Vankobatsid

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VANCOBACID (VANCOBACID)

Composition:

Active substance: vancomycin;

One vial contains vancomycin hydrochloride equivalent to vancomycin 500 mg or 1000 mg.

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: porous mass ranging from white to almost white or light pink in color.

Pharmacotherapeutic group.

Antibacterials 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 (PK)/pharmacodynamic (PD) relationship

Vancomycin demonstrates concentration-independent activity, where the area under the concentration-time curve (AUC) divided by the minimum inhibitory concentration (MIC) for the target organism is the primary pharmacodynamic predictor of efficacy. Based on in vitro and animal study data, as well as limited human data, an AUC/MIC ratio of 400 has been established as the target PK/PD parameter to achieve clinical efficacy of vancomycin. To reach this target when MIC is ≥1.0 mg/L, dosing at the upper end of the range and high serum concentrations (15–20 mg/L) are required (see section "Method of administration and dosage").

Mechanism of resistance

Acquired resistance to glycopeptides is most commonly observed in enterococci and is based on acquisition 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 several countries, an increasing incidence of resistance has been observed, particularly among enterococci; special concern is raised by multidrug-resistant Enterococcus faecium strains.

The van genes are rarely found in Staphylococcus aureus, where alterations in cell wall structure lead to "intermediate" susceptibility, which is usually heterogeneous. Strains of methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin have also been reported. The mechanisms underlying reduced susceptibility or resistance to vancomycin in staphylococci are not fully understood and appear to require the presence of multiple genetic elements and numerous mutations.

Cross-resistance between vancomycin and other classes of antibiotics is absent. However, cross-resistance with other glycopeptide antibiotics, such as teicoplanin, may still occur. Secondary development of resistance during therapy is rare.

Synergy

The combination of vancomycin with an aminoglycoside antibiotic exerts a synergistic effect against many strains of Staphylococcus aureus, non-enterococcal group D streptococci, enterococci, and Viridans group streptococci. The combination of vancomycin with a cephalosporin has a synergistic effect against certain oxacillin-resistant Staphylococcus epidermidis strains, and the combination of vancomycin with rifampicin shows synergistic activity against Staphylococcus epidermidis and partial synergistic activity against certain Staphylococcus aureus strains. Since vancomycin in combination with cephalosporins may also exhibit an antagonistic effect against some strains of Staphylococcus epidermidis, and in combination with rifampicin against some strains of Staphylococcus aureus, preliminary testing for synergy is advisable.

Bacterial cultures should be obtained to isolate and identify causative pathogens and 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 inherently resistant to vancomycin.

The prevalence of acquired resistance in specific species may vary geographically and over time; therefore, local information on resistance patterns is desirable, especially when treating severe infections. Expert advice should be sought if local resistance prevalence raises doubts about the appropriateness of using the drug, at least for certain types of infections. This information provides only a general indication of microbial susceptibility to vancomycin.

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)

1S. aureus with MIC values for vancomycin of 2 mg/L are at the wild-type cutoff boundary, and a 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) over 60 minutes result in 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 the end of infusion, respectively. Plasma levels achieved after multiple dosing 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 m2 body surface area. At serum vancomycin concentrations ranging from 10 mg/L to 100 mg/L, protein binding is approximately 30–55% (measured by ultrafiltration).

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

Biotransformation

Metabolism of this drug is negligible. Within the first 24 hours, approximately 75–90% of the administered dose of vancomycin is excreted in urine via glomerular filtration.

Elimination

The elimination half-life averages 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 vancomycin dose is excreted in urine via glomerular filtration. Impaired renal function delays vancomycin elimination. In patients with renal impairment, elimination of vancomycin is slowed; particularly in patients with a removed kidney, the elimination half-life is 7.5 days.

Due to the ototoxic potential of vancomycin, monitoring of plasma concentrations during therapy 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 observed after a single dose.

Special patient groups

Patients with impaired renal function.

Vancomycin is primarily eliminated via glomerular filtration. In patients with impaired renal function, the terminal elimination half-life of vancomycin is prolonged and total clearance is reduced. Therefore, the optimal dose should be adjusted according to the dosing recommendations provided in the section "Dosage and administration".

Patients with impaired hepatic function.

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

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. Vancomycin distribution may be altered in patients with excess body weight due to increased volume of distribution, increased renal clearance, and potential changes in plasma protein binding. In this subpopulation, serum vancomycin concentrations have been higher than expected in healthy adult males (see section "Special precautions").

