Vancomycin-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Vancomycin-Vista (Vancomycin-Vista)

Composition:

Active substance: vancomycin;

1 vial contains vancomycin hydrochloride equivalent to 500 mg or 1000 mg of vancomycin;

Excipients: sodium hydroxide / hydrochloric acid (may be present for pH adjustment).

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physicochemical properties: white or almost white lyophilized powder.

Pharmacotherapeutic group

Antibacterial agents for systemic use. Glycopeptide antibiotics. ATC code J01XA01 (for intravenous use), ATC code A07AA09 (for oral use).

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Vancomycin is a tricyclic glycopeptide antibiotic that inhibits cell wall synthesis in susceptible bacteria by binding with high affinity to the D-alanyl-D-alanine terminus of cell wall precursors. The drug exhibits slow bactericidal activity against dividing microorganisms. In addition, it disrupts bacterial cell membrane permeability and RNA synthesis.

Pharmacokinetic / pharmacodynamic relationship

Vancomycin demonstrates concentration-independent activity, with the area under the concentration-time curve (AUC) divided by the minimum inhibitory concentration (MIC) of the target organism being the primary pharmacodynamic predictor of efficacy. Based on in vitro and animal studies, as well as limited human data, an AUC/MIC ratio of 400 has been established as the target pharmacokinetic/pharmacodynamic (PK/PD) index to achieve clinical efficacy of vancomycin. To reach this target when MIC ≥ 1 mg/L, dosing at the upper end of the range and high trough serum concentrations (15–20 mg/L) are required.

Mechanism of resistance

Acquired resistance to glycopeptides occurs most commonly in enterococci and is based on the presence of various van gene clusters that modify the D-alanyl-D-alanine target to D-alanyl-D-lactate or D-alanyl-D-serine, which bind vancomycin poorly. In some countries, the incidence of resistance, particularly in enterococci, is increasing, with particular concern regarding multidrug-resistant Enterococcus faecium strains.

Van genes are rarely detected in Staphylococcus aureus, where alterations in cell wall structure lead to "intermediate" susceptibility, which is often heterogeneous. Cases of methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin have also been reported. Reduced susceptibility or resistance to vancomycin in Staphylococcus species is not fully understood. There is no cross-resistance between vancomycin and other classes of antibiotics. However, cross-resistance with other glycopeptide antibiotics, such as teicoplanin, may occur. Secondary development of resistance during therapy is rare.

Synergy

The combination of vancomycin with an aminoglycoside antibiotic exhibits a synergistic effect against many strains of Staphylococcus aureus, non-enterococcal D-streptococci, enterococci, and Viridans group streptococci. The combination of vancomycin with a cephalosporin shows synergistic activity against certain oxacillin-resistant strains of Staphylococcus epidermidis, and the combination of vancomycin with rifampicin demonstrates synergistic activity against Staphylococcus epidermidis and partially synergistic activity against some strains of Staphylococcus aureus. However, vancomycin in combination with cephalosporins may also exhibit antagonistic effects against certain strains of Staphylococcus epidermidis, and in combination with rifampicin, antagonism may occur against some strains of Staphylococcus aureus. Therefore, bacterial cultures should be obtained to isolate and identify causative pathogens and to determine their susceptibility to vancomycin.

Susceptibility testing breakpoints

Vancomycin is active against Gram-positive bacteria, including staphylococci, streptococci, enterococci, pneumococci, and clostridia. Gram-negative bacteria are intrinsically resistant.

The prevalence of acquired resistance may vary geographically and over time for individual species; therefore, up-to-date local information on resistance patterns is desirable, especially when treating severe infections. Expert consultation should be sought if local resistance prevalence is such that the benefit of vancomycin, at least for certain types of infections, is questionable. This information provides only approximate guidance regarding the likely susceptibility of microorganisms to vancomycin.

The minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

Staphylococcus aureus strains with vancomycin MIC values of 2 mg/L are at the wild-type distribution breakpoint, and diminished clinical response may be observed.

Pharmacokinetics

Absorption

Vancomycin is administered intravenously for the treatment of systemic infections.

In patients with normal renal function, multiple intravenous infusions of 1 g vancomycin (15 mg/kg) administered over 60 minutes achieve approximate mean plasma concentrations of 50–60 mg/L, 20–25 mg/L, and 5–10 mg/L immediately, 2 hours, and 11 hours after completion of the infusion, respectively. Plasma levels achieved after multiple doses are similar to those observed after a single dose.

Vancomycin is generally not absorbed into the bloodstream following oral administration. However, absorption may occur after oral administration in patients with (pseudomembranous) colitis. This may lead to accumulation of vancomycin in patients with concomitant renal impairment.

Distribution

The volume of distribution is approximately 60 L/1.73 m^2 body surface area. At serum vancomycin concentrations ranging from 10 mg/L to 100 mg/L, protein binding is approximately 30–55%, as determined by ultrafiltration.

Vancomycin readily diffuses across the placenta and distributes into umbilical cord blood. In non-inflamed meninges, vancomycin penetrates the blood-brain barrier only to a limited extent.

Biotransformation

Vancomycin metabolism is minimal. After parenteral administration, it is excreted almost entirely as microbiologically active substance (approximately 75–90% within 24 hours) via glomerular filtration through the kidneys.

Elimination

The elimination half-life of vancomycin is 4–6 hours in patients with normal renal function and 2.2–3 hours in children. Plasma clearance is approximately 0.058 L/kg/h, and renal clearance is approximately 0.048 L/kg/h. Within the first 24 hours, approximately 80% of the administered dose of vancomycin is excreted in urine via glomerular filtration. Impaired renal function delays vancomycin elimination. In anephric patients, the mean elimination half-life is 7.5 days. Due to the ototoxic potential of vancomycin, adjunctive monitoring of plasma concentrations is indicated in such cases.

Biliary excretion is minimal (less than 5% of the dose).

Although vancomycin is not effectively removed by hemodialysis or peritoneal dialysis, there are reports of increased vancomycin clearance with hemoperfusion and hemofiltration.

After oral administration, only a portion of the administered dose is recovered in urine. Conversely, high concentrations of vancomycin are found in feces (> 3100 mg/kg at doses of 2 g/day).

Linearity / Non-linearity

Vancomycin concentration typically increases proportionally with increasing dose. Plasma concentrations during multiple dosing are similar to those after a single dose.

Characteristics in specific patient populations

Renal impairment

Vancomycin is primarily eliminated by glomerular filtration. In patients with impaired renal function, the terminal elimination half-life is prolonged and total clearance is reduced.

Hepatic impairment

The pharmacokinetics of vancomycin are not altered in patients with hepatic impairment.

Pregnant women

Higher doses may be required to achieve therapeutic serum concentrations in pregnant women (see section "Use during pregnancy or breastfeeding").

Patients with excess body weight

The distribution of vancomycin may be altered in patients with excess body weight due to increased volume of distribution, renal clearance, and possible changes in plasma protein binding. In these subpopulations, serum vancomycin concentrations have been higher than expected compared to healthy adult males (see section "Method of administration and dosage").

Pediatric population

Vancomycin has shown wide interindividual variability in preterm and term neonates. In neonates following intravenous administration, the volume of distribution of vancomycin ranges from 0.38 to 0.97 L/kg, similar to values in adults, while clearance ranges from 0.63 to 1.4 mL/kg/min. The elimination half-life ranges from 3.5 to 10 hours and is longer than in adults, reflecting typically lower clearance values in neonates. In infants and older children, the volume of distribution ranges from 0.26 to 1.05 L/kg, and clearance ranges from 0.33 to 1.87 mL/kg/min.

