Vancomycin vocate

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VANCOCIN VOCATE (VANCOMYCIN VOCATE)

Composition:

Active substance: vancomycin;

One 500 mg vial contains vancomycin hydrochloride equivalent to 500 mg of vancomycin;

One 1000 mg vial contains vancomycin hydrochloride equivalent to 1000 mg of vancomycin.

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: white or almost white or pink porous mass.

Pharmacotherapeutic group.

Antibacterials for systemic use. Glycopeptide antibiotics. Vancomycin. ATC code J01XA01.

Agents affecting the digestive system and metabolism. Antibiotics. Vancomycin.

ATC code A07AA09.

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 exerts a slow bactericidal effect on dividing microorganisms. In addition, it disrupts bacterial cell membrane permeability and RNA synthesis.

Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship

Vancomycin exhibits 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 data, as well as limited human data, an AUC/MIC ratio of 400 has been established as the target PK/PD index 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 "Dosage and Administration").

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. Increasing rates of resistance, particularly among enterococci, have been reported in some countries; multi-resistant strains of Enterococcus faecium are of particular concern.

van genes are rarely found in Staphylococcus aureus, where structural changes in the cell wall lead to intermediate susceptibility, which is often 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 does not occur. Cross-resistance with other glycopeptide antibiotics, such as teicoplanin, may still be present. 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 strains of Staphylococcus epidermidis, and the combination of vancomycin with rifampicin shows synergistic activity against Staphylococcus epidermidis and partial synergy against certain strains of Staphylococcus aureus. Since vancomycin in combination with cephalosporins may also have an antagonistic effect against some strains of Staphylococcus epidermidis, and in combination with rifampicin against certain strains of Staphylococcus aureus, preliminary testing for synergy is advisable.

Bacterial cultures should be obtained to isolate and identify pathogens and determine their susceptibility to vancomycin.

Breakpoints in Susceptibility Testing

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

	Susceptible	Resistant
Staphylococcus aureus1	≤ 2 mg/L	> 2 mg/L
Coagulase-negative staphylococci1	≤ 4 mg/L	> 4 mg/L
Enterococcus species (Enterococcus spp.)	≤ 4 mg/L	> 4 mg/L
Streptococcus species (Streptococcus spp.) groups A, B, C and G	≤ 2 mg/L	> 2 mg/L
Streptococcus pneumoniae	≤ 2 mg/L	> 2 mg/L
Gram-positive anaerobes	≤ 2 mg/L	> 2 mg/L

1 S. aureus with MIC values for vancomycin of 2 mg/l are at the wild-type distribution boundary, and a deterioration in clinical response may be observed.

Commonly susceptible species

Gram-positive: Enterococcus faecalis Staphylococcus aureus Methicillin-resistant Staphylococcus aureus Coagulase-negative staphylococci Streptococcus spp. Streptococcus pneumoniae Enterococcus spp. Staphylococcus spp. Anaerobic species: Clostridioides spp., except Clostridioides innocuum Eubacterium spp. Peptostreptococcus spp.

Species that may develop resistance

Enterococcus faecium

Species with intrinsic resistance

All Gram-negative bacteria Gram-positive aerobic species: Erysipelothrix rhusiopathiae Heterofermentative Lactobacillus Leuconostoc spp. Pediococcus spp. Anaerobic species: Clostridioides innocuum

Vancomycin resistance varies between hospitals, so local microbiological laboratories should be consulted for relevant local information.

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 the end of infusion, respectively. Plasma levels achieved after multiple doses are similar to those attained 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 penetrates the blood-brain barrier only to a limited extent.

Biotransformation

Metabolism of vancomycin is minimal. After parenteral administration, the drug is excreted almost entirely in microbiologically active form (approximately 75–90% within 24 hours) via the kidneys by glomerular filtration.

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 by glomerular filtration. Impaired renal function delays the elimination of vancomycin. In anephric patients, the mean elimination half-life is 7.5 days. Due to the ototoxic potential of vancomycin, monitoring of plasma concentrations during therapy is recommended in such cases.

Biliary excretion is negligible (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 detected in urine. In contrast, 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.

Special patient populations

Patients with impaired renal function. Vancomycin is primarily eliminated by 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 calculated 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. The distribution of vancomycin may be altered in patients with excess body weight due to an increased volume of distribution, increased renal clearance, and potential changes in plasma protein binding. In this subpopulation, serum vancomycin concentrations were 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 Vocate is indicated in all age groups for the treatment of the following infections (see also sections "Method of administration and dosage", "Special instructions" and "Pharmacological properties"):

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

Vancomycin Vocate is also indicated in all age groups for perioperative antibacterial prophylaxis in cases of high risk of developing bacterial endocarditis during major surgical procedures.