Children. Vancomycin pharmacokinetics show wide inter-individual 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 the 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.

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 anaesthetic agents may cause erythema, histamine-like flushing, and anaphylactoid reactions (see section "Special warnings and precautions for use").

There have been reports of increased incidence of infusion-related events when vancomycin is administered concomitantly with anaesthetics. Infusion-related reactions can be minimized by administering vancomycin as a 60-minute infusion prior to anaesthesia. When administered during anaesthesia, doses should be diluted to 5 mg/mL or less and infused slowly, with careful cardiac monitoring. Patients must not move or change their horizontal position until the infusion is complete.

Concomitant or sequential systemic or topical use of other potentially ototoxic or nephrotoxic agents, such as amphotericin B, aminoglycosides, viomycin, bacitracin, polymyxin B, colistin, cisplatin, loop diuretics, piperacillin/tazobactam, and NSAIDs, may increase the toxicity of vancomycin. Such combinations should be used with caution, with appropriate monitoring.

Oral administration

The use of agents that inhibit intestinal peristalsis and proton pump inhibitors should be avoided, in accordance with local guidelines for Clostridium difficile infection.

Special precautions for use.

Serious and sometimes fatal hypersensitivity reactions may occur (see sections "Contraindications" and "Adverse reactions"). If hypersensitivity reactions occur, vancomycin therapy must be discontinued immediately and appropriate emergency measures should be initiated. Periodic monitoring of white blood cell count is required in patients receiving vancomycin for prolonged periods or in combination with other medicinal products that may cause neutropenia or agranulocytosis. All patients receiving vancomycin should undergo regular blood and urine tests, as well as liver and kidney function assessments.

Vancomycin should be used with caution in patients with allergic reactions to teicoplanin, as cross-allergy may occur, including fatal anaphylactic shock.

Antibacterial spectrum of activity

The antibacterial spectrum of vancomycin is limited to Gram-positive microorganisms. It is unsuitable as a monotherapy for certain types of infections unless the causative agent has been documented and classified as susceptible, or there is a high probability that the present pathogens will respond to vancomycin treatment.

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

Ototoxicity

There is a risk of ototoxicity during vancomycin therapy, which may be temporary or permanent (see section "Adverse reactions"), reported in patients with pre-existing hearing loss who received excessive intravenous doses or concomitant therapy with another ototoxic agent, such as an aminoglycoside. Vancomycin should also be avoided in patients with pre-existing hearing loss. Hearing impairment may initially present as tinnitus. Experience with other antibiotics indicates that deafness may progress despite discontinuation of therapy. To reduce the risk of ototoxicity, periodic monitoring of vancomycin blood levels and hearing should be performed. Elderly patients are particularly susceptible to hearing damage. Monitoring of vestibular and auditory function in elderly patients should be conducted during and after treatment. Concomitant or sequential use of other ototoxic substances should be avoided.

Infusion-related reactions

Rapid administration of the drug as a bolus injection (over several minutes) may cause significant arterial hypotension (including shock, rarely with 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 (2.5–5.0 mg/mL) at a rate not exceeding 10 mg/min over at least 60 minutes to avoid rapid infusion-related reactions. Discontinuation of the infusion usually leads to rapid resolution of these reactions. The frequency of infusion-related reactions (arterial hypotension, flushing, erythema, urticaria, and pruritus) increases with concomitant use 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 skin adverse reactions

Severe skin adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis, have been reported with vancomycin use, which may be life-threatening or fatal (see section "Adverse reactions"). Most of these reactions occurred within several days to eight weeks after initiation of vancomycin therapy. Patients should be informed about potential signs and symptoms during treatment, and closely monitored for the development of skin reactions. If signs and symptoms suggestive of these reactions appear, vancomycin must be discontinued immediately and alternative therapy considered. If a patient has experienced severe skin adverse reactions due to vancomycin, vancomycin therapy must never be resumed.

Injection site reactions

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

The efficacy and safety of vancomycin when administered intrathecally, intralumbally, or intraventricularly have not been established.

Nephrotoxicity

Due to the potential nephrotoxicity of vancomycin, it should be used with caution in patients with renal impairment (including anuria), as the likelihood of toxic effects is significantly higher with prolonged presence of high blood concentrations. The risk of toxic effects is significantly increased with high drug concentrations in blood or prolonged therapy.

