Vancomycin-Teva (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Human Serum Production And Medicine Manufacturing, Co. Ltd. (Hungary)

ATC Code

J01XA01 (Vancomycin)

Active Substance

Vancomycin (Rec.INN registered by WHO)

Dosage Forms

	Vancomycin-Teva	Lyophilisate for preparation of solution for infusion 1 g: vial 1 pc.
		Lyophilisate for preparation of solution for infusion 500 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion as an almost white (with a pinkish or light brown tint) powder.

Excipients: hydrochloric acid or sodium hydroxide (to pH 3.2-3.3), nitrogen, water for injections.

Vials (1) – cardboard packs.

Lyophilisate for preparation of solution for infusion as an almost white (with a pinkish or light brown tint) powder.

Excipients: hydrochloric acid or sodium hydroxide (to pH 3.2-3.3), nitrogen, water for injections.

Vials (1) – cardboard packs.

Clinical-Pharmacological Group

Antibiotic of the glycopeptide group

Pharmacotherapeutic Group

Antibiotic-glycopeptide

Pharmacological Action

Vancomycin is a tricyclic glycopeptide antibiotic isolated from Amycolatopsis orientalis.

The bactericidal action of vancomycin results from the inhibition of cell wall biosynthesis. Furthermore, Vancomycin may alter the permeability of the bacterial cell membrane and alter RNA synthesis. There is no cross-resistance between vancomycin and antibiotics of other classes.

In vitro, Vancomycin exhibits activity against gram-positive microorganisms, including: Staphylococcus aureus and Staphylococcus epidermidis (including heterogeneous methicillin-resistant strains), Streptococcus pyogenes, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus agalactiae, the viridans group, Streptococcus bovis and enterococci (e.g., Enterococcus faecalis); Clostridium difficile (e.g., toxigenic strains involved in the development of pseudomembranous enterocolitis) and diphtheroids.

Other microorganisms susceptible to vancomycin in vitro include Listeria monocytogenes, bacteria of the genera Lactobacillus, Actinomyces, Clostridium and Bacillus.

In vitro, some isolated strains of enterococci and staphylococci exhibit resistance to vancomycin. The combination of vancomycin and aminoglycosides acts synergistically in vitro against many strains of Staphylococcus aureus, non-enterococcal group D streptococci, enterococci and bacteria of the Streptococcus group (viridans group).

Vancomycin is inactive in vitro against gram-negative microorganisms, mycobacteria and fungi.

Pharmacokinetics

In individuals with normal renal function, multiple intravenous administrations of 1 g of vancomycin (15 mg/kg) (infusion over 60 min) produced mean plasma concentrations of about 63 mg/l immediately after completion of the infusions; 2 hours after the infusions, mean plasma concentrations were about 23 mg/l, and 11 hours after the infusions – about 8 mg/l.

Multiple infusions of 500 mg administered over 30 min produced mean plasma concentrations of about 49 mg/l after completion of the infusions; 2 hours after the infusions, mean plasma concentrations were about 19 mg/l, and 6 hours later – about 10 mg/l. Plasma concentrations with multiple administration are similar to plasma concentrations with single administration.

The mean plasma T_1/2 of vancomycin is 4-6 hours in patients with normal renal function. About 75% of the administered dose of vancomycin is excreted in the urine via glomerular filtration within the first 24 hours. The mean plasma clearance is about 0.058 L/kg/h, and the mean renal clearance is about 0.048 L/kg/h.

The renal clearance of vancomycin is fairly constant and accounts for 70-80% of its elimination. V_d ranges from 0.3 to 0.43 L/kg. The drug is practically not metabolized. As ultrafiltration has shown, at vancomycin serum concentrations from 10 mg/L to 100 mg/L, 55% of vancomycin is found in a protein-bound state.

After intravenous administration, vancomycin hydrochloride is found in pleural, pericardial, ascitic, synovial fluids and in atrial appendage tissue, as well as in urine and peritoneal fluid at concentrations that inhibit microbial growth. Vancomycin slowly penetrates into the cerebrospinal fluid. In meningitis, penetration of the drug into the cerebrospinal fluid is noted. Vancomycin crosses the placental barrier and into breast milk.

Impaired renal function slows the excretion of vancomycin. In patients with absent kidneys, the mean T_1/2 is 7.5 days. The total systemic and renal clearance of vancomycin may be reduced in elderly patients due to the natural slowing of glomerular filtration.

Indications

• Endocarditis;

Vancomycin is effective both as monotherapy and in combination with aminoglycosides for the treatment of endocarditis caused by Streptococcus viridans or S. bovis. In endocarditis caused by enterococci (e.g., E. faecalis), Vancomycin is effective only in combination with aminoglycosides.

