Vibativ lyophilizate.zii, 750 mg

Telavancin is a semi-synthetic antibacterial drug of the lipoglycopeptide group with concentration-dependent bactericidal action against sensitive Gram-positive bacteria. Telavancin inhibits cell wall biosynthesis by binding to late-stage peptidoglycan precursors, including lipid II. Telavancin also binds to the bacterial membrane, disrupting its barrier function.

Telavancin has been shown to be active against most strains of the following Gram-positive microorganisms both in vitro and in therapy for infections caused by Staphylococcus aureus (including methicillin-resistant strains), Enterococcus faecalis (vancomycin sensitive strains only), Streptococcus agalactiae, Streptococcus anginosus group (including S. anginosus, S. intermedius and S. constellatus), Streptococcus pyogenes. According to the results of in vitro studies, postantibiotic effect of telavancin lasts from 1 to 6 hours.

For more than 90% of Gram-positive microorganisms such as Enterococcus faecium (vancomycin-sensitive isolates only), Staphylococcus haemolyticus, Streptococcus equisimilis, Staphylococcus epidermidis, minimum suppressive concentration (MSC) levels were below or equivalent to the sensitivity threshold to telavancin of related species in in vitro studies. The clinical efficacy of telavancin in the treatment of infections caused by these microorganisms has not been studied.

Some vancomycin-resistant strains of Enterococcus spp. are characterized by reduced sensitivity to telavancin under in vitro conditions.

Telavancin is active only against Gram-positive bacteria. In suspected or detected mixed infections caused by Gram-negative and/or certain types of anaerobic bacteria, telavancin should be used in combination with other appropriate antibacterial agents.

Indications

Telavancin is indicated for the treatment of:

Active ingredient

Composition

How to take, the dosage

The drug telavancin is administered by IV drip. Due to the lack of clinical data on co-administration of telavancin with other drugs for IV administration, other drugs should not be added to the bottle with the drug or administered simultaneously through the same infusion system. If the same infusion system is used for subsequent administration of other drugs, it should be flushed with 5% dextrose solution or 0.9% sodium chloride solution, or Ringer-lactate solution.

Preparation of the infusion solution

The solutions are prepared observing the rules of asepsis!

The drug is reconstituted and diluted to the desired concentration before use.

Reconstitution

The contents of the bottle are added to 45 ml of 5% sterile dextrose d/I solution, sterile d/I water or 0.9% sodium chloride d/I solution.

In order to reduce foaming when preparing the solution the solvent should be slowly injected from the syringe into the bottle with the drug due to the suction pressure of the vacuum in the bottle. Do not force the solvent into the vial. Do not shake the solution bottle.

It usually takes less than 2 min (rarely up to 20 min) to dissolve the drug. The solution should be carefully checked for any undissolved residue. If the tightness of the vial has been compromised (as evidenced by the lack of suction pressure when injecting the solvent), the vial should not be used.

The recovery results in a solution with a telavancine concentration of 15 mg/ml (total volume approximately 50 ml).

Preparing the solution for infusion

The following formula can be used to calculate the volume of the reconstituted telavancin solution:

The dose of telavancin (mg)=10 mg/kg (or 7.5 mg/kg)× patient body weight (in kg)

Volume of reconstituted solution (ml)= dose of telavancin (mg)/15 mg/ml

When using telavancin in doses of 150 to 800 mg, the required volume of diluent for pre-dilution before administration is 100 to 250 ml. Doses less than 150 mg or greater than 800 mg must be diluted to achieve a final concentration of 0.6 to 8 mg/mL.

Avoid shaking the solution when diluting it!

Only a clear solution should be injected. The duration of infusion of a single dose of the drug should be at least 60 minutes.

The reconstituted solution in the vial should be stored for no more than 4 hours at room temperature (15 to 25°C) or no more than 72 hours in the refrigerator at 2 to 8°C.

The diluted (dosed) drug in infusion bags should be stored for no more than 4 hours at room temperature (15 to 25°C) or for no more than 72 hours in the refrigerator at 2 to 8°C.

Please note that the total storage time in the vial and infusion bag should not exceed 4 h at room temperature and 72 h in the refrigerator at 2 to 8°C.

The vial is single-use. Unused contents of the bottle must be disposed of.

How to use

In adults the drug is prescribed in a dose of 10 mg/kg by infusion for at least 60 minutes every 24 hours. A dose adjustment is required in patients with impaired renal function (see Table 2).

The duration of treatment depends on the severity of the disease and its clinical and bacteriological course. On the basis of clinical studies the following duration of therapy with telavancin is recommended:

Table 2. Dose adjustment of telavancin in patients with impaired renal function.

Interaction

The pharmacokinetics of telavancin was not significantly altered by concomitant administration of aztreonam or piperacillin+tazobactam in studies on healthy volunteers. In addition, telavancin has no effect on the pharmacokinetics of aztreonam or piperacillin+tazobactam. Based on pharmacokinetic data, no interactions with other beta-lactams, clindamycin, metronidazole or fluoroquinolones are expected.