Clinical Characteristics

Indications

Intravenous administration

Vancomycin is indicated in all age groups for the treatment of the following infections:

• complicated skin and soft tissue infections;
• bone and joint infections;
• community-acquired pneumonia;
• hospital-acquired pneumonia, including ventilator-associated pneumonia;
• infective endocarditis.

Vancomycin 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 administration

Vancomycin is indicated in all age groups for the treatment of infections caused by Clostridium difficile.

During treatment, attention should be paid to official guidelines regarding appropriate use of antibacterial agents.

Contraindications

Hypersensitivity to vancomycin or to any other component of the medicinal product. Vancomycin must not be administered intramuscularly due to the risk of necrosis at the injection site.

Interaction with other medicinal products and other forms of interaction

Concomitant administration of vancomycin and anaesthetics has been associated with erythema, histamine-like flushing, and anaphylactoid reactions (see section "Special precautions for use").

Reports have indicated that the frequency of infusion-related events increases with concomitant use of anaesthetics. Infusion-related events can be minimized by administering vancomycin as a 60-minute infusion prior to induction of anaesthesia. When administered during anaesthesia, doses should be diluted to 5 mg/mL or less and infused slowly with careful cardiac monitoring. Patient repositioning should be delayed until completion of the infusion.

Concomitant or sequential systemic or local use of other potentially ototoxic or nephrotoxic agents, such as amphotericin B, aminoglycosides, bacitracin, polymyxin B, colistin, viomycin, cisplatin, loop diuretics, piperacillin/tazobactam, and NSAIDs, may increase vancomycin toxicity.

Oral use: consider the possibility of discontinuing proton pump inhibitors and agents that suppress gastrointestinal motility during treatment against Clostridium difficile.

Special precautions for use

Hypersensitivity reactions

Serious and sometimes fatal hypersensitivity reactions may occur (see sections "Contraindications" and "Adverse reactions"). In case of hypersensitivity reactions, vancomycin therapy must be discontinued immediately and appropriate emergency measures should be initiated.

In patients receiving vancomycin for prolonged periods or concurrently with other agents that may cause neutropenia or agranulocytosis, regular monitoring of blood leukocyte counts is required. All patients receiving vancomycin should undergo periodic hematological examinations, urine analysis, and assessment of liver and kidney function. Vancomycin should be used with caution in patients with allergic reactions to teicoplanin, due to the possibility of cross-sensitivity, including fatal anaphylactic shock.

Antibacterial spectrum

Vancomycin has a narrow antibacterial spectrum limited to Gram-positive microorganisms. It is not suitable for use as monotherapy for certain types of infections, except when the causative pathogen has already been documented and known to be susceptible to vancomycin.

When using vancomycin, the bacterial spectrum of activity, safety profile, and suitability of standard antibacterial therapy for the individual patient should be considered.

Ototoxicity

Ototoxicity, which may be temporary or permanent (see section "Adverse reactions"), has been reported in patients with pre-existing hearing loss who received excessive intravenous doses or concomitant therapy with other ototoxic agents, such as aminoglycosides. Vancomycin should also be avoided in patients with pre-existing hearing loss. Experience with other antibiotics indicates that hearing loss may progress despite discontinuation of therapy. To reduce the risk of ototoxicity, serum vancomycin levels should be monitored periodically, and hearing status should be regularly assessed.

Elderly patients are particularly susceptible to hearing damage. Monitoring of vestibular and auditory function should be performed during and after treatment in elderly patients. Concomitant or sequential use of other ototoxic substances should be avoided.

Infusion-related reactions

Rapid bolus administration (i.e., over several minutes) may be associated with increased arterial hypotension (including shock and rarely cardiac arrest), histamine-like reactions, and maculopapular or erythematous rash ("red man syndrome" or "red neck syndrome"). Vancomycin should be administered slowly in diluted solution (2.5–5 mg/mL) at a rate not exceeding 10 mg/min over at least 60 minutes to avoid rapid infusion-related reactions. Discontinuation of infusion usually results in rapid resolution of these reactions.