There is evidence that Vancomycin is effective in the treatment of diphtheroid endocarditis. Vancomycin has been successfully used in combination with rifampicin, aminoglycosides, or both antibiotics for early endocarditis due to S. epidermidis or diphtheroids after valve replacement.

In certain cases, Vancomycin is indicated for the prophylaxis of endocarditis.

• Sepsis;
• Bone and joint infections;
• Lower respiratory tract infections;
• Skin and soft tissue infections;

Vancomycin may also be used for infections caused by gram-positive microorganisms in cases of: penicillin allergy; intolerance or lack of response to treatment with other antibiotics, including penicillins or cephalosporins; infections caused by microorganisms sensitive to vancomycin but resistant to other antimicrobial drugs.

• Pseudomembranous colitis (as an oral solution).

ICD codes

Dosage Regimen

When administering vancomycin, the recommended concentration is no more than 5 mg/ml and the infusion rate is no more than 10 mg/min. In patients requiring fluid restriction, a concentration of up to 10 mg/ml and an infusion rate not exceeding 10 mg/min may be used. However, with such concentrations, the likelihood of developing infusion-related adverse events increases.

Adults

The dose for patients with normal renal function is 2 g IV (500 mg every 6 hours or 1 g every 12 hours). Each dose should be administered at a rate not exceeding 10 mg/min and over a period of at least 60 minutes. The patient’s age and the presence of obesity may require adjustment of the usual dose based on the determination of vancomycin serum concentrations.

Children

The usual dose is 10 mg/kg administered IV every 6 hours. Each dose should be administered over at least 60 minutes.

Infants and Newborns

For newborns, the initial dose should be 15 mg/kg, then 10 mg/kg every 12 hours during the first week of life. Starting from the second week of life – every 8 hours until one month of age. Each dose should be administered over at least 60 minutes.

Patients with Impaired Renal Function and Elderly Patients

The dose must be individually selected for patients with impaired renal function. The serum creatinine level can be used to select the vancomycin dose for this group of patients. In elderly patients, Vancomycin has lower clearance and a larger volume of distribution. In this group, dose selection should be based on vancomycin serum concentrations. In premature infants and elderly patients, a significant dose reduction may be required due to reduced renal function. Vancomycin serum concentrations should be monitored regularly. The table below shows vancomycin doses depending on creatinine clearance.

Vancomycin dosing table for patients with impaired renal function

This table cannot be used to determine the drug dose in anuria. Such patients should be prescribed an initial dose of 15 mg/kg of body weight to rapidly achieve therapeutic serum concentrations of the drug. The dose required to maintain a stable drug concentration is 1.9 mg/kg/24 h. For patients with severe renal failure, it is advisable to administer maintenance doses of 250-1000 mg once every few days (with CC 10-50 ml/min – 1 g every 3-7 days, less than 10 ml/min – 1 g every 7-14 days). In anuria, a dose of 1 g every 7-10 days is recommended.

Instructions for preparation of solution for intravenous administration

The injection solution is prepared immediately before administration of the drug. To do this, the required volume of water for injections is added to the vial with dry, sterile vancomycin powder to obtain a solution with a concentration of 50 mg/ml. Further dilution of the prepared solution is required.

Prepared vancomycin solutions must be further diluted to a concentration not exceeding 5 mg/ml before administration. The required dose of vancomycin, diluted as described above, should be administered by fractional intravenous infusions over at least 60 minutes. 5% dextrose injection solution or 0.9% sodium chloride injection solution can be used as solvents. Before injection, the prepared solution for parenteral administration should be visually inspected, if possible, for the presence of mechanical impurities and color change.

Adverse Reactions

Body as a whole: anaphylactoid reactions.

Cardiovascular system: cardiac arrest; flushing; decreased BP, shock (these symptoms are mainly associated with rapid infusion of the drug).

Gastrointestinal tract: nausea; pseudomembranous colitis.

Blood system: agranulocytosis; eosinophilia; neutropenia; thrombocytopenia.

Effect on kidneys: interstitial nephritis; changes in renal function tests; impaired renal function.

Skin: exfoliative dermatitis; hypersensitivity reactions; benign (IgA) bullous dermatosis; pruritic dermatosis; rash; red man syndrome; Stevens-Johnson syndrome; toxic epidermal necrolysis; urticaria; vasculitis.

Sensory organs: vertigo, tinnitus, ototoxic effects. Ototoxic effects have been observed in a number of patients receiving Vancomycin. It may be transient or permanent. It is reported that most such cases were observed among patients who received excessive doses of vancomycin, had a history of hearing loss, or in patients receiving concurrent treatment with other drugs with potential ototoxicity, such as aminoglycosides.

Other: chills; drug fever; tissue necrosis at injection sites; pain at injection sites; thrombophlebitis.

