Vibativ - instructions for use, dose, side effects, contraindications

Active substanceTelavancinTelavancin

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Vibativ

lyophilizate d / infusion

R-PHARM, CJSC Russia

Dosage form: & nbsplyophilizate for solution for infusion

Composition:

Composition on 1 bottle:

Active substance:

telavancin (in the form of telavancin hydrochloride) 750 mg

Excipients:

Hydroxypropyl betadex 7500.0 mg

mannitol 937.5 mg

Description:Powder or porous mass of white or almost white color.

Pharmacotherapeutic group:Antibiotic glycopeptide

ATX: & nbsp

J.01.X.A.03 Telavancin

Pharmacodynamics:

Telavancin is a semisynthetic antibacterial agent of the group of lipoglycopeptides, which has a concentration-dependent bactericidal action against sensitive Gram-positive bacteria. Telavancin inhibits the biosynthesis of the cell wall by binding to the precursors of the non-antidoglycan of the late stages, including lipid II. Telavancin also binds to the bacterial membrane, violating its barrier function.

It was shown that telavantine is active against most strains of the following Gram-positive microorganisms, both under conditions in vitro, and in the treatment of infections caused by Staphylococcus aureus (including methicillin-resistant strains), Enterococcus faecalis (only strains sensitive to vancomycin), Streptococcus agalactiae, Group Streptococcus anginosus (including S.anginosus, S. intermedius and S.constellatus), Streptococcus pyogenes. Based on research results in vitro, The postantibiotic effect of telavancin lasts from 1 to 6 hours.

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

Some strains Enterococcus spp., resistant to vancomycin, are characterized by reduced sensitivity to telavantine in conditions in vitro.

Telavancin is active only against gram-positive bacteria. With suspected or identified mixed infections caused by gram-negative and / or certain types of anaerobic bacteria, the drug telavantine should be used in combination with other appropriate antibacterial agents.

Pharmacokinetics:

In healthy volunteers, the pharmacokinetics of telavancin with a single intravenous injection at dose of 5-12.5 mg / kg and multiple - at dose 7.5-15 mg / kg one time at day at the course of 7 days was linear.Equilibrium concentrations were achieved on the third day of drug administration.

Mean values of pharmacokinetic parameters telavancin (with a dosage regimen of 10 mg / kg every 24 hours) after single and multiple 60-minute intravenous infusion are shown in Table 1.

Table 1

Pharmacokinetic parameters of body body the adult volunteers when administered at a dose of 10 mg / kg

	Single entry infusion (n=42)	Multiple infusion (n=36)
C_max (μg / ml)	93,6 ± 14,2	108 ±26
AUC₀-∞ (μg * h / ml)	747 ±129	-¹
AUC_0-24_h(μg * h / ml)	666±107	780± 125
t1 / 2 (h)	8,0 ± 1,5	8,1 ±1,5
Cl (ml / h / kg)	13,9 ±2,9	13,1 ±2,0
V_ss (ml / kg)	145 ±23	133 ±24

C_max- mean maximum plasma concentration

AUC - area under the pharmacokinetic curve "concentration-time"

t_1/2- half-life

FROMl - ground clearance

V_ss - apparent volume of distribution in the equilibrium state

^{1 -}no data.

Telavancin demonstrated linear pharmacokinetics in doses up to 15 mg / kg with a daily 60-minute intravenous infusion for 7 days in healthy volunteers. The mean maximum body body concentration (C_m_Oh) was up to 108 ± 26 μg / ml in the stationary state at a dose of 10 mg / kg daily once a day, administered within 1 hour (t_max) and then fell to a value of 8.55 + 2.84 μg / ml (FROM_24h). Average AUC_0-24± standard deviation was 780 ± 125 μg / h / ml.Telavancin characterized by a small amount of distribution. At a dose of 10 mg / kg, the average apparent volume of distribution (V_ss) averages 133 ± 24 ml / kg after repeated administration, corresponding to approximately 10 liters for a person with a body weight of 75 kg. These data show that telavantine not distributed extensively. Telavancin is a drug with a low clearance of 13.1 ± 2.0 ml / h / kg in patients with normal renal function, which corresponds to the general Cl approximately 1 L / h in a subject having a body weight of 75 kg. In combination with small V_ss this explains the value of the half-life (t_1/2), approximately equal to 8 hours.