Oral administration

Vancomycin Vocate is indicated in all age groups for the treatment of Clostridioides difficile infections (see also sections "Method of administration and dosage", "Special instructions" and "Pharmacological properties").

In addition, official recommendations regarding appropriate use of antibacterial agents should be taken into account.

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 use of vancomycin and anesthetics has been associated with erythema, histamine-like flushing, and anaphylactoid reactions (see section "Special instructions").

Increased frequency of infusion-related adverse reactions has been reported with concomitant use of anesthetics. Infusion-related reactions can be minimized by administering vancomycin as a 60-minute infusion prior to administration of anesthetics. When administered during anesthesia, doses should be diluted to 5 mg/mL or less and infused slowly with careful monitoring of cardiac function. Patient repositioning should be delayed until infusion is complete.

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, piperacillin/tazobactam, loop diuretics, and non-steroidal anti-inflammatory drugs (NSAIDs), may increase vancomycin toxicity. Caution and appropriate monitoring are required in such cases (see section "Special instructions").

Combination of vancomycin with an aminoglycoside antibiotic has a synergistic effect against many strains of Staphylococcus aureus, non-enterococcal D-streptococci, enterococci, and Viridans group streptococci.

Combination of vancomycin with rifampicin has a synergistic effect against Staphylococcus epidermidis.

Oral administration: Consideration should be given to discontinuing proton pump inhibitors and motility-inhibiting agents in accordance with local guidelines for Clostridioides difficile infection.

Special precautions for use

Hypersensitivity reactions

Serious and sometimes fatal hypersensitivity reactions may occur (see sections "Contraindications" and "Side effects"). If hypersensitivity reactions occur, 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 white blood cell counts is recommended. All patients receiving vancomycin should undergo periodic blood, urine, liver, and kidney function tests.

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

Antibacterial spectrum

The antibacterial spectrum of vancomycin is limited to Gram-positive microorganisms. Vancomycin should not be used as a single agent for the treatment of certain types of infections, except when the causative organism has already been identified and is known to be susceptible to vancomycin, or when there is a high probability that the likely pathogen is susceptible to vancomycin.

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

Ototoxicity

Ototoxicity, both temporary and irreversible, has been reported in patients with pre-existing hearing loss who received excessive intravenous doses or who were concurrently treated with other ototoxic agents such as aminoglycosides (see section "Side effects"). Vancomycin should also be avoided in patients with pre-existing hearing loss. Tinnitus may precede hearing loss. Experience with other antibiotics indicates that deafness may progress despite discontinuation of therapy. To reduce the risk of ototoxicity, serum vancomycin levels should be monitored periodically and hearing function should be regularly assessed.

Elderly patients are particularly susceptible to hearing damage. Monitoring of vestibular and auditory function in elderly patients should be performed during and after treatment. 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 rash. Rapid intravenous infusion of vancomycin hydrochloride for injection may also be associated with an infusion reaction characterized by pruritus and erythema affecting the face, neck, and upper part of the trunk ("red man syndrome" or "red man syndrome"). Vancomycin should be administered slowly in a 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.

Side effects related to administration depend on both the concentration and the rate of vancomycin infusion. However, infusion-related side effects may occur at any infusion rate or concentration.

The frequency of infusion-related reactions (hypotension, flushing, erythema, urticaria, and pruritus) increases with concomitant use of anesthetics (see section "Interaction with other medicinal products and other forms of interaction"). This risk can be reduced by administering vancomycin via infusion over at least 60 minutes prior to anesthesia induction.

Severe skin adverse reactions

Severe skin adverse reactions (SSARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), have been reported during vancomycin therapy. These reactions may be life-threatening or fatal (see section "Side effects"). Most of these reactions occurred from several days to eight weeks after initiation of vancomycin therapy.

Patients should be informed of the signs and symptoms, and skin reactions should be closely monitored. If symptoms suggestive of these reactions occur, vancomycin should be discontinued immediately and alternative therapy considered. If a patient develops SSARs during vancomycin therapy, vancomycin treatment must never be resumed.

Reactions at the site of administration

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 a diluted solution (see section "Method of administration and dosage") and by regularly changing the infusion site.

The efficacy and safety of vancomycin administered intrathecally, intralumbally, or intraventricularly 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 high serum concentrations are sustained for prolonged periods. The risk of toxicity increases with high serum concentrations or prolonged treatment.

