Vancomycin-pharmex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VANCOCIN-PHARMEK (VANCOMYCIN-PHARMEX)

Composition:

active substance: vancomycin;

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

excipients: sodium hydroxide/hydrochloric acid diluted (may be present due to the need for pH adjustment).

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physicochemical properties: lyophilized porous mass or powder ranging from almost white to light brown in color in vials. A pinkish tint is acceptable.

Pharmacotherapeutic group.

Antimicrobial agents for systemic use. Glycopeptide antibiotics.

ATC code J01X A01.

Pharmacological properties.

Pharmacodynamics.

Vancomycin is a tricyclic glycopeptide antibiotic derived from Amycolatopsis orientalis, effective against many Gram-positive microorganisms. The bactericidal action of vancomycin is due to inhibition of bacterial cell wall synthesis by suppressing peptidoglycan polymerization and selective inhibition of bacterial RNA synthesis. There is no cross-resistance between vancomycin and other antibiotics.

Vancomycin is particularly effective against: staphylococci, including Staphylococcus aureus and
S. epidermidis (including methicillin-resistant strains); streptococci, including Streptococcus pyogenes, S. agalactiae, Enterococcus faecalis (mainly Streptococcus faecalis), S. bovis, hemolytic streptococcal groups, Streptococcus pneumoniae (including penicillin-resistant strains); Clostridium difficile (including toxigenic strains causing pseudomembranous enterocolitis); corynebacteria.

In vitro, Listeria monocytogenes, Lactobacillus species, Actinomyces species, Clostridium species, and Bacillus species are susceptible to vancomycin. It is inactive in vitro against Gram-negative bacteria, fungi, and mycobacteria.

Pharmacokinetics.

After intravenous administration of 1 g of vancomycin, plasma concentration reaches 23 mg/L at 2 hours and 8 mg/L at 11 hours after completion of infusion. Approximately 55% of the administered vancomycin binds to plasma proteins. After intravenous administration, inhibitory concentrations of the drug are achieved in pleural, pericardial, ascitic, and synovial fluids, urine, peritoneal dialysate fluid, and atrial tissue. Despite poor penetration through the meninges under normal conditions, vancomycin penetrates well into cerebrospinal fluid in the presence of inflammation. Metabolism of this drug is minimal. The elimination half-life averages 4–6 hours. Within the first 24 hours, approximately 75% of the administered dose of vancomycin is excreted in urine via glomerular filtration. Elimination of vancomycin is delayed in patients with impaired renal function. For example, in patients with a removed kidney, the elimination half-life is 7.5 days.

Clinical characteristics.

Indications.

Treatment of infections caused by gram-positive microorganisms sensitive to the drug, including in patients with a history of allergy to penicillins and cephalosporins:

• endocarditis;
• sepsis;
• osteomyelitis;
• central nervous system infections;
• lower respiratory tract infections (pneumonia);
• skin and soft tissue infections;
• pseudomembranous colitis (for oral administration).

Prophylaxis of endocarditis in patients with hypersensitivity to penicillin antibiotics. Prevention of infections following surgical procedures in the oral cavity and ENT organs.

Contraindications.

Hypersensitivity to vancomycin or to any other component of the drug.

Interaction with other medicinal products and other types of interactions.

When vancomycin is administered simultaneously or sequentially with other drugs having neurotoxic and/or nephrotoxic effects, particularly gentamicin, ethacrynic acid, amphotericin B, streptomycin, neomycin, kanamycin, amikacin, tobramycin, viomycin, bacitracin, polymyxin B, colistin, and cisplatin, an increased risk of nephrotoxic and/or ototoxic effects of vancomycin may occur.

There is a risk of acute renal failure when vancomycin is used concomitantly with piperacillin/tazobactam therapy (see section "Special precautions").

Due to synergistic action with gentamicin, the maximum dose of vancomycin should be limited to 500 mg every 8 hours.

Concomitant administration of vancomycin and anesthetic agents increases the risk of hypotension and may cause erythema, histamine-like flushing, and anaphylactoid reactions.

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 preparations, as the properties of vancomycin may significantly weaken 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 intestinal peristalsis are contraindicated in pseudomembranous colitis.

Cholestyramine reduces the efficacy of vancomycin.

Special precautions for use.

Rapid administration of the drug as a bolus injection (within several minutes) may cause significant arterial hypotension, including shock, rarely with cardiac arrest. Therefore, to reduce the risk of hypotensive reactions, the patient's arterial pressure should be monitored during drug administration.

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

To prevent adverse reactions, vancomycin solution should be infused over at least 60 minutes. The risk of thrombophlebitis may be reduced by slow infusion of diluted solution (2.5–5 mg/mL) and changing the infusion site.

It should be noted that adverse reactions related to the rate of drug administration may occur at any concentration and infusion rate and usually resolve after completion of drug infusion.

Vancomycin should be used with caution in elderly patients, patients with hearing impairment, or when co-administered with other ototoxic drugs such as aminoglycosides.

During prolonged vancomycin therapy, periodic monitoring of blood and urine parameters and renal function is recommended.