The frequency of infusion-related reactions (hypotension, flushing, erythema, urticaria, and pruritus) increases with concomitant administration of anesthetics (see section "Special precautions for use"). This can be minimized by administering vancomycin via infusion over at least 60 minutes prior to anesthesia induction.

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, have been reported in association with vancomycin use (see section "Adverse reactions"). Most of these reactions occurred within several days up to 8 weeks after initiation of vancomycin therapy.

Patients should be informed about signs and symptoms of SCARs and closely monitored for skin reactions during vancomycin therapy. If signs or symptoms suggestive of these reactions occur, vancomycin should be discontinued immediately and alternative therapy considered. Vancomycin therapy must never be resumed if a patient has developed SCAR during treatment.

Application site reactions

Pain and thrombophlebitis may occur in many patients receiving intravenous vancomycin and may sometimes be severe. The frequency and severity of thrombophlebitis can be minimized by slow administration of the drug in diluted solution (see section "Special precautions for use") and regular rotation of infusion sites.

The efficacy and safety of vancomycin for intrathecal, intralumbar, or intraventricular administration have not been established.

Nephrotoxicity

Vancomycin should be used with caution in patients with renal impairment, including anuria, as the likelihood of toxic effects is significantly higher when prolonged high serum concentrations occur. The risk of toxicity increases with high serum concentrations or prolonged therapy.

Regular monitoring of vancomycin serum levels is indicated during high-dose therapy and long-term treatment, particularly in patients with impaired renal function or hearing, and in those receiving concomitant nephrotoxic or ototoxic agents, respectively (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Vision disorders

Vancomycin is not approved for intracameral or intravitreal use, including prophylaxis of endophthalmitis.

Hemorrhagic occlusive retinal vasculitis, including permanent vision loss, has been observed in isolated cases following intracameral or intravitreal administration of vancomycin during or after cataract surgery.

Pediatric patients

Current recommendations for intravenous dosing in the pediatric population, particularly in children under 12 years of age, may result in subtherapeutic vancomycin levels in a significant number of children. However, the safety of increasing vancomycin dosage has not been adequately evaluated, and doses exceeding 60 mg/kg/day are generally not recommended. Vancomycin should be used with particular caution in preterm neonates and infants due to immature renal function and the potential for increased serum vancomycin concentrations. Therefore, serum vancomycin concentrations should be carefully monitored in these children. Concomitant administration of vancomycin and anesthetics has been associated with erythema and histamine-like manifestations in children. Similarly, concomitant use with nephrotoxic agents such as aminoglycoside antibiotics, NSAIDs (e.g., ibuprofen for closure of patent ductus arteriosus), or amphotericin B is associated with an increased risk of nephrotoxicity (see section "Interaction with other medicinal products and other forms of interaction"), and thus more frequent monitoring of serum vancomycin levels and renal function is recommended.

Use in elderly patients

The natural age-related decline in glomerular filtration rate may lead to elevated serum vancomycin concentrations if the dose is not adjusted (see section "Special precautions for use").

Drug interaction with anesthetics

Vancomycin may potentiate myocardial depression caused by anesthetics. During anesthesia, doses should be adequately diluted and administered slowly with careful monitoring of cardiac function. Patient repositioning should be delayed until infusion is complete (see section "Interaction with other medicinal products and other forms of interaction").

Pseudomembranous enterocolitis

In cases of severe persistent diarrhea, pseudomembranous enterocolitis, which may be life-threatening, should be considered (see section "Special precautions for use"). Antidiarrheal medicinal products should not be used.

Superinfection

Prolonged use of vancomycin may lead to overgrowth of non-susceptible organisms. Careful patient monitoring is required. If superinfection occurs during therapy, appropriate measures should be taken.

