximum daily dose should not exceed 2 g. The loading dose for severe patients is 25-30 mg/kg and can be used to quickly achieve the target concentration of vancomycin in the blood serum.

Children from 1 month to 12 years
The recommended dose is 10 to 15 mg/kg every 6 hours.

Newborns
Before using Vancomycin-Belpharm in full-term newborns (from birth to 27 days of life) and in premature newborns (from birth to the expected date of birth plus 27 days), consultation with a doctor experienced in working with newborns is necessary. Possible dosing methods for this group of patients are given in the following table:

*PCA – postconceptual age (gestational age at birth plus postnatal age).
Perioperative prevention of endocarditis in all age groups
The initial recommended dose is 15 mg/kg and is used before anesthesia. Depending on the duration of the operation, a repeat dose may be administered.

Duration of treatment
The duration of use of Vancomycin-Belpharm is determined depending on the type and severity of the infection, and the individual clinical response, and is shown in the following table:

*Duration of use is determined by the patient's condition, the presence of clinically significant improvements and the absence of fever for 48-72 hours.
**For the treatment of prosthetic joint infections, a longer course of oral appropriate antibacterial agents should be used.
***The need for combination therapy and its duration are determined by the location of the infection and the sensitivity of the body.

Use in elderly patients
Lower maintenance doses may be required due to age-related decline in renal function.

Use for renal failure
In adults and children with renal impairment, consideration should be given to the initial initiation dose and post-administration vancomycin serum concentrations rather than to the planned dosing regimen, especially in patients with severe renal impairment or those undergoing renal replacement therapy.
In patients with mild or moderate renal impairment, the initial dose should not be reduced. In patients with severe renal impairment, it is preferable to prolong the dosing interval rather than reduce the daily dose.
Due attention should be paid to the concomitant administration of drugs that may reduce the clearance of vancomycin and/or increase its side effects.
Vancomycin is poorly removed by intermittent hemodialysis. However, the use of membranes with high hydraulic permeability and continuous renal replacement therapy increase the clearance of vancomycin and in most cases require dose adjustment (usually after a session of intermittent hemodialysis).

Adults
Dose adjustments in adult patients may be based on an estimate of glomerular filtration rate (GFR) using the following formula:
Men: [Body weight (kg) * 140 - age (years)] / 72 * serum creatinine (mg/dL).
Women: 0.85 * [value calculated using the above formula].
For adult patients with creatinine clearance from 20 to 49 ml/min, the initial dose is
15-20 mg/kg body weight and administered every 24 hours. In patients with severe renal impairment (creatinine clearance <20 ml/min) or in patients on renal replacement therapy, the frequency of administration and the number of subsequent doses depend on the type of renal replacement therapy, the level of vancomycin in the blood serum and residual renal function (see section "Special Instructions"). Depending on the clinical situation, it may be recommended to delay the administration of the next dose until the results of vancomycin serum levels are obtained.
For critically ill patients with renal failure, the initial loading dose (25-30 mg/kg) should not be reduced.

Children
Dose adjustments in children 1 year of age and older may also be based on an estimate of GFR using the modified Schwartz formula:
GFR (ml/min/1.73 m2) = (height (cm) * 0.413) / serum creatinine (mg/dl).
GFR (ml/min/1.73 m2) = (height (cm) * 36.2) / serum creatinine (µmol/l).

Dose adjustment in newborns and children under 1 year of age is carried out only by a physician experienced in working with newborns. The above modified Schwartz formula is not applicable to children under 1 year of age. Approximate dosage recommendations for this group of patients are given in the table:

*Interval between doses and their number depend on the type of renal replacement therapy and should be calculated taking into account the level of vancomycin in the blood serum and residual renal function. Depending on the clinical situation, the next dose may not be administered until serum vancomycin levels are available.

Use for liver dysfunction
No dose adjustment is required.

Use during pregnancy
To achieve therapeutic concentrations of vancomycin in the blood serum, an increase in dose may be required (see section "Special Instructions").