Distribution: The apparent volume of distribution of telavancin in a stationary state in healthy volunteers is about 133 ml / kg.

Binding to human plasma proteins (mainly with serum albumins) is about 90%, unchanged in patients with impaired renal and hepatic function.

After administration of the drug to healthy volunteers at a dose of 10 mg / kg once a day for 3 days, the bodywassin concentration in the fluid obtained from bronchoalveolar lavage and alveolar macrophages exceeded the MIC₉₀ Staphylococcus aureus (0.5 μg / ml) for more than 24 hours after the administration of the drug.

Concentrations of bodywort in the skin in healthy volunteers after 3 days of drug administration at a dose of 7.5 mg / kg accounted for 40% of the concentration in the blood plasma.

Metabolism: None of the isoenzymes CYP 450 (CYP 1A2, 2C9, 2C19, 2D6, 3A4, 3A5, 4A11) did not demonstrate the ability to metabolize telavantine.

In the study of mass balance in male volunteers, 3 hydroxylated metabolites of telavancin were identified (predominantly THRX-651540), constituting <10% of the concentration of the drug in the urine and <2% - in the blood plasma. AUC prevailing metabolite (THRX-651540) was about 2-3% AUC telavancin.

Excretion: Renal excretion is the main way to remove telavancin. In healthy young volunteers, after infusion of telavancin, approximately 76% of the administered dose was excreted by the kidneys, and less than 1% of the dose was excreted by the intestine. Telavancin, basically, it is output in unchanged form (~ 82%). The half-life in persons with normal renal function is about 8 hours.

Since renal excretion is the main way of excretion, dose adjustment in patients with creatinine clearance (CK) of less than 50 ml / min is necessary.

Indications:

Telavancin is indicated for treatment of:

- complicated skin and soft tissue infections,

- nosocomial pneumonia (including ventilator-associated pneumonia).

Contraindications:

Hypersensitivity to telavantine or any auxiliary substance.

Acute kidney failure.

Terminal stage of renal failure.

Simultaneous intravenous administration of unfractionated heparin sodium, since activated partial thromboplastin time is prolonged from 0 to 18 hours after the administration of telavancin.

Children under 18 years.

Pregnancy.

Breastfeeding period.

Carefully:

- In case of impaired renal function:

- patients with renal insufficiency with CC less than 50 ml / min and more than 10 ml / min,

- patients receiving concomitant therapy with nephrotoxic drugs,

- patients with concomitant diseases, often accompanied by impaired renal function (diabetes mellitus, chronic heart failure, hypertension, etc.).

- Interval lengthening QT: Use the drug with caution in patients with impaired intracardiac conduction. Care must be taken when using the drug in patients taking other medicines,extension intervals QT;

- a drug telavantine should be used with caution in patients with known hypersensitivity to vancomycin.

Pregnancy and lactation:

Application of the drug telavantine contraindicated in pregnancy, as there is no clinical experience of the drug in pregnant women. In studies of embryo and fetotoxicity in animals, defects in fetal development and an increase in the frequency of premature termination of pregnancy were noted, which indicates a potential negative effect on the fetus in humans.

Presence of pregnancy in women of childbearing age is established before the beginning of the use of telavancin. Women of childbearing age should use effective methods of contraception during treatment.

It is not established whether the telavantine with breast milk. Excretion of telavancin with milk in animals has not been studied. The decision to discontinue or continue therapy with telavantine should be made taking into account the benefits of breastfeeding for the baby and the benefits of bodybuilding therapy for a woman.