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

Visual disturbances

Intracameral or intravitreal administration of vancomycin, including for the prophylaxis of endophthalmitis, is not permitted.

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

Clostridioides difficile-associated diarrhea

Cases of Clostridioides difficile-associated diarrhea (CDAD) have been reported with the use of nearly all antibacterial agents, including vancomycin. This diarrhea may range in severity from mild diarrhea to fatal colitis. Antibacterial therapy alters the normal gut flora, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxigenic strains of C. difficile are associated with increased morbidity and mortality, as these infections may be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who develop diarrhea after antibiotic use. Since CDAD may occur up to two months after administration of antibacterial agents, a careful patient history should be obtained.

If CDAD is suspected or confirmed, antibiotics not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, treatment of C. difficile with antibiotics, and surgical evaluation should be initiated as appropriate based on the clinical presentation.

Children

Recommended intravenous doses for children, especially those under 12 years of age, may not achieve therapeutic vancomycin levels in a significant number of children. However, the safety of increasing the vancomycin dose has not been adequately evaluated, and doses above 60 mg/kg/day are generally not recommended.

Vancomycin should be used with particular caution in premature neonates and young children (from 1 month (28 days) to 23 months) due to immature renal function and the potential for increased serum vancomycin concentrations. Serum vancomycin concentrations should be closely monitored in these children.

Concomitant administration of vancomycin and anesthetics has been associated with erythema and histamine-like hyperemia 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"); therefore, more frequent monitoring of serum vancomycin levels and renal function is required.

Elderly patients

The natural age-related decline in glomerular filtration rate may lead to increased 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 well diluted and administered slowly with careful monitoring of cardiac function. Position changes should be delayed until after completion of the infusion (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 "Side effects"). Antidiarrheal agents should not be administered.

Superinfection

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

Oral administration

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

Testing for Clostridioides difficile colonization or toxin is not recommended in children under 1 year of age due to a high rate 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 Clostridioides 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 Clostridioides difficile. These patients are at increased 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 diseases.

Nephrotoxicity

Sequential monitoring of renal function should be performed in patients with impaired renal function 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 ototoxic agents such as aminoglycosides.

Interaction with motility inhibitors and proton pump inhibitors

Motility-inhibiting agents should be avoided, and the use of proton pump inhibitors should be reviewed.

Development of drug-resistant bacteria

Oral use of vancomycin increases the likelihood of developing vancomycin-resistant enterococci in the gastrointestinal tract. Therefore, cautious use of oral vancomycin is recommended.

Use during pregnancy or breastfeeding

Pregnancy

Teratogenicity studies in animals (rats and rabbits) receiving doses of vancomycin 5 and 3 times, respectively, higher than human doses showed no evidence of fetal harm.

In a controlled clinical study, potential ototoxic and nephrotoxic effects of vancomycin hydrochloride on infants were evaluated when the drug was administered to pregnant women for serious staphylococcal infections. Vancomycin hydrochloride was detected in umbilical cord blood. No sensorineural hearing loss or vancomycin-related nephrotoxicity 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 harms the fetus. Vancomycin should be administered during pregnancy only if clearly needed, and serum drug levels should be carefully monitored to minimize the risk of toxic effects on the fetus. However, it has been reported that pregnant patients may require significantly higher doses of vancomycin to achieve therapeutic serum concentrations.

Breastfeeding

Vancomycin hydrochloride is excreted in breast milk. Vancomycin should be used with caution in breastfeeding women. The amount of vancomycin that may pass into the infant via breast milk is considered negligible.

Ability to affect reaction speed when driving 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 should 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 (do not exceed 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 trough serum concentration of vancomycin.

Children aged 1 month to 12 years

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

Term newborns (from birth to 27 days) and preterm newborns (from birth to expected delivery date plus 27 days)

To establish a dosing regimen for newborns, advice should be sought from a physician experienced in treating newborns. An example of vancomycin dosing for newborns is provided in the table below (see also section "Special Instructions").

PMA (weeks)	Dose (mg/kg)	Administration interval (h)
< 29	15	24
29–35	15	12
> 35	15	8

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.

Duration of treatment

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

Indications	Treatment duration
Complicated skin and soft tissue infections without necrosis with necrosis
	7–14 days 4–6 weeks*
Bone and joint infections	4–6 weeks**
Community-acquired pneumonia	7–14 days
Hospital-acquired pneumonia, including ventilator-associated pneumonia	7–14 days
Infective endocarditis	4–6 weeks***

*Continue until there is no further need for wound management and until the patient shows clinical improvement. Discontinue if the patient continues to have fever for 48–72 hours.