Telavancin had no effect on the pharmacokinetics of midazolam (for intravenous administration), which is a sensitive substrate for the CYP3A4 isoenzyme. In in vitro experiments it was shown that telavancin does not affect the pharmacokinetics of drugs metabolized by CYP1A2, 2C9, 2C19 and 2D6 isoenzymes. No significant interactions of telavancin with inhibitors or inducers of CYP450 isoenzyme system are expected.

Telavancin may affect the validity of tests used to monitor the clotting system when the tests are performed using samples collected between 0 and 18 h after administration of telavancin when administered to patients administered once every 24 h. Blood samples for coagulation tests should be collected if possible before the next dose of telavancin or use a test that is not affected by telavancin (see Table 3).

Table 3. Potential effects of telavancin on coagulation tests

Special Instructions

In patients with moderate to severe renal impairment (CK ≤50 ml/min) treated with telavancin for nosocomial (hospital-acquired) pneumonia, including ventilator-associated pneumonia, an increased risk of legal outcome has been noted in clinical trials compared to patients receiving vancomycin therapy. The possibility of using telavancin in patients with moderate and severe renal dysfunction (CK ≤50 ml/min) should be considered only if the expected benefits of treatment exceed the potential risk to the patient. For this reason, the use of telavancin in patients with pre-existing acute renal failure and terminal renal failure is contraindicated.

In patients with moderate to severe renal insufficiency and CKR ≤50 ml/min, a decrease in the effectiveness of telavancin therapy compared to vancomycin has been noted. The degree of renal impairment should be considered when selecting antibiotic therapy in this patient population.

Nephrotoxicity: cases of newly detected renal dysfunction and progression of existing renal dysfunction have been observed. In all patients taking telavancin, renal function (serum creatinine concentration and urine excretion rate) should be monitored at least daily for the first 3-5 days of therapy and then every 48-72 hours. Initial dose and dosing regimen adjustment should be determined on the basis of estimated or measured CK. If renal function decreased significantly during treatment, the appropriateness of continuing telavancin should be evaluated.

For routine monitoring of renal function, serum creatinine concentration or calculated CK is recommended.

General abnormalities and disorders at the site of administration. During therapy with telavancin, reactions at the site of administration are possible. Rapid IV administration of antimicrobial drugs of the glycopeptide class may result in “red man syndrome” type reactions, including upper body flushes, urticaria, itching, or rash. Stopping or slowing down the infusion leads to resolution of the reaction. To reduce the likelihood of infusion reactions, the drug should be administered for at least 1 hour.

Hypersensitivity reactions. Serious, sometimes fatal, hypersensitivity reactions, including anaphylactic reactions, may develop after the first or subsequent doses of telavancin. Telavancin should be discontinued if a skin rash or other signs of a hypersensitivity reaction develop. Telavancin is a semi-synthetic vancomycin derivative, and it is unknown how patients with hypersensitivity to vancomycin will react to telavancin administration. Therefore, telavancin should be used with caution in patients with known vancomycin hypersensitivity.

Longening of the QT interval. Clinical studies of the effect of telavancin on the QT interval compared with solvent and moxifloxacin (400 mg) showed that administration of the drug at doses of 7.5 mg/kg and 15 mg/kg for 3 days resulted in an increase in QT with F (adjusted by the Friederick formula) of 4.1 and 4.5 ms, respectively, compared to 9.2 ms (for moxifloxacin). Caution should be exercised when using telavancin to treat patients taking drugs for which the effects of QT interval prolongation are known. In addition, telavancin should be used with caution to treat patients with congenital QT interval prolongation syndrome, known QT interval prolongation, uncompensated heart failure or severe left ventricular hypertrophy. Patients with these conditions have not been included in clinical trials of telavancin.

Like other glycopeptides, telavancin may have toxic effects on the hearing organs. Patients who show signs of hearing or vestibular impairment during telavancin treatment should be monitored closely. Patients taking telavancin in combination with or after the use of other medications with known ototoxic potential should be monitored closely, and the appropriateness of telavancin should be evaluated if hearing deteriorates.

Colitis caused by Clostridium difficile: Diarrhea caused by Clostridium difficile (pseudomembranous colitis) may develop when using the drug, both at the foyer of administration and 2-3 weeks after stopping treatment. It may appear in different forms from mild diarrhea to severe pseudomembranous colitis. If diarrhea develops, a careful diagnosis and assessment of the relationship to treatment should be made. In mild cases, withdrawal of treatment is sufficient; in severe cases, fluid, electrolyte and protein replacement and drug therapy are indicated. Drugs that inhibit intestinal peristalsis should not be used.

Impact on coagulogram: the use of telavancin affects a number of coagulogram parameters, including prothrombin time, INR and ACTV. No increased risk of bleeding has been observed in clinical trials. Telavancin has no effect on platelet aggregation. Moreover, no hypercoagulation was observed; normal levels of D-dimer and fibrin degradation products were observed in healthy volunteers taking telavancin.

Telavancin affects the results of qualitative urine protein determination methods using test strips (e.g., based on the use of pyrogallol red-molybdate). And the results of the urine microalbuminuria tests are independent of the drug being tested and can be used to monitor proteinuria during treatment.