Use in obese patients
An initial dose should be individualized according to total body weight.

Oral administration
Adults and children from 12 years old
For the treatment of pseudomembranous colitis caused by Clostridium difficile, Vancomycin-Belpharm is prescribed orally at a dose of 125 mg every 6 hours for 10 days in case of mild disease. In more severe cases and in case of complications, the dose can be increased to 500 mg every 6 hours for 10 days. The maximum daily dose should not exceed 2 g.
In patients with multiple relapses, consider treating the current episode of infection with Vancomycin-Belpharm 125 mg four times daily for 10 days, then either gradually reduce the dose to 125 mg/day or use a pulse regimen -therapy, i.e. 125-500 mg/day every 2-3 days for at least 3 weeks.

Newborns and children under 12 years of age
Recommended dose of Vancomycin-Belpharm is 10 mg/kg orally every 6 hours for 10 days. Maximum daily dose should not exceed 2 g.
Duration of treatment of infections caused by Clostridium difficile with Vancomycin-Belpharm is determined depending on the course of the disease in each individual patient. If possible, it is necessary to discontinue the use of antibacterial drugs suspected of causing Clostridium difficile-associated infections. It is necessary to ensure adequate replenishment of fluids and electrolytes.

Monitoring Vancomycin Concentrations
The frequency of measurement of vancomycin serum concentrations depends on the clinical situation and response to treatment and can range from daily testing in hemodynamically unstable patients to at least once weekly in stable patients showing response. for treatment. In patients with normal renal function, vancomycin serum concentrations should be monitored on the second day of treatment immediately before the subsequent dose.
In patients on intermittent hemodialysis, vancomycin levels should be measured before starting the hemodialysis session.
After oral administration, serum concentrations of vancomycin should be monitored in patients with inflammatory bowel disease.
Therapeutic (minimum) levels of vancomycin in the blood should be from 10 to 20 mg/l, depending on the location of the infection and the sensitivity of the pathogen. For sensitive microorganisms with MIC ≥ 1 mg/l, the recommended maintenance concentrations of Vancomycin-Belpharm are 15-20 mg/l.
It is possible to use model methods to predict individual dosing to achieve adequate AUC. The model approach can be used both to calculate an individual initial dose and to adjust the dose.

Rules for preparing solutions
Preparation of solution for infusion
When preparing Vancomycin-Belpharm solutions, standard aseptic rules should be followed.
To obtain a reconstituted solution, add the required volume of water for injection to the Vancomycin-Belpharm vial to obtain a solution with a concentration of 50 mg/ml (10 ml in a 500 mg vial, and 20 ml in a 1000 mg vial).
The appearance of the reconstituted solution is a clear solution.
The reconstituted solution in the vial retains its physical and chemical stability for 24 hours at a temperature of 2-8 °C (refrigerator).
Reconstituted solutions must be further diluted in 100 ml (for a dose of 500 mg) or 200 ml (for a dose of 1000 mg) of solvent to a concentration of no more than 5 mg/ml. As solvents, you can use 0.9% sodium chloride solution for intravenous administration or 5% dextrose solution for intravenous administration.
Appearance of the diluted solution is a clear solution.
Solution diluted for infusion retains its physical and chemical stability for 24 hours at a temperature of 2-8 °C (refrigerator).

Preparation of a solution for oral use
An oral solution is prepared by dissolving the recommended dose of Vancomycin-Belpharm in 30 ml of water for injection at room temperature. The prepared solution can be prescribed for drinking or administered to the patient through a tube. To improve the taste of the solution, food syrups can be used.
The prepared solution for oral use retains its physical and chemical stability for 96 hours at a temperature of 2-8 °C (refrigerator).
From a microbiological point of view, the drug should be used immediately, otherwise responsibility for the time and storage conditions during use rests with the consumer.