Oral administration

Intravenous administration of vancomycin is ineffective for the treatment of Clostridium difficile infection. For this indication, vancomycin should be administered orally.

Testing for Clostridium difficile colonization or toxin is not recommended in children under 1 year of age due to high rates of asymptomatic colonization, except in cases of severe diarrhea in infants with risk factors for stasis, such as Hirschsprung's disease, surgically corrected anal atresia, or other serious motility disorders. Alternative etiologies should always be sought, and Clostridium difficile-associated enterocolitis should be confirmed.

Potential for systemic absorption

Absorption may be enhanced in patients with inflammatory bowel disease or pseudomembranous colitis caused by Clostridium difficile. These patients may be at risk of adverse reactions, especially if concomitant renal impairment is present. The greater the degree of renal dysfunction, the higher the risk of adverse reactions associated with parenteral vancomycin administration. Serum vancomycin concentration monitoring should be performed in patients with inflammatory bowel disease.

Nephrotoxicity

Sequential monitoring of renal function should be performed during treatment in patients with impaired renal function or those receiving concomitant therapy with aminoglycosides or other nephrotoxic agents.

Ototoxicity

Serial hearing function tests may be useful to minimize the risk of ototoxicity in patients with pre-existing hearing loss or those receiving concomitant therapy with ototoxic medicinal products such as aminoglycosides.

Drug interaction with motility-reducing agents and proton pump inhibitors
Motility-reducing agents should be avoided, and the use of proton pump inhibitors should be reviewed.

Development of drug-resistant bacteria

Oral administration of vancomycin increases the likelihood of colonization with vancomycin-resistant Enterococci in the gastrointestinal tract. Therefore, cautious use of oral vancomycin is recommended.

Use during pregnancy or breastfeeding

Pregnancy

Teratogenic studies were conducted at doses 5 times the human dose in rats and 3 times the human dose in rabbits, and showed no evidence of fetal harm due to vancomycin. A controlled clinical study evaluated the potential ototoxic and nephrotoxic effects of vancomycin hydrochloride on infants when administered to pregnant women for serious staphylococcal infections, concurrently with intravenous narcotics. Vancomycin hydrochloride was detected in umbilical cord blood. No sensorineural hearing loss or nephrotoxicity related to vancomycin was observed. One infant whose mother received vancomycin in the third trimester had conductive hearing loss, which was not related to vancomycin. Since vancomycin was administered only during the second and third trimesters, it is unknown whether it causes fetal harm. Vancomycin should be administered during pregnancy only if clearly needed, and serum levels should be carefully monitored to minimize the risk of fetal toxicity. Higher doses of vancomycin may be required in pregnant patients to achieve therapeutic serum concentrations.

Breastfeeding

Vancomycin passes into breast milk. The drug should be used with caution in breastfeeding women. It is unlikely that a breastfed infant would absorb a significant amount of vancomycin from breast milk.

Ability to affect reaction speed when driving or operating machinery

During treatment with this medicinal product, the ability to concentrate may be reduced. This should be taken into account when driving a vehicle or performing work requiring heightened attention.

Method of Administration and Dosage

Dosage

If necessary, vancomycin should be used in combination with other antibacterial agents.

Intravenous Administration

The initial dose should be based on total body weight. Subsequent dose adjustments should be based on serum concentrations to achieve target therapeutic levels. For subsequent doses and dosing intervals, renal function should be taken into account.

Patients aged 12 years and older

The recommended dose is 15–20 mg/kg of body weight every 8–12 hours (do not exceed 2 g per dose).

In critically ill patients, a loading dose of 25–30 mg/kg of body weight may be administered to achieve rapid attainment of the target trough serum concentration of vancomycin.

Children aged 1 month to 12 years

The recommended dose is 10–15 mg/kg of body weight every 6 hours (see section "Special Instructions").

