Vancomycin

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

Composition:

Active substance: vancomycin;

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

Excipients: sodium hydroxide, hydrochloric acid, water for injections.

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physicochemical properties:

Lyophilized powder or mass of white to yellow-brown color.

Pharmacotherapeutic group.

Antibacterials for systemic use. Glycopeptide antibiotics.

ATC code J01XA01.

Pharmacological properties.

Pharmacodynamics.

Vancomycin is a tricyclic glycopeptide antibiotic derived from Amycolatopsis orientalis, effective against many gram-positive microorganisms. The bactericidal action of vancomycin results from inhibition of bacterial cell wall synthesis by interfering with peptidoglycan polymerization and selective inhibition of bacterial RNA synthesis. Cross-resistance between vancomycin and other antibiotics does not occur. Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria, or fungi.

The combination of vancomycin and an aminoglycoside acts synergistically in vitro against many strains of Staphylococcus aureus, Streptococcus bovis, enterococci, and viridans group streptococci.

Vancomycin has been shown to be effective against most strains of the following microorganisms, both in vitro and in clinical infections, as described in the section "Dosage and administration".

Aerobic gram-positive microorganisms

Diphtheroids
Enterococci (e.g., Enterococcus faecalis)
Staphylococci, including Staphylococcus aureus and Staphylococcus epidermidis (including heterogeneous methicillin-resistant strains)
Streptococcus bovis
Streptococci of the viridans group

The following in vitro susceptibility data are available, but their clinical significance is unknown.

Vancomycin demonstrated in vitro MIC (minimum inhibitory concentration) values of 1 µg/mL or less against most (≥ 90%) of the following streptococcal strains, and MIC values of 4 µg/mL or less against most (≥ 90%) of the other listed microorganisms; however, the safety and efficacy of vancomycin in treating clinical infections caused by these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms

Listeria monocytogenes

Streptococcus pyogenes

Streptococcus pneumoniae (including penicillin-resistant strains)

Streptococcus agalactiae

Anaerobic gram-positive microorganisms

Actinomyces species

Lactobacillus species

Pharmacokinetics.

Vancomycin is poorly absorbed after oral administration.

In patients with normal renal function, multiple intravenous doses of 1 g vancomycin (15 mg/kg) administered over 60 minutes result in mean plasma concentrations of approximately 63 µg/mL immediately after completion of infusion, 23 µg/mL at 2 hours after infusion, and 8 µg/mL at 11 hours after the end of infusion. Repeated administration of 500 mg given over 30 minutes results in mean plasma concentrations of about 49 µg/mL after completion of infusion, 19 µg/mL at 2 hours after infusion, and 10 µg/mL at 6 hours after infusion. Plasma concentrations during repeated dosing are similar to those after a single dose.

The mean elimination half-life of vancomycin in plasma ranges from 4 to 6 hours in patients with normal renal function. Within the first 24 hours, approximately 75% of the administered dose of vancomycin is excreted in urine by glomerular filtration. Mean plasma clearance is approximately 0.058 L/kg/h, and mean renal clearance is about 0.048 L/kg/h. Renal dysfunction slows the elimination of vancomycin. In patients with nephrectomy, the mean elimination half-life is 7.5 days. The volume of distribution ranges from 0.3 to 0.43 L/kg. There is no apparent metabolism of the drug. Approximately 60% of an intraperitoneal dose of vancomycin administered during peritoneal dialysis is systemically absorbed within 6 hours. Serum concentrations of about 10 µg/mL are achieved after intraperitoneal injection of 30 mg/kg vancomycin.

However, the safety and efficacy of intraperitoneal administration of vancomycin have not been established in adequate and well-controlled studies (see section "Special precautions").

Total systemic and renal clearance of vancomycin may be reduced in elderly individuals.

Approximately 55% of administered vancomycin is protein-bound in plasma at serum vancomycin concentrations ranging from 10 to 100 µg/mL. After intravenous administration of vancomycin, inhibitory concentrations are present in pleural, pericardial, ascitic, and synovial fluids; in urine; in peritoneal dialysis fluid; and in atrial appendage tissue. Vancomycin does not readily diffuse through normal meninges into cerebrospinal fluid; however, when meninges are inflamed, penetration into cerebrospinal fluid occurs.

Clinical characteristics.

Indications.