During or shortly after too rapid infusion of vancomycin, patients may develop anaphylactoid reactions. Rapid administration of the drug can also cause red man syndrome, redness of the upper body, or pain and muscle spasm in the chest and back. After stopping the infusion, these reactions usually resolve within 20 minutes, but can sometimes last for several hours.

Contraindications

• Pregnancy (1st trimester);
• Lactation period;
• Acoustic neuritis;
• Renal failure;
• Hypersensitivity to vancomycin.

Use with caution in hearing impairment (including history), during pregnancy (II and III trimester).

Use in Pregnancy and Lactation

Use in the II-III trimester of pregnancy is possible only for vital indications.

Use in Renal Impairment

Vancomycin should be used with caution in patients with renal failure (it is advisable to determine vancomycin serum concentrations in renal failure in patients over 60 years of age), since high, prolonged blood concentrations of the drug may increase the risk of toxic effects (peak concentrations should not exceed 40 µg/ml, and trough concentrations should not exceed 10 µg/ml, concentrations above 80 µg/ml are considered toxic). For patients with renal failure, vancomycin doses should be individually selected.

Pediatric Use

The usual dose is 10 mg/kg administered IV every 6 hours. Each dose should be administered over at least 60 minutes.

For newborns, the initial dose should be 15 mg/kg, then 10 mg/kg every 12 hours during the first week of life. Starting from the second week of life – every 8 hours until one month of age. Each dose should be administered over at least 60 minutes.

Geriatric Use

In elderly patients, Vancomycin has lower clearance and a larger volume of distribution. In this group, dose selection should be based on vancomycin serum concentrations. In elderly patients, a significant dose reduction may be required due to reduced renal function.

Special Precautions

When prescribing to newborns, monitoring of serum concentrations is desirable.

Rapid administration (e.g., over a few minutes) of vancomycin may be accompanied by a marked decrease in BP and, in rare cases, cardiac arrest. Vancomycin should be administered as a diluted solution over at least 60 minutes to avoid infusion-related adverse reactions.

Vancomycin should be prescribed with caution to patients allergic to teicoplanin, as cases of cross-allergy have been reported.

Patients receiving Vancomycin IV should periodically have blood tests and renal function monitoring.

Vancomycin should be used with caution in patients with renal failure (it is advisable to determine vancomycin serum concentrations in renal failure in patients over 60 years of age), since high, prolonged blood concentrations of the drug may increase the risk of toxic effects (peak concentrations should not exceed 40 µg/ml, and trough concentrations should not exceed 10 µg/ml, concentrations above 80 µg/ml are considered toxic). For patients with renal failure, vancomycin doses should be individually selected.

Vancomycin is an “irritating” agent and therefore diffusion of the dissolved drug through the vascular wall can cause necrosis of adjacent tissues. Thrombophlebitis may occur, although the likelihood of its development can be reduced by slow administration of diluted solutions (2.5-5 g/L) and rotation of the injection sites.

Overdose

Symptoms: increased severity of adverse reactions.

Treatment: corrective therapy aimed at maintaining glomerular filtration. Vancomycin is poorly removed by dialysis. There is evidence that hemofiltration and hemoperfusion through a polysulfone ion-exchange resin leads to an increase in vancomycin clearance.

Drug Interactions

With simultaneous intravenous administration of vancomycin and anesthetics, erythema, skin redness and anaphylactoid reactions have been noted, and there may be a risk of decreased BP or the development of neuromuscular blockade. Administration of vancomycin as a 60-minute infusion before anesthetic administration may reduce the likelihood of these reactions.

With simultaneous and/or sequential systemic or topical use of other potentially ototoxic and/or nephrotoxic drugs (aminoglycosides, amphotericin B, ASA or other salicylates, bacitracin, capreomycin, carmustine, paromomycin, cyclosporine, loop diuretics, polymyxin B, cisplatin, ethacrynic acid), careful monitoring for the possible development of these symptoms is required.

Colestyramine reduces activity.

Antihistamines, meclozine, phenothiazines, and thioxanthenes may mask the symptoms of vancomycin ototoxicity (tinnitus, vertigo).

Vancomycin solution has a low pH, which may cause physical or chemical instability when mixed with other solutions. Mixing with alkaline solutions should be avoided.

Solutions of Vancomycin and beta-lactam antibiotics are physically incompatible when mixed. The likelihood of precipitation increases with higher vancomycin concentrations. The intravenous system must be adequately flushed between administrations of these antibiotics. Furthermore, it is recommended to reduce the Vancomycin concentration to 5 mg/ml or less.

Storage Conditions

Store in a light-protected place at a temperature of 15°-25°C (59°-77°F). Keep out of reach of children.

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.