Term newborns (from birth up to 27 days postnatal age) and preterm newborns (from birth up to estimated date of delivery plus 27 days)

To establish a dosing regimen for newborns, advice should be sought from a physician experienced in treating neonates. One of the possible vancomycin dosing regimens for newborns is illustrated in the following table (see section "Special Instructions").

PMA: postmenstrual age [time elapsed from day 1 of the last menstrual period to birth (gestational age) plus time elapsed after birth (postnatal age)].

Perioperative prophylaxis of bacterial endocarditis in all age groups The recommended dose is an initial dose of 15 mg/kg given prior to induction of anesthesia. Depending on the duration of surgery, a second dose of vancomycin may be required.

Duration of treatment

The recommended duration of treatment is presented in the table below. In any case, the duration of treatment should be adjusted according to the type and severity of infection and the individual patient's clinical response.

*Continue until further wound management is not required, the patient's condition improves, and the patient remains febrile for 48–72 hours.

**Longer courses of oral suppressive therapy should be considered for infections of prosthetic joints.

***The duration and need for combination therapy depend on the type of valve and the causative organism.

Special patient groups

Elderly patients

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

Renal impairment

In adults and children with impaired renal function, an initial dose followed by monitoring of serum vancomycin trough levels should be considered instead of a fixed dosing regimen, especially in patients with severe renal impairment or those undergoing renal replacement therapy (RRT), taking into account multiple factors that may influence vancomycin levels.

Initial doses should not be reduced in patients with mild or moderate renal insufficiency. In patients with severe renal insufficiency, it is preferable to extend the dosing interval rather than administer lower daily doses.

Concomitant use of medicinal products that may reduce vancomycin clearance and/or enhance its adverse effects should be carefully considered (see section "Special precautions").

Vancomycin is poorly removed by hemodialysis. However, the use of high-permeability membranes and continuous renal replacement therapy increases vancomycin clearance and generally requires supplemental dosing (usually after a hemodialysis session in the case of intermittent hemodialysis).

Adult patients

Dose adjustment in adult patients may be based on estimation of glomerular filtration rate (eGFR) using the following formula:

Women: 0.85 × the value obtained by the formula given above.

The usual initial dose for adult patients is 15 to 20 mg/kg, which can be administered every 24 hours to patients with a creatinine clearance of 20 to 49 mL/min. In patients with severe renal impairment (creatinine clearance below 20 mL/min) or patients receiving renal replacement therapy (RRT), the appropriate timing and dosage of subsequent doses depend significantly on the RRT modality and should be based on trough vancomycin serum levels and residual renal function (see section "Dosage adjustments"). Depending on the clinical situation, withholding the next dose until vancomycin level results are available may be considered.

In critically ill patients with renal impairment, the initial loading dose (25–30 mg/kg) should not be reduced.

Pediatric patients

Dose adjustment in children aged 1 year and older may be based on estimation of glomerular filtration rate (eGFR) using the updated Schwartz formula:

eGFR (mL/min/1.73 m²) = (height in cm × 0.413) / serum creatinine (mg/dL)

eGFR (mL/min/1.73 m²) = (height in cm × 36.2) / serum creatinine (μmol/L)

For neonates and infants under 1 year of age, expert consultation is recommended, as the updated Schwartz formula does not apply to this population.

Guideline recommendations for dosing in the pediatric population are provided in the table below, consistent with the same principles applied to adult patients.

* The appropriate timing and amount of subsequent doses depend largely on the method of RRT and should be based on pre-dose vancomycin serum levels and residual renal function. Depending on the clinical situation, consideration may be given to withholding the next dose until vancomycin level results are available.

Hepatic impairment

Dose adjustment is not required in patients with hepatic impairment.

Pregnancy

Higher doses may be required to achieve therapeutic serum concentrations in pregnant women (see section "Use during pregnancy or breastfeeding").

Obese patients

For obese patients, the initial dose should be individualized according to total body weight, as in patients without obesity.