Therapeutic drug monitoring of vancomycin blood levels is indicated during high-dose therapy and long-term use, especially in patients with impaired renal function or hearing, and during concomitant use of nephrotoxic or ototoxic agents, respectively (see sections "Method of administration and dosage" and "Interaction with other medicinal products and other forms of interaction").

Effect on vision

Vancomycin is not indicated for intracameral or intravitreal administration, 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.

Paediatric patients

Current recommendations for intravenous dosing in paediatric patients may result in subtherapeutic vancomycin levels in a significant number of children, especially those under 12 years of age. The safety of higher vancomycin doses has not been thoroughly studied; therefore, doses above 60 mg/kg/day are generally not recommended.

Vancomycin should be used with particular caution in premature infants due to immature renal function, which may lead to increased serum vancomycin concentrations. Monitoring of serum vancomycin levels in premature neonates and infants is recommended. Concomitant administration of vancomycin and anesthetics has been associated with erythema and histamine-like flushing in children. Similarly, concomitant use of nephrotoxic medicinal products 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"), 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 "Method of administration and dosage").

Interaction with anesthetics

Vancomycin may potentiate myocardial depression caused by anesthetics. During anesthesia, doses should be adequately diluted and administered slowly, accompanied by careful monitoring of cardiac function. Patients should not move or change their horizontal position until the infusion is complete.

Pseudomembranous enterocolitis

In cases of prolonged severe diarrhea, pseudomembranous enterocolitis, which may be life-threatening, should be considered (see section "Adverse reactions"). Antidiarrheal agents should not be used.

Superinfection

Prolonged use of vancomycin may lead to the development of resistant microorganisms and fungi. Careful patient monitoring is essential. If superinfection (secondary infection during ongoing infectious disease) 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 colonization or Clostridium difficile 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 considered, and Clostridium difficile-induced enterocolitis should be confirmed.

Potential for systemic absorption

Absorption may be enhanced in patients with inflammatory bowel diseases 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 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 diseases.

Nephrotoxicity

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

Ototoxicity

Sequential 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 an ototoxic agent such as an aminoglycoside.

Interaction of vancomycin with motility-inhibiting drugs and proton pump inhibitors

The use of motility-inhibiting drugs 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 vancomycin-resistant enterococci colonization in the gastrointestinal tract. Therefore, cautious use of oral vancomycin is recommended.

Use during pregnancy or breastfeeding.

Pregnancy

Teratogenic studies in animals, in which rats and rabbits were administered vancomycin doses 5 and 3 times higher, respectively, than human doses, showed no evidence of fetal harm.

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. 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 unrelated to vancomycin. Since vancomycin was administered only during the second and third trimesters, it is unknown whether it harms the fetus. Vancomycin should be used during pregnancy only if clearly needed, and serum drug levels should be carefully monitored to minimize the risk of fetal toxicity. However, it has been reported that pregnant patients may require significantly higher vancomycin doses to achieve therapeutic serum concentrations.

Period of breastfeeding

Vancomycin is excreted in breast milk.

Vancomycin should be prescribed with caution to breastfeeding women. The amount of vancomycin that may pass into the infant's body through breast milk is considered negligible.

Ability to affect reaction rate when driving vehicles or operating machinery.

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

Method of Administration and Dosage

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

Intravenous Administration

The initial dose should be determined according to total body weight. Subsequent dose adjustments should be based on serum concentrations to achieve target therapeutic levels. When prescribing 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 body weight every 8–12 hours (not exceeding 2 g per dose).

For critically ill patients, a loading dose of 25–30 mg/kg body weight may be administered to facilitate rapid achievement of the target minimum serum vancomycin concentration.

Children aged 1 month to 12 years: The recommended dose of vancomycin is 10–15 mg/kg body weight every 6 hours.

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 possible vancomycin dosing regimen for newborns is illustrated in Table 1.

Table 1

PMA: postmenstrual age [time elapsed from the first day 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 prior to induction of anesthesia. Depending on the duration of surgery, a second dose of vancomycin may be required.

Treatment duration
The recommended duration of treatment is shown in Table 2. In any case, the duration of treatment should be adapted according to the type and severity of infection and the individual clinical response.

Table 2

*Continue treatment until there is no further need for wound care, until the patient shows clinical improvement, and while the patient has fever for 48–72 hours.