The co-administration of antibiotic therapy. Telavancin acts only on Gram-positive bacteria. In polymicrobial infections where Gram-negative and/or certain types of anaerobic microorganisms are suspected, telavancin should be used together with other antibacterial drugs active against these pathogens.

Particular patient groups

Women of childbearing age

A serum pregnancy test should be performed before starting treatment with telavancin.

Elderly patients

There are no clinically significant age-related differences in the pharmacokinetics of telavancin. Thus, no dose adjustment is required in elderly patients except those with CK ≤50 mL/min.

Gender differences

There are no clinically significant gender-related differences in the pharmacokinetics of telavancin.

Impact on ability to drive vehicles, machinery

Special studies of the effect of telavancin on the ability to drive vehicles, machinery have not been conducted. Dizziness, drowsiness, mental confusion and blurred vision may occur when using the drug, which may affect the ability to operate vehicles and machinery.

Contraindications

Side effects

The most commonly reported adverse drug-related adverse reactions (occurring in >1% of patients) were fungal infections, insomnia, dysgeusia, headache, dizziness, nausea, constipation, diarrhea, vomiting, increased alanine aminotransferase activity, increased aspartataminotransferase activity, itching. rash, acute renal failure, increased blood creatinine concentration, urinary abnormalities (frothy urine), fatigue, and chills.

The incidence of unwanted adverse reactions, according to the WHO recommendation, was defined as follows: Very frequent (≥1/10); frequent (≥1/100-< 1/10); infrequent (≥1/1000-< 1/100); rare (≥1/10000-< 1/1000); very rare (< 1/10 000); frequency unknown (cannot be estimated from available data).

Infectious and parasitic diseases: frequent – fungal infections; infrequent – pseudomembranous colitis, urinary tract infections.

Blood and lymphatic system disorders: infrequent – anemia, leukopenia, thrombocythemia, thrombocytopenia, eosinophilia, neutrophil leukocytosis.

Immune system disorders: infrequent – hypersensitivity; frequency unknown – anaphylaxis.

Disorders of metabolism and nutrition: infrequent – decreased appetite, hyperglycemia, hyperkalemia, hypoglycemia, hypokalemia, hypomagnesemia.

Mental disorders: frequent – insomnia; infrequent – agitation, anxiety, confusion, depression.

Nervous system disorders: very frequent – dysgeusia; frequent – headache, dizziness; infrequent – agueusia, migraine, paresthesia, parasmia, somnolence, tremor.

Visual disorders: infrequent – eye irritation, blurred vision.

Hearing and labyrinth disorders: infrequent – tinnitus; rare – deafness.

Cardiac disorders: infrequent – angina pectoris, atrial fibrillation, bradycardia, chronic heart failure, prolonged QT interval, palpitations, sinus tachycardia, supraventricular extrasystole, ventricular extrasystole.

Vascular disorders: infrequent – hyperemia, increased BP, decreased BP, phlebitis.

Respiratory system, thoracic and mediastinal disorders: infrequent – dyspnea, hiccups, nasal congestion, pain in the pharyngeal area.

Gastrointestinal disorders: very common – nausea; common – constipation, diarrhea, vomiting; infrequent – abdominal pain, dry mouth, dyspepsia, flatulence, decreased sensitivity of the oral mucosa.

Liver and biliary tract disorders: infrequent – hepatitis.

Skin and subcutaneous tissue disorders: frequent – itching, rash; infrequent – erythema, facial edema, hyperhidrosis, urticaria.

Muscular and connective tissue disorders: infrequent – joint pain, back pain, muscle cramps, muscle pain.

Kidney and urinary tract disorders: frequent – acute renal failure, frothy urine; infrequent – oliguria, pollakiuria, impaired renal function, change in urine odor.

General and injection site disorders: frequent – fatigue, chills; infrequent – asthenia, injection site reactions, malaise, non-cardiac chest pain, peripheral edema, pain, pyrexia, “red man” syndrome.

Laboratory and instrumental data: frequent – increased alanine aminotransferase activity, increased aspartate aminotransferase activity, increased blood creatinine concentration; infrequent – increased blood urea concentration, hematuria, microalbuminuria, increased INR.

Overdose

In healthy volunteers receiving telavancin at a dose of 15 mg/kg, adverse reactions such as dysgeusia, nausea, vomiting, redness at the injection site, headache, macular rash and “red man” syndrome were observed with higher frequency.

In case of overdose, the use of telavancin should be discontinued and maintenance treatment to maintain glomerular filtration accompanied by monitoring of renal function should be prescribed.

In patients with end-stage renal failure, after a single dose of 7.5 mg/kg of telavancin, approximately 5.9% of the administered telavancin dose was excreted into the dialysate after 4 hours of hemodialysis. However, there is no information on the efficacy of hemodialysis in overdose.

The clearance of telavancin by continuous venovenous hemofiltration (CVH) was evaluated in an in vitro study. Telavancin was excreted by NVH, and telavancin clearance increased with increasing ultrafiltration rate. However, the effect of NVH on telavancin clearance has not been evaluated in clinical studies; therefore, the clinical relevance of these data and the possibility of using NVH in overdose are unknown.