Dosing and Administration:

A drug telavantine is injected intravenously.In view of the lack of clinical data on the joint use of telavancin with other drugs for intravenous administration, it is not necessary to add other medications to the vial of the drug or to inject simultaneously through one infusion system. If the same infusion system is used for subsequent administration of other drugs, it should be washed with 5% dextrose solution or 0.9% sodium chloride solution or Ringer-lactate solution.

Preparation of a solution for infusions

Solutions are prepared, observing the rules of asepsis!

Before use, the preparation is reconstituted and diluted to the required concentration.

Recovery:

45 ml of 5% sterile solution of dextrose for injection, sterile water for injection or 0.9% solution of sodium chloride for injection are added to the contents of the vial.

To reduce foaming during solution preparation, slow Introduce the solvent from the syringe into the vial with the drug due to the suction pressure of the vacuum in the vial. Do not force the solvent into the bottle. Do not shake the vial with solution.

To dissolve the drug, it usually takes less than 2 minutes (in rare cases, up to 20 minutes). You should carefully check the solution for the absence of undissolved residue. If the tightness of the bottle was broken (as evidenced by the lack of suction pressure when introducing a solvent into it), such a bottle can not be used.

As a result of the reduction, a solution with a body-vanadium concentration of 15 mg / ml is obtained (total volume of approximately 50 ml).

Preparation of solution for infusion:

To calculate the volume of the reconstituted solution of telavancin, the following formula can be used:

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

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

When using telavancin in a dose of 150 to 800 mg, the required volume of diluent for preliminary dilution before administration is 100 to 250 ml. Doses less than 150 mg or more than 800 mg should be diluted to a final concentration of 0.6 to 8 mg / ml.

Avoid shaking the solution while diluting it!

You can only enter transparent solution. The duration of infusion of one 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 not more than 72 hours - in a refrigerator at a temperature of 2 to 8 ° C.

Diluted (dosed) drug in packets for infusions should be stored no more than 4 hours at room temperature (15 to 25 ° C) or ns more than 72 hours - in the refrigerator at a temperature of 2 to 8 ° C.

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

The bottle is disposable. Dispose of unused contents of the vial.

Mode of application

For adults, the drug is given at a dose of 10 mg / kg by intravenous infusion lasting at least 60 minutes every 24 hours. In patients with impaired renal function, dose adjustment is required (see Table 2).

The duration of treatment depends on the severity of the disease, its clinical and bacteriological course. Based on the clinical studies conducted, the following duration of therapy with telavantine is recommended:

- Complicated skin and soft tissue infections - from 7 to 14 days;

- Nosocomial pneumonia (including ventilator-associated pneumonia) - The duration of therapy is from 7 to 21 days.

Table 2. Dose adjustment telavantine in patients with impaired renal function.

Creatinine clearance (ml / min) *	Dosage regimen of the drug telavantzin
>50	10 mg / kg every 24 hours
30-50	7.5 mg / kg every 24 hours
10-30	K) mg / kg every 48 hours

* Calculated using the Cockcroft-Gault formula and ideal body weight. Use the indicator of actual body weight and the case if it is less than ideal.

At present, there is insufficient data for recommendations on the dosage of the drug in patients with creatinine clearance less than 10 ml / min, including those on hemodialysis.

Side effects:

The most frequently reported adverse reactions associated with taking the drug (which occurred in> 1% of patients) were fungal infections.

insomnia, dysgeusia, headache, dizziness, nausea, constipation, diarrhea, vomiting, increased activity of alanine aminotransferase, increased activity of aspartate aminotransferase, pruritus, rash, acute renal insufficiency, increased creatinine concentration in the blood, urine deviations (foamy urine), fatigue and chills.

The incidence of adverse reactions, as recommended by WHO. was defined as follows: very frequent (≥1/10), frequent (≥1/100 - <1/10); infrequent (≥1/1000 - <1/100); rare (≥1/10 000 - <1/1000); very rare (<1/10 000); frequency unknown (can not be estimated based on available data).

Infectious and parasitic diseases

Frequent: fungal infections.

Infrequent: pseudomembranous colitis, urinary tract infections.