Oral administration

Patients aged 12 years and older

Treatment of Clostridium difficile infection (CDI)

The recommended dose of vancomycin is 125 mg every 6 hours for 10 days for a first episode of mild CDI. This dose may be increased to 500 mg every 6 hours for 10 days in severe or complicated disease. The maximum daily dose should not exceed 2 g.

In patients with multiple recurrences, treatment of the current CDI episode with vancomycin 125 mg four times daily for 10 days followed by dose tapering, i.e. gradual reduction to 125 mg daily, or pulse dosing, i.e. 125–500 mg/day every 2–3 days for at least 3 weeks, may be considered.

Neonates, infants, and children under 12 years of age

The recommended dose of vancomycin is 10 mg/kg orally every 6 hours for 10 days. The maximum daily dose should not exceed 2 g.

The duration of vancomycin treatment may be adapted according to the clinical course of individual patients. Concomitant antibacterial agents likely to have caused CDI should be discontinued if possible. Adequate fluid and electrolyte replacement should be ensured. Monitoring of vancomycin serum concentrations

The frequency of therapeutic drug monitoring (TDM) should be individualized according to the clinical situation and response to treatment, ranging from daily sampling, which may be required in some hemodynamically unstable patients, to at least once weekly in stable patients showing response to treatment. In patients with normal renal function, serum vancomycin concentrations should be monitored on day 2 of treatment immediately before the next dose. In patients undergoing intermittent hemodialysis, vancomycin levels should generally be measured before the start of a hemodialysis session.

Serum vancomycin concentration monitoring should be performed after oral administration in patients with inflammatory bowel disease (see section "Special warnings and precautions for use").

The therapeutic trough level of vancomycin in blood is generally recommended to be 10–20 mg/L, depending on the site of infection and pathogen susceptibility. Clinical laboratories often recommend trough levels of 15–20 mg/L to better cover isolates with MIC ≥ 1 mg/L (see sections "Special warnings and precautions for use" and "Pharmacodynamics"). Model-based methods may be useful for predicting individual dose requirements to achieve adequate AUC. A model-based approach can be used both for calculating a personalized initial dose and for dose adjustment based on TDM results (see section "Pharmacodynamics"). Method of administration

Intravenous infusion

Vancomycin is usually administered intravenously as an intermittent infusion, and the dosing recommendations provided in this section for the intravenous route refer to this mode of administration.

Vancomycin should only be given as a slow intravenous infusion over at least 1 hour or at a maximum rate of 10 mg/min (whichever is longer), adequately diluted (at least 100 mL per 500 mg or at least 200 mL per 1000 mg) (see section "Special warnings and precautions for use").

Patients who require fluid restriction may also receive a solution of 500 mg/50 mL or 1000 mg/100 mL, although the risk of infusion-related adverse effects may increase with such high concentrations.

Information on solution preparation

For single use only.

Any unused portion of the medicinal product must be discarded.

The powder must be reconstituted before use, and the resulting concentrate must be diluted. Preparation of reconstituted solution

To reconstitute, add 10 mL of Water for Injections to the vial. Reconstituted vials have a concentration of 50 mg/mL. The powder dissolves in water to form a clear solution.

FURTHER DILUTION IS REQUIRED. Read the following instructions: Intermittent infusion is the preferred method of administration. Reconstituted solutions containing 500 mg of vancomycin must be diluted in at least 100 mL of Sodium Chloride for Infusion or 5% Dextrose Solution. The required dose should be administered by intravenous infusion over at least 60 minutes. Administration over a shorter period or at higher concentrations may lead to marked hypotension in addition to thrombophlebitis. Rapid infusion may also cause flushing and transient rash on the neck and shoulders.

Continuous infusion (should only be used when intermittent infusion is not feasible). 2–4 vials (1–2 g) may be added to a sufficiently large volume of Sodium Chloride for Infusion or 5% Dextrose Solution so that the desired daily dose can be administered slowly by intravenous infusion over 24 hours. Recommended concentrations should not exceed 5 mg/mL. In some patients requiring fluid restriction, concentrations up to 10 mg/mL may be used.