• For the treatment of serious or severe infections caused by methicillin-resistant (β-lactam-resistant) staphylococcal strains.
• For the treatment of patients with allergy to penicillins and cephalosporins, including cases where other agents, including penicillins or cephalosporins, have failed to produce positive results.
• For the treatment of infections caused by vancomycin-susceptible microorganisms resistant to other antimicrobial agents.
• For the treatment of staphylococcal endocarditis caused by S. viridans or S. bovis. Vancomycin is effective against enterococcal endocarditis (e.g., E. faecalis) only in combination with aminoglycosides.
• For the treatment of diphtheroid endocarditis.
• For the treatment of early prosthetic valve endocarditis caused by S. epidermidis or diphtheroids, in combination with rifampicin, an aminoglycoside, or both agents.
• For the treatment of other staphylococcal infections, including septicemia, bone infections, lower respiratory tract infections, and skin and skin structure infections.
• For the treatment of localized purulent staphylococcal infections as an adjunct to appropriate surgical interventions.
• For the treatment of antibiotic-associated pseudomembranous colitis caused by Clostridium difficile (oral administration).

Contraindications.

Hypersensitivity to vancomycin or to any other component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

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

Renal function monitoring is recommended in patients receiving vancomycin concomitantly or sequentially with other potentially neurotoxic and/or nephrotoxic medicinal products administered systemically or locally, such as amphotericin B, aminoglycosides, bacitracin, polymyxin B, colistin, viomycin, or cisplatin (see section "Special precautions for use"). Due to synergistic effects with gentamicin, the maximum dose of vancomycin should be limited to 500 mg every 8 hours.

When vancomycin is administered during or immediately after surgery, the effect of muscle relaxants such as succinylcholine may be enhanced or prolonged. Vancomycin should not be mixed with aminophylline or fluorouracil, as the properties of vancomycin may be significantly reduced over time. The combination of vancomycin with aminoglycosides acts synergistically in vitro against Staphylococcus aureus, non-enterococcal group D streptococci, enterococci, and Streptococcus species (various species). Medicinal products that reduce gastrointestinal motility are contraindicated in pseudomembranous colitis. Cholestyramine reduces the efficacy of vancomycin.

Concomitant administration of vancomycin and piperacillin/tazobactam may lead to the development of acute renal failure.

Special precautions for use.

Infusion site reactions.

Rapid bolus administration (e.g., over several minutes) may lead to excessive arterial hypotension, including shock and, rarely, cardiac arrest. Therefore, to reduce the risk of hypotensive reactions, the patient's blood pressure should be monitored during drug administration.

Vancomycin should be administered intravenously only due to the risk of soft tissue necrosis following extravasation.

Vancomycin hydrochloride for injection should be administered as a diluted solution over not less than 60 minutes to prevent infusion-related reactions. Discontinuation of the infusion usually results in rapid resolution of these reactions. Reactions related to the rate of administration may occur at any concentration and rate of infusion and typically resolve after completion of drug administration.

Nephrotoxicity.

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

Regular monitoring of vancomycin serum concentrations is recommended when high doses are used, during prolonged treatment, in patients with impaired renal function or hearing loss, and in those receiving concomitant nephrotoxic agents (e.g., piperacillin/tazobactam) (see sections "Dosage and administration" and "Interaction with other medicinal products").

Systemic exposure to vancomycin may lead to the development of acute kidney injury (AKI). The risk of AKI increases with higher systemic exposure / serum drug concentrations. Renal function should be monitored in all patients, particularly in those with pre-existing renal impairment, comorbid conditions predisposing to renal failure, and in patients receiving concomitant nephrotoxic drugs.

Ototoxicity.

There is a risk of ototoxic effects during vancomycin therapy. Ototoxicity may be transient or permanent. It has been observed primarily in patients who received excessive doses, had pre-existing hearing impairment, or were concurrently receiving other ototoxic drugs (e.g., aminoglycosides). Vancomycin should be used with caution in patients with renal impairment due to the significantly increased risk of toxicity associated with prolonged high blood concentrations.

Dosage of vancomycin must be adjusted in patients with renal dysfunction (see section "Dosage and administration").

Severe skin adverse reactions.

During vancomycin therapy, severe adverse skin reactions have been observed, including Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be fatal (see section "Adverse reactions"). Reported skin symptoms include skin rashes, mucosal lesions, and blistering. Most such reactions occurred from several days to 8 weeks after initiation of vancomycin therapy.

Patients should be informed about the symptoms of potentially life-threatening skin reactions when vancomycin is prescribed. If signs or symptoms of such reactions occur, vancomycin should be discontinued immediately and alternative therapy considered. Vancomycin therapy should never be restarted in patients with a history of serious skin reactions to vancomycin.