Side effects
The most common adverse reactions associated with too rapid intravenous infusion of vancomycin are phlebitis, pseudoallergic reactions, and flushing of the upper body (red neck syndrome).
When taken orally, the absorption of vancomycin from the gastrointestinal tract is negligible. However, with severe inflammation of the intestinal mucosa, especially in combination with renal failure, adverse reactions that occur with parenteral administration of vancomycin may be observed.
Adverse reactions are given in accordance with system-organ classification and frequency of occurrence. When indicating frequency, the following categories are used: very often
(≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency unknown (based on the available data, the frequency of occurrence cannot be determined).
Disorders of blood and lymphatic system: rarely - reversible neutropenia, agranulocytosis, eosinophilia, thrombocytopenia, pancytopenia.
Immune system disorders: rarely – hypersensitivity reactions, anaphylactic reactions.
Disorders of organ of hearing and labyrinth: infrequently - temporary or permanent hearing loss; rarely – vertigo, tinnitus, dizziness.
Cardiac disorders: very rarely - cardiac arrest.
Vascular disorders: often – decreased blood pressure; rarely – vasculitis.
Disorders of the respiratory system, thorax and mediastinal organs: often - shortness of breath, stridor.
Gastrointestinal disorders: rarely – nausea; very rarely - pseudomembranous enterocolitis; frequency unknown - vomiting, diarrhea.
Disorders of the skin and subcutaneous tissues: often - “red man” syndrome, exanthema, inflammation of the mucous membrane, itching, urticaria; very rarely - exfoliative dermatitis, Stevens-Johnson syndrome, Lyell's syndrome, linear IgA-dependent bullous dermatosis; frequency unknown - eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis.
Renal and urinary tract disorders: often – renal failure, manifested mainly by an increase in serum creatinine and serum urea; rarely – interstitial nephritis, acute renal failure; frequency unknown - acute tubular necrosis.
General disorders and reactions at the injection site: often - phlebitis, redness of the upper body and face; rarely - drug fever, tremor, pain and spasm of the muscles of the chest and back.

Description of selected adverse reactions
Reversible neutropenia usually begins a week or more after the start of intravenous therapy, or after a total dose of more than 25 g.
As a result of rapid administration of the drug, post-infusion reactions may occur: anaphylactoid and anaphylactic reactions, including broncho-obstructive syndrome. Once the infusion is stopped, such reactions usually disappear within 20 minutes to 2 hours. Vancomycin-Belpharm should be administered slowly.
Tinnitus, which may precede hearing loss, should be considered a symptom indicating the need to discontinue vancomycin therapy.
Ototoxicity has primarily been reported in patients receiving high doses, or in patients with concomitant use of other ototoxic drugs such as aminoglycosides, or in patients with a history of decreased renal function or hearing loss.
If a bullous skin disorder is suspected, use of Vancomycin-Belpharm should be discontinued and a specialized dermatological evaluation should be performed.


Children
The safety profile in children generally corresponds to the safety profile in adults. Nephrotoxicity has been described in children, usually in association with concomitant use of other nephrotoxic drugs such as aminoglycosides.

Reporting Adverse Reactions
It is important to report suspected adverse reactions after drug approval to ensure ongoing benefit-risk monitoring. Healthcare professionals are encouraged to report any suspected adverse drug reactions through national adverse reaction reporting systems.
If any adverse reactions occur, patients are advised to consult a physician or report adverse reactions to the Adverse Drug Reactions Information Database.
This recommendation applies to any possible adverse reactions, including those not listed in the instructions for medical use of the drug. Reports of adverse reactions provide more information about the safety of a drug.

Contraindications
Hypersensitivity to the active substance.
Vancomycin-Belpharm cannot be administered intramuscularly due to the risk of necrosis at the injection site!