Violations of the blood and lymphatic system

Infrequent: anemia, leukopenia, thrombocythemia, thrombocytopenia, eosinophilia, neutrophilic leukocytosis.

Hthe immune system systems

Infrequent: hypersensitivity.

Frequency unknown: anaphylaxis.

Hmetabolic and nutritional disorders

Infrequent: a decrease in appetite, hyperglycemia, hyperkalemia, hypoglycemia, hypokalemia, hypomagnesemia.

Disorders of the psyche

Frequent: insomnia.

Infrequent: agitation, anxiety, confusion, depression.

Disturbances from the nervous system

Very Frequent: dysgeusia.

Frequent: headache, dizziness.

Infrequent: agavezia, migraine, paresthesia, parosmia, drowsiness, tremor.

Disturbances on the part of the organ of sight

Infrequent: eye irritation, blurred vision.

Hearing disorders and labyrinthine disorders

Infrequent: noise in ears.

Rare: deafness.

Heart Disease

Infrequent: angina pectoris, atrial fibrillation, bradycardia, chronic heart failure, lengthening of the interval QT, heart palpitations, sinus tachycardia, supraventricular extrasystole, ventricular extrasystole.

Violations from vessels

Infrequent: hyperemia, increased blood pressure, lower blood pressure, phlebitis.

Disturbances from the respiratory system, chest and mediastinal organs

Infrequent: dyspnoea, hiccups, nasal congestion, pain in the pharyngeal region.

Hgastrointestinal tract disorders

Very Frequent: nausea.

Frequent: constipation, diarrhea, vomiting.

Infrequent: abdominal pain, dry mouth, dyspepsia, flatulence, decreased sensitivity of the oral mucosa.

Disturbances from the liver and bile ducts

Infrequent: hepatitis.

Disturbances from the skin and subcutaneous tissues

Frequent: itching, rash;

Infrequent: erythema, facial edema, hyperhidrosis, urticaria.

Disturbances from musculoskeletal and connective tissue

Infrequent: pain in the joints, back pain, muscle cramps, muscle pain.

Disorders from the kidneys and urinary tract

Frequent: acute renal failure, foamy urine;

Infrequent: oliguria. pollakiuria, impaired renal function, a change in the smell of urine.

General violations and violations at the site of introduction

Frequent: fatigue, chills;

Infrequent: asthenia, reactions at the injection site, malaise, non-cardiac pain in the chest, peripheral edema, pain, pyrexia, "red man" syndrome;

Laboratory and instrumental data

Frequent: increased activity of alanine aminotransferase, increased activity of aspartate aminotransferase, increased creatinine concentration in the blood.

Infrequent: an increase in the concentration of urea in the blood, hematuria, microalbuminuria, an increase in the international normalized relationship.

Overdose:

In healthy volunteers who received telavantine in a dose of 15 mg / kg, such undesirable side reactions as dysgeusia, nausea, vomiting, redness at the injection site, headache, macular rash and red man syndrome were observed with greater frequency.

In case of an overdose, the use of telavancin should be discontinued and maintenance treatment aimed at maintaining glomerular filtration accompanied by monitoring kidney function should be prescribed.

In patients with terminal stage of renal insufficiency, after a single administration of telavancin at a dose of 7.5 mg / kg, about 5.9% of the administered dose of telavancin was isolated in dialysate after 4 hours of hemodialysis. However, there is no information on the effectiveness of hemodialysis in case of an overdose.

Telavancin clearance by continuous venous-venous hemofiltration (HDVG) was evaluated in a study in vitro. Telavancin was excreted by HBVH, and telavancin clearance was increased with an increase in ultrafiltration rate. However, the effect of HBVH on the clearance of telavancin was not evaluated in clinical studies, therefore, the clinical significance of these data and the possibility of using HDB in overdose are unknown.