Clostridioides difficile-associated diarrhea (CDAD)

Cases of Clostridioides difficile-associated diarrhea have been reported with nearly all antibacterial agents, including vancomycin. The severity of this diarrhea may range 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 should be considered in all patients who develop diarrhea following antibiotic use. Since CDAD has been reported to occur up to two months after antibiotic administration, a careful patient history should be obtained.

If CDAD is suspected or confirmed, ongoing use of 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 clinically indicated.

Ocular disorders

Vancomycin is not intended for intracameral or intravitreal administration.

Retinal hemorrhagic occlusive vasculitis

Hemorrhagic occlusive retinal vasculitis, including irreversible vision loss, has occurred in patients who received vancomycin during or after cataract surgery via intracameral or intravitreal routes. The safety and efficacy of vancomycin administered by intracameral or intravitreal routes have not been established. Vancomycin is not indicated for the prevention of endophthalmitis.

Clinically significant serum concentrations have been observed in some patients receiving multiple oral doses of vancomycin for the treatment of active pseudomembranous colitis caused by C. difficile.

Prolonged use of vancomycin may result in overgrowth of nonsusceptible microorganisms. Careful patient observation is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Pseudomembranous colitis due to C. difficile has been rarely reported in patients receiving intravenous vancomycin.

Serial hearing function tests may be useful in minimizing the risk of ototoxicity.

Reversible neutropenia has been reported in patients receiving vancomycin (see section "Adverse reactions"). Leukocyte counts should be monitored periodically in patients undergoing prolonged vancomycin therapy and in those receiving concomitant drugs known to cause neutropenia.

Vancomycin is irritating to tissues and should be administered intravenously only. Intramuscular injection or extravasation may result in pain, tenderness, and tissue necrosis. Thrombophlebitis may occur; its frequency and severity can be minimized by slow infusion of the diluted drug solution (2.5–5 g/L) and by rotating infusion sites.

The incidence of infusion-related complications (including arterial hypotension, flushing, erythema, urticaria, and pruritus) increases when vancomycin is administered concomitantly with anesthetics. Therefore, anesthesia should be initiated after completion of the slow (60-minute) vancomycin infusion.

The safety and efficacy of vancomycin administered by intrathecal (intralumbar or intraventricular) routes have not been established.

Cases have been reported where intraperitoneal administration of sterile vancomycin during continuous ambulatory peritoneal dialysis (CAPD) resulted in chemical peritonitis syndrome. This syndrome is characterized by the appearance of cloudy dialysate, which may be accompanied by abdominal pain of varying severity and fever. This syndrome is transient and resolves after discontinuation of intraperitoneal vancomycin.

Prescribing vancomycin in the absence of proven or strongly suspected bacterial infection or for prophylactic use is unlikely to benefit the patient and increases the risk of development of drug-resistant bacteria.

Children.

Therapeutic drug monitoring to confirm desired serum vancomycin concentrations is advisable in pediatric patients. Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing in children.

Geriatric patients.

The natural age-related decline in glomerular filtration rate may lead to elevated serum vancomycin concentrations if dosage adjustments are not made. Vancomycin dosage should be adjusted in elderly patients.

Liver function should be monitored, as hepatic disorders may be exacerbated during vancomycin therapy, with increases in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and, rarely, lactate dehydrogenase and gamma-glutamyl transferase levels.

Vancomycin should be used with caution in patients with allergic reactions to teicoplanin, as cross-allergic reactions have been reported. In some patients with inflammatory bowel diseases, significant systemic absorption may occur following oral vancomycin, thereby increasing the risk of adverse reactions associated with parenteral vancomycin administration. Vancomycin should be used with particular caution in premature infants due to immature renal function, which may result in elevated serum vancomycin concentrations.

Monitoring of vancomycin serum concentrations is recommended in premature neonates and infants.

Patients with burns have been observed to have higher total vancomycin clearance and therefore may require more frequent dosing with increased doses. Individualized dosing and close monitoring are recommended during treatment of such patients.

Information for patients

Patients should be informed that antibacterial agents, including vancomycin hydrochloride for injection, should be used only to treat bacterial infections and are ineffective against viral infections (e.g., the common cold). If vancomycin is prescribed for a bacterial infection, patients should be advised that although they may feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may reduce treatment effectiveness and increase the likelihood of bacterial resistance, rendering vancomycin hydrochloride for injection or other antibacterial agents ineffective in the future.

