Ksidalba TM (XydalbaTM)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
Read on
Active substanceDalbavancinDalbavancin
Similar drugsTo uncover
  • Ksidalba TM
    lyophilizate d / infusion 
    Aziande Kimike Riounite Angelini Francesco AKR.A.A. SpA     Italy
    • Dosage form: & nbsplyophilizate for the preparation of concentrate for the preparation of a solution for infusions
    Composition:

    Each vial contains:

    Active substance:

    dalbavancin hydrochloride 515 mg

    equivalent to dalbavancin 500 mg

    Excipients: Mannitol 128.8 mg, lactose monohydrate 128.8 mg, sodium hydroxide q.s., hydrochloric acid q.s.

    Description:

    Lyophilizate

    The solid is in the form of a powder from white or almost white to light yellow with separate inclusions of the pressed mass.

    The reconstituted solution (formed when the lyophilizate is completely dissolved in water)

    Transparent solution from colorless to yellow.

    Pharmacotherapeutic group:Antibiotic glycopeptide
    ATX: & nbsp

    J.01.X.A.04   Dalbavancin

    Pharmacodynamics:

    Mechanism of action

    The drug Ksidalba contains dalbavancin, which is a bactericidal glycopeptide synthesized from a fermentation product of species Nonomuraea.

    Its mechanism of action is the violation of the synthesis of the cell wall: by binding to the terminal dipeptide D-alanyl-D-alanine peptidoglycan stem peptide formed cell wall, dabavancin prevents the formation of cross-links(transpeptidation and transglycosylation) of disaccharide subunits, which leads to destruction of the cell wall.

    Resistance

    All gram-negative microorganisms are initially resistant to dalbavancin. Resistance to dalbavancin in species Staphylococcus and Enterococcus is due to VanA, genotype, which leads to the modification of the target peptide in the resulting cell wall. The activity of dalbavancin is not affected by other classes of resistance genes to vancomycin.

    In clinical trials in patients infected with Staphylococcus aureus or Streptococcus pyogenes, at the baseline level (before the initiation of dalbavancin therapy), no microorganisms with a minimum inhibitory concentration (MIC) of dalbavancin> 0.125 mg / l were detected. Also, there were no significant changes in sensitivity to dalbavancin among any other microorganisms that were subsequently isolated during the treatment with the drug.

    IPC dalbavancin is higher for staphylococci with intermediate sensitivity to vancomycin (VISA-vancomycin-intermediate staphylococci aureus), than for strains completely sensitive to vancomycin. Cross-resistance between dalbavancin and other classes of antibiotics in studies in vitro was not observed.

    Interaction with other antibacterial agents

    In studies in vitro There was no antagonism between dalbavancin and other commonly used antibiotics (for example, cefepime, ceftazidime, ceftriaxone, imipenem, meropenem, amikacin, aztreonam, ciprofloxacin, piperacillin / tazobactam and trimethoprim / sulfamethoxazole) when tested against 12 species of Gram-negative microorganisms.

    Interrelation of pharmacokinetics / pharmacodynamics parameters

    The bactericidal activity of dalbavancin against staphylococci in vitro (depends on time. In vivo relationship pharmacokinetics and pharmacodynamics dalbavancin for S.aureus was determined using a neutropenic model of infection in animals, which showed that the absolute decrease log10 colony-forming units (CFU) was large in the administration of large doses with a lower frequency.

    Boundary values ​​for sensitivity testing

    The boundary values ​​of the minimum inhibitory concentration (MIC) were proposed by the European Committee for Testing Antimicrobial Susceptibility (EUCAST):

    - Staphylococcus spp.: sensitive - ≤0,125 mg / l; resistant -> 0,125 mg / l;

    - Streptococcus beta-haemolyticus: (groups A, B, C, G) sensitive - ≤0,125 mg / l; resistant -> 0,125 mg / l.

    - DGroup Streptococcus viridans (only Streptococcus anginosus) sensitive - ≤0,125 mg / l; resistant -> 0,125 mg / l.

    Clinical efficacy against individual microorganisms

    Clinical studies have shown efficacy against pathogens that cause acute bacterial infections of the skin and soft tissues that have been susceptible to dalbavancin in vitro:

    Staphylococcus aureus

    Streptococcus pyogenes

    Streptococcus agalactiae

    Streptococcus dysgalactiae

    Group Streptococcus anginosus (including S.anginosus, S.intermedius and S.constellatus) Microorganisms from natural resistance

    Gram-negative bacteria

    Enterococci with resistance to vancomycin type VanA.