** In prosthetic joint infections, consider the possibility of longer courses of oral suppressive therapy.

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

Special patient groups

Elderly patients

Due to age-related decline in renal function, lower maintenance doses may be required.

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 various factors that may influence vancomycin levels.

In patients with mild or moderate renal impairment, the initial dose should not be reduced. 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").

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 after an intermittent hemodialysis session).

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

Men: [weight (kg) × (140 – age (years))] / (72 × serum creatinine (mg/dL))

Women: 0.85 × value calculated by the above formula

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. For patients with severe renal impairment (creatinine clearance <20 mL/min) or those receiving renal replacement therapy, dosing and the number of subsequent doses largely depend on the type of renal replacement therapy (RRT) and should be based on trough serum vancomycin levels and residual renal function (see section "Special precautions"). Depending on the clinical situation, subsequent doses may be withheld until serum vancomycin concentration results are available.

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

Children. Dose adjustment in children aged 1 year and older may be based on estimated glomerular filtration rate (GFR) using the 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)

Expert consultation should be sought when treating children under 1 year of age, as the Schwartz formula does not apply to this age group.

The table below provides dosing recommendations for children, which follow the same principles as those for adult patients.

eGFR (mL/min/1.73 m2)	Intravenous dose	Frequency
50–30	15 mg/kg	12 hours
29–10	15 mg/kg	24 hours
< 10	10–15 mg/kg	Repeat doses according to vancomycin levels*
Intermittent hemodialysis
Peritoneal dialysis
Continuous renal replacement therapy	15 mg/kg	Repeat doses according to vancomycin levels*

* The dosing and number of subsequent doses largely depend on the method of RRT and should be based on serum vancomycin levels and residual renal function. Depending on the clinical situation, the next dose may not be administered until serum vancomycin concentration 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 individually adjusted according to total body weight, as in patients without obesity.

Oral administration

Patients aged 12 years and older

Treatment of Clostridioides difficile infection (CDI): the recommended dose of vancomycin is 125 mg every 6 hours for 10 days for the 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.

For patients with multiple recurrences, treatment of the current CDI episode may include 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 every 6 hours for 10 days. The maximum daily dose should not exceed 2 g.

The duration of vancomycin treatment may be adjusted according to the individual clinical course of CDI. Antibacterial agents likely to have caused CDI should be discontinued if possible. Adequate fluid and electrolyte replacement should be ensured.

Monitoring of serum vancomycin concentrations

The frequency of therapeutic drug monitoring (TDM) should be individualized and depend on the clinical situation and response to treatment: from daily sampling, which may be required in certain hemodynamically unstable patients, to at least once weekly in stable patients showing response to therapy. 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 prior to the start of a hemodialysis session.

Following oral administration, serum vancomycin concentrations should be monitored in patients with inflammatory bowel disease (see section "Special precautions").

The trough serum vancomycin level should generally be maintained between 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 pathogens classified as susceptible with MIC > 1 mg/L (see sections "Special precautions" and "Pharmacological properties").

Methods based on modeling may be used to determine individualized dosing to achieve adequate AUC. This approach may be used both for calculating the initial dose and for dose adjustment based on TDM results (see section "Pharmacological properties").

Method of administration

Intravenous administration

This medicinal product must be reconstituted and diluted before intravenous administration.

Vancomycin is typically administered intravenously as an intermittent infusion, and the dosing recommendations for intravenous administration provided in this section correspond to this route.

Vancomycin should be administered only by slow intravenous infusion over at least one hour or at a maximum rate of 10 mg/min (whichever is longer). The solution should be sufficiently diluted (at least 100 mL per 500 mg or at least 200 mL per 1000 mg). See also section "Special precautions".

Patients requiring fluid restriction may receive a solution of 500 mg / 50 mL or 1000 mg / 100 mL, although the risk of infusion-related adverse effects increases with higher concentrations.

Preparation of reconstituted solution

Add 20 mL of water for injections to the vial containing the lyophilized powder. This will yield a solution of 50 mg/mL. After reconstitution, a clear solution is formed.

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

Intermittent infusion is the preferred method of administration. Reconstituted solutions containing 1 g of vancomycin hydrochloride should be further diluted in at least 200 mL of 0.9% sodium chloride for intravenous infusion or 5% dextrose for intravenous infusion. The desired dose should be administered by intravenous infusion over at least 60 minutes. Rapid administration or 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). One to two vials (1–2 g) may be added to a sufficiently large volume of 0.9% sodium chloride for intravenous infusion or 5% dextrose for intravenous infusion so that the desired daily dose can be administered slowly via intravenous infusion over 24 hours.