Interaction:

In studies on healthy volunteers, the pharmacokinetics of telavancin did not undergo significant changes with simultaneous use of aztreonam or piperacillin + tazobactam. Besides, telavantine does not affect the pharmacokinetics of aztreonama or piperacillin + tazobactam. Based on the data on the pharmacokinetic properties of ns, 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 isoenzyme CYP3A4. In experiments in vitro it was shown that telavantine does not affect the pharmacokinetics

drugs metabolized by isoenzymes CYP 1A2, 2C9, 2C19 and 2D6. No significant interactions of telavancin with inhibitors or inducers of the isoenzyme system are expected CYP450.

Telavancin can affect the validity of tests used to monitor the blood coagulation system when tests are performed using samples collected between 0 and 18 hours after the administration of telavancin when administered to patients administered once every 24 hours. Blood samples for coagulation tests should be taken but before the next dose of telavancin is administered or a test for which telavantine does not affect (see Table 3).

Table 3. Potential influence of telavancin on coagulation tests.

Tests for which telavantine has an impact

Tests for which telavantine does not affect

Prothrombin time / international normalized ratio

Activated partial thromboplastin time

Activated clotting time

Coagulation analysis based on X factor activity

Thrombin time

The coagulation time for whole blood by Lee-White

Aggregation ability of platelets

Chromogenic analysis of anti-Xa factor

Chromogenic (functional) X factor analysis

Bleeding time

D-dimer

Products of fibrin degradation

Special instructions:

- In patients with moderate to severe renal impairment (QC ≤ 50 ml / min), who received treatment with the drug telavantine in connection with nosocomial (nosocomial) pneumonia, including ventilator-associated pneumonia, clinical studies have shown an increased risk of a legal outcome compared with patients receiving vancomycin therapy. Possibility of using the drug telavantine in patients with moderate to severe renal impairment (QC ≤ 50 mL / min) should be considered only if the expected benefit of the treatment exceeds the potential risk to the patient. For this reason contraindicated the use of telavancin in patients with pre-existing acute renal failure and terminal stage of renal failure.

- In patients with mild-to-severe renal insufficiency and a clearance of creatinine ≤ 50 ml / min. a decrease in the effectiveness of therapy with telavantine compared with vancomycin. It is necessary to take into account the degree of renal failure in the choice of antibiotic therapy in this population of patients.

- Nephrotoxicity: there were cases of newly diagnosed disturbance of the function of the nights and the progression of the already existing one. In all patients taking the drug telavantine, the kidney function (the concentration of serum creatinine and the amount of urine released) should be monitored, but at least in the first 3-5 days of therapy - daily, then every 48-72 hours. The initial dose and dosage regimen correction should be determined based on calculated or measured creatinine clearance.If the kidney function significantly decreased during treatment, the expediency of continuing the use of the drug should be assessed telavantine.

For routine monitoring of renal function, it is recommended to use a determination of serum creatinine concentration or calculated creatinine clearance.

- General violations and violations at the place of introduction. When therapy with telavantine, reactions at the site of administration are possible. The rapid intravenous administration of antimicrobial drugs of the class of glycopeptides may lead to the development of reactions such as "red man" syndrome, including hot flashes in the upper body, urticaria, pruritus or rash. The termination or slowdown of the infusion leads to a resolution of the reaction. To reduce the likelihood of developing infusion reactions, the drug should be injected for at least 1 hour.

- Hypersensitivity reactions. After the administration of the first or subsequent dose of telavancin, serious, sometimes fatal hypersensitivity reactions may develop, including anaphylactic ones. Telavancin should be discarded when skin rash or other signs of hypersensitivity reaction develop. Telavancin is a semisynthetic derivative of vancomycin, and it is not known how patients with hypersensitivity to vancomycin will respond to the administration of telavancin. In this regard, in patients with known hypersensitivity to vancomycin, telavantine should be used with caution.