Drug interactions
With the simultaneous use of vancomycin and drugs for anesthesia, erythema, histamine-like hyperemia and anaphylactoid reactions were observed.
The incidence of infusion-related reactions has been reported to increase with concomitant administration of anesthetics. Administering vancomycin as a 60-minute infusion before induction of anesthesia may reduce the likelihood of infusion-related reactions. If administration is necessary during anesthesia, the concentration of vancomycin in the solution should not exceed 5 mg/ml; the solution should be administered slowly with careful monitoring of cardiac function. The patient's body position should not be changed until the infusion is completed. Simultaneous or sequential, systemic or local use of other potentially ototoxic and/or nephrotoxic drugs (aminoglycosides, cisplatin, amphotericin B, bacit-racin, polymyxin B, colistin, viomycin, loop diuretics, non-steroidal anti-inflammatory drugs) may increase toxicity vancomycin; If such use is necessary, special caution and careful monitoring of toxicity are required.
With the simultaneous use of vancomycin and muscle relaxants, neuromuscular blockade may develop.
Vancomycin solution has a low pH, which may cause chemical or physical instability when mixed with other compounds. Mixing with alkaline solutions should be avoided.
It is known that mixtures of solutions of vancomycin and beta-lactam antibiotics are physically incompatible. The likelihood of precipitation increases with increasing vancomycin concentrations. It is recommended that the IV system be adequately flushed between uses of these antibiotics. It is also recommended that vancomycin solutions be diluted to 5 mg/mL or less.
When using Vancomycin-Belpharm orally, the possibility of discontinuing proton pump inhibitors and agents that inhibit intestinal motility should be considered in accordance with the recommendations for the treatment of C. difficile-associated infection.

Special instructions
Use during pregnancy and lactation
In teratological studies using doses 5 times and 3 times higher than the human dose in rats and rabbits, respectively, no evidence of harm to the fetus from vancomycin was established. In a controlled clinical trial, the potential oto- and nephrotoxic effects of vancomycin hydrochloride in children were assessed when administered to pregnant women with serious staphylococcal infections. Vancomycin hydrochloride was detected in cord blood, but no sensorineural hearing loss or nephrotoxicity associated with vancomycin was detected. Because vancomycin was only given in the second and third trimesters, it is unknown whether it causes harm to the fetus. The use of Vancomycin-Belpharm during pregnancy is possible only for health reasons in cases where the expected benefit of therapy for the mother exceeds the potential risk for the fetus. Vancomycin blood levels should be carefully monitored to minimize the risk of toxicity to the fetus. However, it has been reported that significantly increased doses of vancomycin are required to achieve therapeutic serum concentrations in pregnant patients.
Vancomycin hydrochloride is excreted into breast milk. Absorption of a significant amount of vancomycin from the gastrointestinal tract of a child is unlikely. However, caution should be exercised when prescribing vancomycin to a nursing woman. Due to possible side effects in the child, the risk of disturbances in the intestinal flora with diarrhea, fungal growth and possible sensitization, discontinuation of feeding or discontinuation of the drug should be considered, taking into account the importance of the drug for the nursing mother and breastfeeding for regeneration.

Effect on ability to drive a car and operate complex mechanisms
Effect of vancomycin on the ability to drive vehicles and operate machinery has not been identified.

Special instructions
Intravenous use
Vancomycin-Belpharm is recommended for use only in a hospital setting. Due to the pain of injections and the possible development of tissue necrosis at the injection site, Vancomycin-Belpharm cannot be administered intravenously as a bolus or intramuscularly!

Hypersensitivity reactions
Serious and sometimes fatal hypersensitivity reactions may occur with Vancomycin-Belpharm. In case of hypersensitivity reactions, treatment with Vancomycin-Belpharm must be stopped immediately and appropriate emergency measures must be taken.
In patients receiving Vancomycin-Belpharm for a long time or concomitantly with other drugs that can cause neutropenia or agranulocytosis, the white blood cell count should be regularly monitored. All patients receiving Vancomycin-Belpharm should be periodically monitored with blood tests, urine tests, and liver and kidney function tests.
Vancomycin-Belpharm should be used with caution in patients with allergic reactions to teicoplanin, as cross-hypersensitivity reactions, including anaphylactic shock, are possible.