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

***The duration and necessity of combination therapy depend on the type of valve and organism.

Special patient populations

Elderly patients: dose reduction may be required due to age-related decline in renal function.

Patients with renal impairment

For adults and children with renal impairment, dose adjustment based on serum vancomycin levels may be necessary, especially in patients with severe renal impairment or those undergoing renal replacement therapy (RRT), due to multiple factors that may influence vancomycin levels.

Initial doses should not be reduced in patients with mild or moderate renal impairment. For patients with severe renal impairment, it is preferable to prolong 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 for use").

Vancomycin is poorly cleared during intermittent hemodialysis. However, the use of high-flux membranes and continuous renal replacement therapy (CRRT) increases vancomycin clearance and generally requires dose adjustment (usually administered after a session of intermittent hemodialysis).

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

Women: 0.85 × the value obtained using the formula above.

The usual initial dose for adult patients is 15 to 20 mg/kg, which may 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, dosing and subsequent dose adjustments depend significantly on the type of renal replacement therapy and should be based on trough serum vancomycin levels and residual renal function (see section "Special precautions"). Depending on the clinical situation, the next dose may be withheld until vancomycin serum level results are available.

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

Paediatric patients

Dose adjustment in children aged 1 year and older may be based on estimated 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).

Expert consultation is recommended for neonates and infants under 1 year of age, as the updated Schwartz formula is not applicable to this population.

Guidelines for dosing in the paediatric population are provided in Table 3 and follow the same principles as those for adult patients.

Table 3

*The appropriate timing and amount of subsequent doses largely depend on the method of CRRT and should be based on the serum vancomycin concentration obtained prior to dosing and on residual renal function. Depending on the clinical situation, the administration of the next dose may be withheld until vancomycin level results are available.

Patients with hepatic impairment: do not require adjustment of the daily dose.

Pregnancy

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

Patients with obesity

For patients with obesity, the initial dose should be individually adjusted according to total body weight, as in patients without obesity.

Oral administration

Patients aged 12 years and older

Treatment of infections caused by Clostridium difficile:

The recommended dose of vancomycin is 125 mg every 6 hours for 10 days for the first episode of mild disease. This dose may be increased to 500 mg every 6 hours for 10 days in cases of severe or complicated disease.

The maximum daily dose should not exceed 2 g.

In patients with multiple recurrences, treatment of the current episode may be considered 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.

Neonates, infants, and children under 12 years of age

The recommended dose of vancomycin is 10 mg/kg orally, administered 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 in each individual patient. Whenever possible, antibiotics likely to have caused Clostridium difficile-associated disease should be discontinued. Adequate fluid and electrolyte replacement should be ensured.

Monitoring of serum vancomycin 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 certain hemodynamically unstable patients, to at least once weekly in stable patients showing a positive response to therapy. In patients with normal renal function, serum vancomycin concentrations should be monitored on the second day 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 in patients after oral administration if they have inflammatory bowel disease (see section "Special precautions").

The therapeutic trough (minimum) serum vancomycin level is generally 10–20 mg/L, depending on the site of infection and pathogen susceptibility. Clinical laboratories usually recommend trough values of 15–20 mg/L to better cover organisms classified as susceptible with an MIC ≥ 1 mg/L (see sections "Pharmacodynamics" and "Special precautions").

Model-based methods may be useful for predicting individual dose requirements to achieve adequate AUC. Model-based approaches 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 administration

Reconstitute the contents of a 500 mg vial in 10 mL or a 1 g vial in 20 mL of water for injections.

For intravenous use, the reconstituted solution should be diluted immediately after preparation. After dilution, the solution in vials remains stable for 24 hours when stored refrigerated at 2 °C to 8 °C.

Further dilution is required: to a solution containing 500 mg or 1 g of vancomycin, add at least 100 mL or 200 mL of 0.9% sodium chloride injection or 5% glucose injection, respectively.

The resulting solution remains stable for 96 hours when refrigerated at 2 °C to 8 °C.

From a microbiological standpoint, the solution should ideally be administered immediately after dilution. The final concentration of the prepared vancomycin solution should not exceed 5 mg/mL. Aqueous vancomycin solution may also be diluted with the following infusion solutions:

• 5% glucose injection and 0.9% sodium chloride injection mixture;
• lactated Ringer's solution;
• lactated Ringer's solution and 5% glucose injection;
• acetated Ringer's solution.