- Interval lengthening QT. Clinical studies on the effect of telavancin on the interval QT in comparison with the solvent and moxifloxacin (400 mg) showed that administration of the drug at a dose of 7.5 mg / kg and 15 mg / kg for 3 days resulted in an increase QT from F (with an amendment according to Frederick's formula) by 4.1 and 4.5 msec, respectively, from 9.2 msec (for moxifloxacin). It should be used with caution telavantine for the treatment of patients taking medications for which the effects of lengthening of the interval are known QT. In addition, caution should be exercised telavantine for the treatment of patients with the syndrome of congenital lengthening of the interval QT, known interval elongation QT, uncompensated heart failure or severe left ventricular hypertrophy. Patients with these conditions were not included in the clinical studies of telavancin.

- Like other glycopeptides, telavantine can have a toxic effect on the hearing.Care should be taken to monitor patients who experienced signs of hearing or vestibular damage during treatment with telavantine. Patients receiving telavantine in combination or after the use of other drugs with a known toxic potential should be carefully observed, and with deterioration in hearing, the feasibility of using telavancin should be evaluated.

- Colitis caused by Clostridium difficile: When using the drug, both at the reception foyer and 2-3 weeks after discontinuation of treatment, it is possible to develop diarrhea caused by Clostridium difficile (pseudomembranous colitis). It can manifest itself in various forms from mild diarrhea to severe pseudomembranous colitis. In the case of diarrhea, a thorough diagnosis and assessment of the association with the treatment should be carried out. In mild cases, treatment cancellation is sufficient, in severe cases, compensation for loss of fluid, electrolytes and protein, and drug therapy are shown. Do not use drugs that inhibit the intestinal motility.

- Effect on the coagulogram: the use of telavancin affects a number of coagulogram indices.including prothrombin time, the international normalized ratio (INR) and activated partial thromboplastin time (APTT). In clinical studies, there was no increased risk of bleeding. Telavancin does not affect the aggregation of platelets. Moreover, there was no hypercoagulation; in healthy volunteers who took telavantine, there was a normal level D-dimer and degradation products of fibrin.

- Telavancin affects the results of applying methods for the qualitative determination of protein in the urine using test strips (for example, based on the use of pyrogallol red mole iodate). And the results of the tests for determining microalbuminuria in the urine are independent of the study medication and can be used to monitor proteinuria during treatment.

- Joint antibiotic therapy. Telavancin acts only on gram-positive bacteria. In case of polymicrobial infections, when gram-negative and / or certain types of anaerobic microorganisms are assumed, telavantine should be used in conjunction with other antibacterial drugs that are active against these pathogens.

Specials groups patients

Women of childbearing age

Before starting treatment with the drug telavantine it is necessary to carry out a serum pregnancy test.

Elderly patients

There are no clinically significant age differences in the pharmacokinetics of telavancin. Thus, dose adjustment is not required in elderly patients, except for those with creatinine clearance ≤ 50 ml / min.

Sexual differences

Clinically significant differences in the pharmacokinetics of telavancin associated with sex were not observed.

Effect on the ability to drive transp. cf. and fur:

Special studies of the influence of telavancin on the ability to drive vehicles and mechanisms were not carried out. When using the drug, dizziness, drowsiness, confusion and blurred vision may occur, which can affect the ability to drive vehicles and mechanisms.

Form release / dosage:

Lyophilizate for solution for infusion, 750 mg.

Packaging:

For 750 mg of bodyvanicin (in the form of telavancin hydrochloride) in a bottle with a capacity of 50 ml of glass (type I USP), Sealed with siliconized cork made of butyl rubber, crimped with an aluminum cap with a plastic lid "flip-off".

1 bottle with instructions for use in a cardboard box.

Storage conditions:

Store in the original packaging in a dark place at a temperature of 2 to 8 ° C.

Keep out of the reach of children.

Shelf life:

4 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003046

Date of registration:18.06.2015 / 21.07.2016

Expiration Date:18.06.2020

The owner of the registration certificate:R-PHARM, CJSC R-PHARM, CJSC Russia

Manufacturer: & nbsp

HOSPIRA, Inc. USA

Representation: & nbspR-PHARM, JSC R-PHARM, JSC Russia

Information update date: & nbsp09.01.2017

Illustrated instructions

Instructions

Vibativ (Vibativ)