Antibacterial activity
The spectrum of antibacterial activity of vancomycin is limited to gram-positive microorganisms. Therefore, it is not suitable for use as monotherapy in the treatment of certain types of infections, except those caused by bacteria with established sensitivity to vancomycin.
When prescribing Vancomycin-Belpharm, it is necessary to take into account the bacterial sensitivity spectrum, safety profile and suitability of standard antibacterial therapy for the treatment of each individual patient.

Ototoxicity
Cases of temporary or permanent hearing loss have been reported in patients with pre-existing deafness who received high doses of intravenous vancomycin or concomitant treatment with other ototoxic drugs such as aminoglycosides. Vancomycin-Belpharm should also be avoided in patients with a history of hearing loss. Deafness may be preceded by a feeling of constant ringing in the ears. To reduce the risk of ototoxicity, vancomycin blood levels and hearing function should be periodically monitored.
Elderly patients are especially at risk of hearing loss. During and after treatment with vancomycin in the elderly, vestibular and auditory function should be periodically monitored. Concomitant or sequential use of other ototoxic drugs should be avoided.

Infusion-related reactions
Bolus administration over several minutes may cause acute hypotension (including shock and, in rare cases, cardiac arrest), histamine-like reactions, and a maculopapular or erythematous rash (red man syndrome or red neck syndrome). Vancomycin-Belpharm should be administered slowly as a solution at a concentration of 2.5 to 5.0 mg/mL at a rate of no more than 10 mg/min over at least 60 minutes to avoid rapid infusion reactions. Stopping the infusion usually results in rapid resolution of these reactions.
The frequency of infusion reactions (hypotension, hyperemia, erythema, urticaria and itching) increases with the simultaneous administration of anesthetics. This effect can be reduced by administering Vancomycin-Belpharm by infusion for at least 60 minutes before anesthesia.

Severe bullous reactions
Stevens-Johnson syndrome (SJS) may occur when using Vancomycin-Belpharm. If symptoms or signs of SSc are present (eg, progressive skin rash, often with blistering or mucosal lesions), treatment with Vancomycin-Belpharm should be stopped immediately and a specialized dermatological evaluation performed.

Reactions at the injection site
When Vancomycin-Belpharm is administered intravenously, pain may occur or thrombophlebitis may develop. The incidence and severity of thrombophlebitis can be reduced by properly diluting the original solution and alternating the sites of drug administration.
The efficacy and safety of Vancomycin-Belpharm has not been established for the intrathecal, intralumbar and intraventricular routes of administration.
Vancomycin-Belpharm cannot be administered intravenously as a bolus or intramuscularly due to the risk of necrosis at the injection site!

Nephrotoxicity
Vancomycin-Belpharm should be used with caution in patients with renal failure, including anuria, since the development of toxic effects when maintaining high concentrations of the drug in the blood for a long time. The risk of toxicity increases when vancomycin blood concentrations are maintained at high levels or during long-term therapy.
Regular monitoring of vancomycin blood levels and monitoring of renal function is mandatory during high-dose and long-term use, especially in patients with renal dysfunction and hearing impairment, as well as during concomitant administration of nephrotoxic or ototoxic drugs.

Use in children
The safety of large doses of vancomycin in children has not been sufficiently studied. Recommended doses for children, especially those under 12 years of age, may result in subtherapeutic levels of vancomycin in a significant number of children. The safety of increasing the dose of vancomycin in children has not been adequately established, and doses exceeding 60 mg/kg/day cannot be recommended.
Vancomycin-Belpharm should be used with extreme caution in premature newborns and infants due to renal immaturity and possible increased vancomycin serum concentrations. In this group of patients, the concentration of vancomycin in the blood should be constantly monitored. Simultaneous administration of Vancomycin-Belpharm and anesthetics may be accompanied by erythema and histamine-like hyperemia in children. Concomitant use with nephrotoxic agents, such as aminoglycoside antibiotics, nonsteroidal anti-inflammatory drugs (eg, ibuprofen) or amphotericin B, is associated with an increased risk of nephrotoxicity. More frequent monitoring of vancomycin serum concentrations and renal function is recommended.