Antibiotic-associated diarrhea usually resolves after discontinuation of the antibiotic. However, patients may develop watery stools with blood (with or without abdominal cramps and fever) even up to two or more months after the last dose of antibiotic. If this occurs, patients should contact their physician immediately.

Use during pregnancy or breastfeeding

Pregnancy

Reproductive toxicity studies of vancomycin in animals have not been conducted. It is unknown whether vancomycin affects fertility.

In a controlled clinical study, the potential ototoxic and nephrotoxic effects of vancomycin on infants were evaluated when the drug was administered to pregnant women with severe staphylococcal infections associated with intravenous drug abuse. Vancomycin was detected in umbilical cord blood. No sensorineural hearing loss or nephrotoxicity related to vancomycin exposure was observed. One infant whose mother received vancomycin in the third trimester experienced conductive hearing loss, which was not attributed to vancomycin. Because the number of patients treated in this study was limited and vancomycin was administered only during the second and third trimesters, the potential for fetal harm is unknown. Vancomycin should be used during pregnancy only if clearly needed, when the potential benefit justifies the potential risk to the fetus, and serum vancomycin concentrations should be monitored.

Breastfeeding

The drug passes into breast milk. Caution should be exercised during breastfeeding. Due to the potential for adverse reactions in the nursing infant, a decision should be made whether to discontinue vancomycin or to discontinue breastfeeding, taking into account the necessity of the drug for the mother.

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.

Administration and Dosage

Vancomycin is intended for intravenous administration in the treatment of life-threatening infections. Under no circumstances should vancomycin be administered as a bolus injection or intramuscularly due to pain and the risk of tissue necrosis at the injection site.

Adverse reactions to the drug may depend on both the concentration of the solution and the rate of infusion. For adult patients, it is recommended that the concentration during administration does not exceed 5 mg/mL and the infusion rate does not exceed 10 mg/min. For selected patients in whom fluid volume must be restricted, the drug may be administered at concentrations up to 10 mg/mL, provided that the infusion rate does not exceed 10 mg/min. An infusion rate of 10 mg/min or less is associated with a lower incidence of infusion-related adverse events (see section "Adverse Reactions"). However, infusion-related adverse reactions may occur at any infusion rate or concentration.

The duration of treatment depends on the therapeutic indications for which the drug is prescribed.

Patients with normal renal function

The usual daily intravenous dose is 2 g, administered either as 500 mg every 6 hours or 1 g every 12 hours. Each dose should be administered at a rate not exceeding 10 mg/min or over a period of at least 60 minutes, whichever is longer. Other patient-specific factors such as age or presence of obesity may require modification of the standard daily intravenous dose.

Children

The usual dose of vancomycin is 10 mg/kg body weight administered every 6 hours. The solution should be infused over at least 60 minutes. Careful monitoring of serum vancomycin concentrations may be warranted in these patients.

Neonates

The maximum daily dose may need to be reduced.

Neonates under 7 days of age: initial dose is 15 mg/kg body weight, followed by 10 mg/kg body weight every 12 hours.

Neonates aged 7 days to 1 month: initial dose is 15 mg/kg body weight, followed by 10 mg/kg body weight every 8 hours. Each dose should be administered over 60 minutes.

Premature infants: vancomycin clearance is reduced in premature infants, which may necessitate longer dosing intervals. Dose reduction may be required due to impaired renal function. Careful monitoring of serum vancomycin concentrations is recommended in these patients.

Patients with impaired renal function and elderly patients

Dosage adjustment is required for patients with impaired renal function. A greater dose reduction than expected may be necessary in premature neonates and elderly patients due to reduced renal function.

Monitoring of serum vancomycin concentrations may be useful in optimizing therapy, especially in critically ill patients with renal impairment. Serum vancomycin concentrations can be determined using microbiological assays, radioimmunoassay, fluorescence polarization immunoassay, fluorescence immunoassay, or high-performance liquid chromatography.

If creatinine clearance can be measured or accurately estimated, dosing for most patients with renal insufficiency can be calculated using the table below. The daily vancomycin dose in mg is approximately 15 times the glomerular filtration rate in mL/min. Dosage should be adjusted according to creatinine clearance as shown in Table 1.

Table 1

Creatinine clearance (ml/min)	Vancomycin dose (mg/day)
100	1545
90	1390
80	1235
70	1080
60	925
50	770
40	620
30	465
20	310
10	155

The initial dose of the drug should be 15 mg/kg of body weight, including for patients with mild to moderate renal insufficiency.