Each dose should be administered at a rate not exceeding 10 mg/min.

Before administration, reconstituted and diluted solutions should be inspected visually for particulate matter and discoloration. Only clear, colorless solutions free of particles should be used.

Continuous infusion of vancomycin may be considered, for example, in patients with unstable vancomycin clearance.

Oral administration

The contents of vials may be used for oral administration. Each dose may be dissolved in 30 mL of water and given to the patient to drink or administered via a nasogastric tube (see section "Incompatibilities"). To improve palatability, standard flavoring syrups may be added to the solution at the time of administration.

Children

The medicinal product may be administered to children immediately after birth.

Overdose

Symptoms.

Overdose is characterized by an intensification of adverse effects. Treatment aimed at maintaining adequate glomerular filtration is recommended.

Treatment.

Vancomycin is poorly removed by dialysis. Excess vancomycin may be removed by hemofiltration and hemodialysis using polysulfone membranes.

No specific antidote is known.

Adverse Reactions

Short description of safety profile

The most commonly observed adverse reactions are phlebitis, pseudoallergic reactions, and redness of the upper part of the body ("red man syndrome") associated with too rapid intravenous infusion of vancomycin. Absorption of vancomycin from the gastrointestinal tract is negligible. However, in cases of severe intestinal mucosal inflammation, particularly in combination with renal impairment, adverse reactions associated with parenteral administration of vancomycin may occur. Severe cutaneous adverse reactions (SCAR) have been reported with vancomycin treatment, including Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) (see section "Special precautions").

Tabulated list of adverse reactions

Within each frequency group, adverse effects are listed in order of decreasing severity. The adverse reactions listed below are categorized according to the MedDRA system organ class and frequency classification:

Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data).

Description of individual adverse reactions associated with vancomycin use

Reversible neutropenia usually begins one week or more after initiation of intravenous therapy or following a total dose exceeding 25 g.

Anaphylactic/anaphylactoid reactions, including bronchospasm, may occur during or shortly after rapid infusion. These reactions typically resolve within 20 minutes to 2 hours after discontinuation of the infusion. Vancomycin should be administered slowly (see sections "Dosage and administration" and "Special precautions"). Necrosis may occur after intramuscular injection. Tinnitus, which may precede hearing loss, should be considered an indication to discontinue treatment. Ototoxicity has been mainly reported in patients receiving high doses, those concurrently receiving other ototoxic agents such as aminoglycosides, or those with pre-existing renal impairment or hearing loss.

Pediatric patients

The safety profile is generally similar in children and adult patients. Nephrotoxicity has been described in pediatric patients, usually in association with concomitant use of other nephrotoxic agents such as aminoglycosides.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25°C.

Keep out of reach of children.

Incompatibilities

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. Mixtures of vancomycin and beta-lactam antibiotics have been shown to be physically incompatible. The likelihood of precipitation increases with higher concentrations of vancomycin. It is recommended to adequately flush intravenous lines between administration of these antibiotics. It is also recommended to dilute vancomycin solutions to 5 mg/mL or less. Although intravitreal injection is not an approved route of administration for vancomycin, precipitation has been reported after intravitreal injection of vancomycin and ceftazidime for the treatment of endophthalmitis using separate syringes and needles. The precipitate gradually dissolved, with complete clearance of the vitreous cavity within two months and improvement in visual acuity.

Packaging

500 mg in a 10 mL glass vial, 1 vial per cardboard box.

1000 mg in a 20 mL glass vial, 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer

VEM Ilac San. ve Tic. A.S.

Manufacturer's address and location of manufacturing operations

Cerkezkoy Organized Industrial Zone, Karagac Mahallesi, Fatih Boulevard No. 38, Kapakli / Tekirdag / Turkey.