Recommended concentrations should not exceed 5 mg/mL. For individual 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.

After reconstitution and dilution with 0.9% sodium chloride for intravenous infusion or 5% dextrose for intravenous infusion, the osmolarity of the reconstituted and diluted solution is approximately 270 mOsm/kg, and the pH ranges from 2.5 to 4.5.

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

Reconstituted solution for intravenous administration: chemical and physical stability has been demonstrated for 24 hours at 2–8°C.

From a microbiological standpoint, the solution should be used immediately. If not used immediately, the responsibility for storage conditions and duration lies with the user.

Oral solution: chemical and physical stability has been demonstrated for 96 hours at 2–8°C.

Oral administration

The medicinal product may be administered orally.

The dose should be dissolved in 30 mL of water and given to the patient to drink or administered via a nasogastric tube.

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

Children

Vancomycin Vocate may be used in children from 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

Summary of safety profile

The most commonly reported adverse reactions are phlebitis, pseudoallergic reactions, and redness of the upper body (so-called "red man syndrome") associated with too rapid intravenous infusion of vancomycin.

Parenteral formulations for oral use: absorption of vancomycin from the gastrointestinal tract is negligible. However, in cases of severe inflammation of the intestinal mucosa, especially in combination with renal impairment, adverse reactions associated with parenteral administration of vancomycin may occur.

Serious skin adverse reactions (SSARs) have been reported with vancomycin treatment, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (see section "Special Warnings and Precautions for Use").

List of adverse reactions

The adverse reactions listed below are categorized by organ systems according to MedDRA [Medical Dictionary for Regulatory Activities]. The frequency of adverse reactions is classified as follows: 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), frequency not known (cannot be estimated from the available data). Within each frequency group, adverse effects are listed in order of decreasing severity.

Frequency	Adverse reaction
Blood and lymphatic system disorders
Isolated	Reversible neutropenia1, agranulocytosis, eosinophilia, thrombocytopenia, pancytopenia
Immune system disorders
Isolated	Hypersensitivity reactions, anaphylactic reactions2, including anaphylaxis, vancomycin infusion reaction5
Ear and labyrinth disorders
Uncommon	Temporary or irreversible hearing loss4
Isolated	Vertigo, tinnitus3, dizziness
Cardiac disorders
Rare	Cardiac arrest
Vascular disorders
Common	Decreased blood pressure
Isolated	Vasculitis
Respiratory, thoracic and mediastinal disorders
Common	Dyspnea, stridor
Gastrointestinal disorders
Isolated	Nausea
Rare	Pseudomembranous enterocolitis
Frequency unknown	Vomiting, diarrhea
Skin and subcutaneous tissue disorders
Common	Upper body flushing ("red man syndrome"), exanthema and mucosal inflammation, pruritus, urticaria
Rare	Exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), linear IgA bullous dermatosis
Frequency unknown	Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis
Renal and urinary disorders
Common	Renal failure – predominantly manifested by increased serum creatinine and serum urea
Isolated	Interstitial nephritis, acute renal failure
Frequency unknown	Acute tubular necrosis
General disorders and administration site conditions
Common	Phlebitis, redness of upper body and face
Isolated	Drug fever, chills, chest and back muscle pain and spasms

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

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

3 Tinnitus, which may precede onset of deafness, should be considered an indication for discontinuation of therapy.

4 Ototoxicity has mainly been observed in patients receiving high doses, or those receiving other ototoxic agents such as aminoglycosides concomitantly, as well as in patients who already had impaired renal function or hearing.

5 Reaction occurred during clinical trials.

Children

The safety profile is generally similar in pediatric, adolescent, and adult patients. Nephrotoxicity has been described in children, usually when vancomycin was administered concomitantly with other nephrotoxic agents such as aminoglycosides.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, 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 reach and sight of children.

Incompatibility

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 a concentration of 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 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. 1 or 10 vials with powder in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Laboratorios Reig Jofre S.A., Spain.

Manufacturer's address and location of manufacturing site.

Calle Gran Capità 10, Sant Joan Despí, 08970, Spain.

Marketing Authorization Holder.

Pharmaceutical Company "Vocate S.A.", Greece.

Address of the Marketing Authorization Holder.

150 Athinas Street, Glyfada 16674, Athens, Greece.