Vancomycin solutions prepared with the above-mentioned diluents may be stored refrigerated at 2 °C to 8 °C for up to 8 hours. Before administration, ensure that no precipitate or color change is present.

The medicinal product should be administered by continuous intravenous infusion over 60 minutes.

Oral administration

The contents of parenteral vials may be used. Each dose can be dissolved in 30 mL of water and given orally or administered via a nasogastric tube.

To improve palatability, standard flavoring syrups may be added to the solution at the time of administration.

Children

The medicinal product may be used in children immediately after birth.

Overdose

Supportive therapy with maintenance of glomerular filtration is recommended. Vancomycin is poorly removed from blood by hemodialysis or peritoneal dialysis. Hemoperfusion using Amberlite XAD-4 resin has been reported to have limited benefit.

Adverse Reactions.

Short description of safety profile

The most commonly reported adverse reactions are phlebitis, pseudoallergic reactions, and redness of the upper part of the body ("red man syndrome").

Vancomycin absorption from the gastrointestinal tract is negligible. However, in cases of severe intestinal mucosal inflammation, especially in combination with renal impairment, adverse reactions associated with parenteral administration of vancomycin may occur.

Severe skin reactions (SCARs) have been reported, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis. All adverse reactions are listed by system organ classes and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders:
Rare: transient neutropenia, agranulocytosis, thrombocytopenia, eosinophilia, pancytopenia.

Immune system disorders:
Rare: anaphylactic reactions, hypersensitivity reactions.

Ear and labyrinth disorders:
Rare: tinnitus, vertigo, dizziness; uncommon: temporary or permanent hearing loss.

Cardiac disorders:
Common: arterial hypotension; rare: vasculitis; very rare: cardiac arrest.

Respiratory, thoracic and mediastinal disorders:
Common: stridor, dyspnea.

Gastrointestinal disorders:
Rare: nausea; very rare: pseudomembranous colitis; frequency not known: vomiting, diarrhea.

Skin and subcutaneous tissue disorders:
Common: redness of the upper part of the body ("red man syndrome"), pruritus, urticaria, exanthema, mucosal inflammation; very rare: Stevens-Johnson syndrome, exfoliative dermatitis, IgA bullous dermatitis, toxic epidermal necrolysis; frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), AGEP (acute generalized exanthematous pustulosis).

Renal and urinary disorders:
Common: renal failure, predominantly manifested by increased serum creatinine and serum urea levels; rare: interstitial nephritis, acute renal failure; frequency not known: acute tubular necrosis.

General disorders and administration site conditions:
Common: phlebitis, redness of the upper body and face.
Rare: drug fever, chills, chest and back muscle pain and spasms, tremor.

Description of selected adverse reactions to vancomycin

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

Anaphylactic/anaphylactoid reactions, including wheezing, may occur during or shortly after rapid infusion. These reactions subside after discontinuation of the infusion, usually within 20 minutes to 2 hours. Vancomycin should be administered slowly (see sections "Special precautions" and "Method of administration and dosage"). Necrosis may occur after intramuscular injection.

Tinnitus, which may precede hearing loss, should be considered an indication to discontinue treatment.

Ototoxicity has mainly been reported in patients receiving high doses, those receiving concomitant ototoxic agents such as aminoglycosides, or those with pre-existing renal impairment or hearing loss.

Paediatric patients

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

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and 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. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach and sight of children.

Incompatibilities.

Vancomycin solution (prepared by dissolving the powder in sterile water for injection and subsequent dilution with 0.9% sodium chloride solution or 5% glucose solution) has a low pH, which may lead to physical or chemical instability when mixed with other components. Vancomycin solutions should not be mixed with other solutions unless compatibility has been established.

Simultaneous use and mixing of vancomycin solutions with chloramphenicol, corticosteroids, methicillin, heparin, aminophylline, cephalosporin antibiotics, and phenobarbital is not recommended.

Packaging.

500 mg of powder in a vial; 1 or 10 vials per cardboard box.

1000 mg of powder in a vial; 1 or 10 vials per cardboard box.

Prescription status. Prescription only.

Manufacturer.

LABORATORIO REY HUELFER, S.A.

Manufacturer's address and site of operation.

C/Gran Capitan, 10, Sant Joan Despi, Barcelona, 08970, Spain.