Use in elderly patients
The decrease in glomerular filtration rate with age may result in elevated vancomycin serum concentrations if the dose is not adjusted accordingly (see Dosage and Administration).

Interaction with anesthetics
Vancomycin may potentiate anesthetic-induced myocardial depression. During anesthesia, doses of anesthetics should be well diluted and administered slowly with careful monitoring of cardiac function. Changes in body position should be delayed until the infusion is completed.

Pseudomembranous enterocolitis
In cases of severe persistent diarrhea, the possibility of developing pseudomembranous enterocolitis, which can be life-threatening, must be considered. Anti-diarrheal drugs should not be used.

Superinfection
Long-term use of vancomycin may lead to an increase in the number of nonsusceptible microorganisms. Careful monitoring of the patient is necessary. If superinfection occurs during therapy, appropriate measures should be taken.

Oral use
Vancomycin-Belpharm can be given orally only for the treatment of pseudomembranous colitis caused by Clostridium difficile.
Specific tests for colonization or Clostridium difficile toxin are not recommended in children under 1 year of age due to frequent asymptomatic colonization, with the exception of children with severe diarrhea and the presence of risk factors for coprostasis (Hirschsprung's disease, operated on anal atresia or other severe motor impairment). In all cases, it is necessary to search for an alternative etiology. The etiological diagnosis of enterocolitis caused by Clostridium difficile requires confirmation.

Enhanced systemic absorption
In patients with inflammatory disorders of the intestinal mucosa or pseudomembranous colitis induced by Clostridium difficile, the systemic absorption of vancomycin may be increased. Therefore, there is a risk of developing adverse reactions associated with parenteral use of vancomycin, especially with concomitant renal failure. The more severe the renal failure, the higher the risk of developing adverse reactions associated with parenteral administration of vancomycin. Vancomycin serum concentrations should be monitored in patients with inflammatory disorders of the intestinal mucosa.

Nephrotoxicity
When treating patients with renal dysfunction or patients receiving concomitant therapy with aminoglycosides or other nephrotoxic drugs, renal function should be monitored.

Ototoxicity
To minimize the risk of ototoxicity in patients with hearing changes or those receiving concomitant therapy with ototoxic drugs such as aminoglycosides, monitoring of hearing function is recommended.

Interaction with antiperistaltic drugs and proton pump inhibitors
The use of drugs that inhibit intestinal motility should be avoided, and the use of a proton pump inhibitor should be reconsidered.

Development of resistance
The use of vancomycin orally increases the likelihood of the emergence of vancomycin-resistant enterococci populations in the gastrointestinal tract. Therefore, it is recommended to use Vancomycin-Belpharm orally with caution.

Overdose
In case of overdose, maintenance therapy with maintenance of glomerular filtration is recommended. Vancomycin is poorly removed from the blood by hemodialysis or peritoneal dialysis. Limited benefit of hemoperfusion with XAD-4 amberlite resin has been reported.

Release form
500 mg in a 10 ml injection bottle or 1000 mg in a 20 ml injection bottle.
1 bottle or 5 bottles each along with instructions for medical use in a cardboard box.

Packaging for hospitals: 36 bottles with a dosage of 500 mg or 25 bottles with a dosage of 1000 mg together with instructions for medical use (at least 3) in a cardboard box for hospitals.

Storage conditions
Should be stored in a dry place, protected from light, at a temperature of 2 °C to 8 °C.
Should be kept out of the reach of children.

Expiration date
Expiration date: 2 years.
Should not be used after the expiration date.

Conditions for release from pharmacies
The medicine is released according to a doctor's prescription.

Manufacturer / Name and address of the organization accepting claims (suggestions) regarding the quality of the medicinal product in the territory of the Republic of Uzbekistan
FC BELPHARM LLC,
100084, Republic of Uzbekistan, Tashkent,
Chingiza Aitmatova str., 37.
+998 (55) 506-28-28
www.belpharm.uz