Liver function should be continuously monitored, as liver disorders during vancomycin treatment may worsen due to elevated levels of bilirubin, AST, ALT, alkaline phosphatase, and, rarely, increased lactate dehydrogenase and gamma-glutamyltransferase.

The frequency of infusion-related complications (including arterial hypotension, flushing, hyperemia, urticaria, and pruritus) increases when anesthetics are co-administered; therefore, anesthesia should be initiated after completion of vancomycin infusion.

Vancomycin should be used cautiously in patients with allergic reactions to teicoplanin, as cases of cross-allergic reactions have been reported.

In some patients with inflammatory diseases of the intestinal mucosa, significant systemic absorption may occur after oral intake of vancomycin. Therefore, there is a risk of adverse reactions associated with parenteral administration of vancomycin.

Vancomycin should be used with particular caution in premature infants due to immature renal function, which may lead to increased serum vancomycin concentration.

Monitoring of vancomycin serum concentration is recommended in premature newborns and infants.

There is a risk of ototoxic effects during vancomycin therapy; therefore, the drug should be used cautiously in patients with hearing impairment or when co-administered with other ototoxic drugs such as aminoglycosides.

Prolonged use of vancomycin may lead to development of resistant microorganisms and fungi. Careful patient monitoring is essential. If superinfection (secondary infection occurring during an ongoing infectious disease) develops during therapy, appropriate measures should be taken.

Cases of pseudomembranous colitis caused by Clostridium difficile have been reported in patients receiving intravenous vancomycin.

Patients with burns have been reported to have higher total vancomycin clearance and therefore may require more frequent dosing with increased doses. Individual dose adjustment and careful monitoring are recommended when administering vancomycin to such patients.

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, which may be life-threatening or fatal, have been reported in association with vancomycin therapy.

Most of these reactions occurred within several days to eight weeks after initiation of vancomycin treatment. Patients should be informed about signs and symptoms of these reactions, and skin reactions should be closely monitored during vancomycin therapy. If signs or symptoms indicating these reactions appear, vancomycin should be discontinued immediately and alternative therapy considered. Vancomycin therapy should not be resumed at any time in patients who have experienced severe skin adverse reactions associated with vancomycin.

Ocular disorders. Vancomycin is not approved for intracameral or intravitreal use, including prophylaxis of endophthalmitis. Hemorrhagic occlusive retinal vasculitis, including permanent vision loss, has been observed after intracameral or intravitreal administration of vancomycin during or following cataract surgery.

Nephrotoxicity. Vancomycin should be used cautiously in patients with renal impairment, including anuria, due to the potential for toxic effects. The risk of toxicity increases with elevated blood vancomycin concentrations or prolonged therapy. Regular monitoring of vancomycin blood levels is indicated during high-dose therapy and prolonged treatment, especially in patients with impaired renal function or hearing, and when co-administered with nephrotoxic or ototoxic agents, respectively (see section "Interaction with other medicinal products").

Use during pregnancy or breastfeeding.

There are no data on the safety of vancomycin use during pregnancy. Administration of vancomycin in the first trimester of pregnancy is contraindicated. Use during the second and third trimesters is possible only under life-threatening conditions when the expected benefit to the mother outweighs the risk to the fetus, with mandatory monitoring of vancomycin serum concentration.

The drug passes into breast milk; therefore, if its use is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed while driving or operating machinery.

During treatment with the drug, the ability to concentrate may be reduced. This should be considered 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 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. In individual patients requiring restriction of fluid volume, the drug may be administered at a concentration of up to 10 mg/mL, but the infusion rate must not exceed 10 mg/min. High concentrations of the infused drug increase the risk of adverse reactions.

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

Intravenous Administration of the Drug

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

After reconstitution, the solution in vials remains stable for 24 hours at 25 °C or for 96 hours when stored in a refrigerator at +2 °C to +8 °C.

Further dilution is required: add at least 100 mL or 200 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection, respectively, to the solution containing 500 mg or 1 g of vancomycin. The resulting solution remains stable for 48 hours when stored in a refrigerator at +2 °C to +8 °C or for 24 hours at 25 °C.

From a microbiological standpoint, the solution should ideally be administered immediately after reconstitution.

The final concentration of the prepared vancomycin solution must not exceed 5 mg/mL.

Aqueous vancomycin solution may also be diluted with the following infusion solutions:

• Lactated Ringer’s solution,
• Lactated Ringer’s solution and 5% Dextrose Injection,
• Acetated Ringer’s solution.

Vancomycin solutions prepared with the above-mentioned diluents may be stored in a refrigerator at +2 °C to +8 °C for up to 96 hours.

Before administration, ensure that no precipitate or color change is present in the diluted solution.

The drug should be administered by continuous intravenous infusion over at least 60 minutes.

Patients with Normal Renal Function

Adults: 500 mg every 6 hours or 1000 mg every 12 hours. The solution should be administered by intravenous infusion over at least 60 minutes. Maximum single dose – 1000 mg; maximum daily dose – 2 g.

Children

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

Newborns from 7 days to 1 month of age: initial dose is 15 mg/kg body weight, followed by 10 mg/kg body weight every 8 hours.