The table does not apply to the treatment of patients with a single functioning kidney. In such cases, the initial dose of vancomycin 15 mg/kg body weight should be administered until the therapeutic serum concentration is achieved. The maintenance dose is 1.9 mg/kg/day. For patients with severe renal insufficiency, it is recommended to administer 250–1000 mg of the drug once daily with several days' interval. In anuria, the recommended dose is 1000 mg every 7–10 days.

When the serum creatinine concentration is known, the following formula (taking into account the patient's gender, body weight, and age) should be used to determine creatinine clearance. However, to obtain an accurate value, creatinine clearance should be measured directly.

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

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

Serum creatinine should be measured under conditions of stable renal function. Otherwise, the calculated creatinine clearance value may be inaccurate. The calculated clearance is an overestimation of the actual clearance in patients in the following conditions: (1) characterized by reduced renal function, such as shock, severe heart failure, or oliguria; (2) in which the normal relationship between muscle mass and total body weight is absent, for example in patients with obesity, liver disease, edema, or ascites; (3) conditions associated with cachexia, malnutrition, or immobility.

The safety and efficacy of intrathecal (intralumbar or intraventricular) administration of vancomycin have not been established. The recommended route of vancomycin administration is intermittent infusion.

Intravenous administration

For use, dissolve the contents of the vancomycin hydrochloride for injection vial in sterile water for injection to a vancomycin concentration of 50 mg/mL (see Table 2).

Table 2

Vancomycin nominal content in the vial	Solvent volume
500 mg	10 ml
1000 mg	20 ml

Reconstituted solution should be stored at 2–8 °C for up to 96 hours.

The reconstituted solution requires further dilution: to the solution containing 500 mg in 10 ml, add 100 ml of one of the infusion fluids listed below; to the solution containing 1000 mg in 20 ml, add 200 ml of one of the infusion fluids listed below. The required dose, thus diluted, should be administered by intermittent intravenous infusion over at least 60 minutes.

From a microbiological standpoint, the solution should preferably be used immediately after dilution. The final concentration of the prepared vancomycin solution must not exceed 5 mg/ml.

Compatibility with intravenous fluids

The reconstituted vancomycin solution may be diluted with the following infusion fluids:

• 5 % glucose injection solution;
• 5 % glucose injection solution and 0.9 % sodium chloride injection solution;
• Ringer’s lactate injection solution;
• Ringer’s lactate injection solution and 5 % glucose injection solution;
• 0.9 % sodium chloride injection solution.

Prior to administration, ensure that the solution is clear, colorless, and free from particulate matter.

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

Vancomycin solution has a low pH and may cause chemical or physical instability of other compounds when mixed.

Vancomycin and beta-lactam antibiotics have been shown to be physically incompatible. The likelihood of precipitation increases with increasing vancomycin concentration. It is recommended to thoroughly 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, cases of precipitation have been reported after intravitreal administration of vancomycin and ceftazidime for the treatment of endophthalmitis using separate syringes and needles. The precipitates gradually dissolved with complete clearance of the vitreous over two months and improvement in visual acuity.

Oral administration

Vancomycin is poorly absorbed after oral administration; therefore, it can be administered orally only for the treatment of Clostridium difficile-associated pseudomembranous colitis. Vancomycin is not effective when administered orally for the treatment of other types of infections.

Adults: The usual daily dose is 500 mg to 2000 mg, divided into 3–4 doses, administered over 7–10 days. The maximum daily dose should not exceed 2 g.

Children: The usual daily dose is 40 mg/kg body weight, divided into 3–4 doses, administered over 7–10 days. The maximum daily dose should not exceed 2 g.

The oral solution is prepared by adding approximately 30 ml of water to the contents of a 500 mg vancomycin vial. To improve palatability, a sweet syrup with flavoring agents may be added to the solution.

The resulting solution may be administered orally or via a nasogastric tube.

Children

The medicinal product may be used in children from birth.

Overdose

Symptoms: Overdose is characterized by an intensification of adverse reactions.

Treatment: Management should focus on maintaining adequate glomerular filtration.

Vancomycin is poorly removed by dialysis.

Hemofiltration and hemoperfusion using polysulfone resin have been shown to increase vancomycin clearance. The average lethal dose following intravenous administration is 319 mg/kg in rats and 400 mg/kg in mice.