Children from 1 month of age: usual dose of vancomycin is 10 mg/kg body weight every 6 hours.

The maximum single dose for children is 15 mg/kg body weight; maximum daily dose – 2 g.

The concentration of the prepared vancomycin solution for children must not exceed 2.5–5 mg/mL. The solution should be infused over at least 60 minutes.

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

Patients with excessive body weight: standard daily dosage may require adjustment.

Patients with hepatic impairment: do not require dosage adjustment.

Patients with Renal Impairment

Dosage should be adjusted according to creatinine clearance as indicated in the table below.

When serum creatinine concentration is known, the following formula (taking into account patient’s sex, body weight, and age) should be used to estimate creatinine clearance.

The calculated creatinine clearance (mL/min) provides only an estimate; the actual creatinine clearance should be measured.

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

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

In anuria, the initial vancomycin dose of 15 mg/kg of body weight should be administered until 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 intervals of several days.

Dosing regimen during hemodialysis

For patients undergoing dialysis, the loading dose is 1000 mg, and the maintenance dose is 1000 mg of the drug every 7–10 days. When polysulfone membranes are used for hemodialysis, an increase in the maintenance dose of vancomycin is required.

Serum creatinine levels should be a consistent indicator of kidney function. Otherwise, the obtained creatinine clearance values are invalid. Monitoring of serum vancomycin concentrations is recommended when the risk of toxicity exceeds the following thresholds: 2 hours after infusion of 1 g of the drug, peak concentration ranges from 20 to 50 mg/L, and trough concentration before the next dose is 5–10 mg/L. If these thresholds are exceeded, dosage adjustment is recommended.

Oral administration

Vancomycin is poorly absorbed after oral administration; therefore, it can be administered by this route only for the treatment of pseudomembranous colitis caused by Clostridium difficile.

The oral solution is prepared by adding 30 mL of water to the contents of a 500 mg vancomycin vial. The resulting solution can be administered orally or via a nasogastric tube. To improve taste, sweet syrup with flavoring additives may be added to the solution.

Adults: The usual daily dose is 500–1000 mg, divided into 3–4 doses, for 7–10 days. The maximum daily dose should not exceed 2 g.

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

Children

The drug can be administered to children immediately after birth.

Overdose

Overdose is characterized by an intensification of adverse effects.

Treatment aimed at maintaining adequate glomerular filtration is recommended. Vancomycin is poorly eliminated by dialysis. Excess vancomycin should be removed by hemofiltration and hemodialysis using polysulfone membranes.

There is no specific antidote.

Side effects

Anaphylactic reactions (arterial hypotension, dyspnea, dyspnoea, urticaria, or pruritus), and cardiac disorders (heart failure up to cardiac arrest) may occur during or immediately after rapid administration of the drug in individual cases. Rapid infusion may also cause flushing of the upper body or chest and back muscle pain or spasms. These reactions usually resolve within 20 minutes but may persist for several hours. Such reactions are practically avoided when the drug is administered slowly over 60 minutes.

Blood and lymphatic system disorders: neutropenia*, agranulocytosis, thrombocytopenia, eosinophilia.

*Reversible neutropenia is possible. It usually begins one week or later after initiation of vancomycin therapy or after receiving a total dose of 25 g or more.

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

Respiratory system disorders: dyspnoea, dyspnea.

Gastrointestinal disorders: nausea, vomiting, diarrhea, abdominal pain, pseudomembranous colitis.

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

Ear and labyrinth disorders: tinnitus, hearing loss, vertigo.

Ototoxic effects have been most frequently observed during high-dose therapy, concomitant administration with other ototoxic drugs, or 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).

Infections and infestations: pseudomembranous colitis.

Laboratory test results: increased serum creatinine levels, increased blood urea nitrogen (BUN) levels, elevated levels of AST, ALT, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyltransferase, bilirubin, leucine aminopeptidase.

Musculoskeletal and connective tissue disorders: muscle spasms (infusion-related reaction).

Nervous system disorders: dizziness, paresthesia.

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

*Renal function impairment (usually accompanied by increased serum creatinine or serum urea nitrogen levels) may occur, primarily after administration of high doses of the drug. Interstitial nephritis is rare. Most such adverse effects have been reported in patients who received concomitant aminoglycosides with vancomycin or had a history of renal dysfunction. Azotemia resolved 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, chest and back muscle pain and spasms, overgrowth of resistant bacteria and fungi, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), lacrimation, mucosal inflammation, redness of the upper body and face.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Incompatibilities.

Vancomycin solution (prepared by dissolving the powder in sterile water for injection and further dilution with 0.9% sodium chloride solution or 5% glucose solution) has a low pH, which may cause 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, methicillin, heparin, aminophylline, cephalosporin antibiotics, and phenobarbital are not recommended.

Packaging.

500 or 1000 mg in a glass vial, 1 vial in a blister pack, 1 blister pack in a carton.

Prescription status. Prescription only.

Manufacturer.

LLC "FARMEKS GROUP".

Manufacturer's address and place of business.

100 Shevchenka Street, Boryspil, Kyiv Oblast, 08301, Ukraine.