In managing overdose, potential overdoses of multiple medicinal products, their interactions, and individual patient pharmacokinetic characteristics should be considered.

Adverse reactions.

During or immediately after rapid administration of the medicinal product, anaphylactic reactions (arterial hypotension, dyspnea, shortness of breath, urticaria or pruritus) and cardiac disorders (heart failure, up to cardiac arrest) may occur in rare cases. Rapid administration of the medicinal product may also cause flushing of the upper body or pain and muscle spasms in the chest and back. These reactions usually resolve within 20 minutes but may persist for several hours. Such reactions occur almost exclusively when the drug is administered rapidly and are rarely observed when the drug is infused slowly over 60 minutes.

Blood and lymphatic system disorders: reversible neutropenia (usually beginning 1 week or later after initiation of vancomycin therapy or after receiving a cumulative dose exceeding 25 g), agranulocytosis, thrombocytopenia, eosinophilia.

Cardiovascular system disorders: heart failure, arterial hypotension, phlebitis, vasculitis, cardiac arrest (these reactions are primarily associated with rapid infusion of the medicinal product).

Respiratory system disorders: dyspnea, shortness of breath.

Gastrointestinal disorders: nausea, vomiting, diarrhea, abdominal pain, pseudomembranous colitis; symptoms may appear both during and after completion of therapy.

Cases of chemical peritonitis have been reported following intraperitoneal administration of the drug (see section "Special precautions for use").

Skin and subcutaneous tissue disorders: pruritus, urticaria, exanthema, Stevens-Johnson syndrome, exfoliative dermatitis, IgA-dermatitis, toxic epidermal necrolysis (very rare).

Severe skin reactions have been observed in patients during vancomycin therapy, including Stevens-Johnson syndrome, toxic epidermal necrolysis (very rare), drug reaction with eosinophilia and systemic symptoms (DRESS), which may be fatal (see section "Special precautions for use").

Auditory and vestibular disorders: tinnitus, hearing loss, vertigo. Ototoxic effects have been most frequently observed when the drug is used at high doses or concomitantly with other ototoxic agents, as well as in patients with impaired renal function or pre-existing hearing damage.

Immune system disorders: anaphylactoid reaction (infusion-related reaction), hypersensitivity reactions, anaphylactoid shock (infusion-related reaction).

Laboratory test abnormalities: increased serum creatinine levels, increased serum urea levels, elevated AST, ALT, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyltransferase, bilirubin, leucine aminopeptidase.

Nervous system disorders: dizziness, paresthesia.

Renal and urinary disorders: interstitial nephritis*, azotemia, acute renal failure.

*Renal function impairment (usually accompanied by increased serum creatinine or serum blood urea nitrogen levels) may occur, primarily after administration of high doses of the drug. Interstitial nephritis is rare. These adverse reactions are mostly observed in patients who have received concomitant aminoglycosides with vancomycin or have a history of renal dysfunction. Azotemia resolves in nearly all patients upon discontinuation of vancomycin therapy.

General disorders and administration site conditions: drug fever, chills, injection site reactions including pain, inflammation, irritation, tissue necrosis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), lacrimation, mucosal inflammation.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national pharmacovigilance system.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging, protected from light, at a temperature not exceeding 25 °C.

Keep out of reach of children.

The reconstituted solution should be stored at 2–8 °C for up to 96 hours.

Incompatibilities.

Mixtures of vancomycin and beta-lactam antibiotics have been shown to be physically incompatible. The likelihood of precipitate formation increases with higher vancomycin concentrations. It is recommended to thoroughly flush infusion systems between administration of these antibiotics. It is also recommended to dilute vancomycin solutions to a concentration of 5 mg/mL or less.

The diluted vancomycin solution has a low pH value, 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.

Concomitant use and mixing of vancomycin solutions with chloramphenicol, corticosteroids, barbiturates, benzylpenicillins, chlorothiazide, dexamethasone, methicillin, heparin, aminophylline, sodium bicarbonate, nitrofurantoin, neomycin, phenytoin, sulfadiazine, sulfafurazole diethanolamine, cephalosporin antibiotics, and phenobarbital is not recommended.

Packaging.

500 mg or 1000 mg of lyophilisate in a glass vial stoppered with a rubber plug and sealed with an aluminum crimp cap and a "flip-off" cap.

1 or 10 vials per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Hainan Poly Pharm Co., Ltd.

Manufacturer's address and place of business.

Guilinyan Economic Development Area, Meilan District, Haikou, Hainan 571127, China.