    Pharmacokinetics:

    The pharmacokinetics of dalbavancin was studied in healthy volunteers, in patients, including in special patient groups. Systemic action dalbavancin is dozoproportsionalnym with unit doses ranging from 140 mg to 1120, indicating that linear pharmacokinetics of dalbavancin. Dalbavancin accumulation after multiple intravenous infusions, held once a week during the period of 8 weeks (1000 mg on the first day and 500 mg in the period up to 7 weeks) in healthy adult volunteers was observed. The average half-life in the final phase (t1/2) was 327 (from 333 to 405) hours. The pharmacokinetics of dalbavancin are best described using three-component model (αиβ phase distribution followed by the final phase of excretion). Thus, the half-distribution period (t1/2β), which represents the major part of clinically significant concentration-time profile, is 5 to 7 days and is stable when applied once a week.

    The expected pharmacokinetic parameters of dalbavancin in single and double dosing regimens are presented in the table below.

    The average pharmacokinetic parameters of dalbavancin during the pharmacokinetic study1

    Parameter

    Single mode2

    Double mode3

    Cmax (mg/l)

    Day 1: 411 (86)

    Day 1: 281 (52)

    Day 8: 141 (26)

    AUC ∞-day 14 (mg * h / l)

    20300 (5300)

    18100 (4600)

    Clearance (l / h)

    0,049 (0,0096)

    0,048 (0,0086)

    1 A source DAL-MS-01

    2 1500 mg once, study DUR001-303

    3 1000 mg on day 1 + 500 mg on day 8, study DUR001-303

    Distribution

    The clearance and volume of distribution at an equilibrium state are comparable in healthy individuals and patients with infections. The volume of distribution in the equilibrium state correlated with the volume of the extracellular fluid. Dalbavancin reversibly binds to human plasma proteins, primarily with albumins.The binding of dalbavancin to plasma proteins is 93% and does not depend on the concentration of the drug, the presence of renal failure or liver failure. On day 7 after a single intravenous injection of 1000 mg of dalbavancin to healthy volunteers, the value of the area under the concentration-time curve (AUC) in the serous fluid of skin blisters was (bound and unbound dalbavancin) about 60% of the area under the concentration-time curve (AUC) in the plasma.

    Biotransformation

    Metabolites in human plasma were detected in a small amount. Metabolites hydroxydalbavancin and mannosyl aglikon are found in urine (<25% of the administered dose). Metabolic pathways responsible for the formation of these metabolites are not established; However, due to the relatively low contribution of metabolism to the overall elimination of dalbavancin, drug-drug interactions through inhibition or induction of dalbavancin metabolism are not expected. Hydroxydalbavancin and mannosyl aglycon demonstrate significantly lower antibacterial activity than dalbavancin.

    Excretion

    After the administration of a single dose of 1000 mg of dalbavancin to healthy volunteers, an average of 19-33% of the administered dose was excreted by the kidneys in the form of dalbavancin and 8-12% as a metabolite of hydroxydalbavancin.About 20% of the administered dose was excreted through the intestine.

    Special patient groups

    Renal insufficiency

    The pharmacokinetics of dalbavancin was evaluated in 28 patients with varying degrees of renal insufficiency and in 15 volunteers with normal renal function from the control group. After a single administration of 500 mg or 1000 mg of dalbavancin, the average plasma clearance (CLT) was lower by 11%, 35% and 47% in persons with mild severity (CLCR 50-79 ml / min), medium severity (CLCR 30-49 ml / min) and severe severity (CLCR <30 ml / min) of renal failure, respectively, compared with individuals with normal function of the kidneys. The average area under the concentration-time curve for people with creatinine clearance <30 ml / min was almost 2 times higher. Clinical significance of reducing the average plasma clearance (CLT) and the associated increase in the area under the concentration-time curve 0- ∞, noted in these studies pharmacokinetics dalbavancin in persons with severe renal failure, is not established. Pharmacokinetics of dalbavancin in patients with terminal stage of renal failure undergoing regular hemodialysis procedures (3 times a week) is similar to that of people with mild or moderate severity of renal failure.Less than 6% of the administered dose is removed after 3 hours of hemodialysis.

    Liver failure

    The pharmacokinetics of dalbavancin was evaluated in 17 patients with mild, moderate and severe severity of liver failure and compared with the pharmacokinetics of 9 healthy volunteers with normal liver function. The average area under the concentration-time curve in patients with mild liver failure in comparison with those with normal liver function did not change; however, the area under the concentration-time curve decreased by 28% and 31%, respectively, in patients with moderate to severe hepatic impairment. The cause and clinical significance of reduced rates in patients with moderate to severe hepatic impairment are unknown.

    Floor

    Clinically significant differences associated with sex in the pharmacokinetics of dalbavancin were not detected in healthy volunteers or in patients with infectious diseases. Correction of dose depending on sex is not required.

    Elderly people

    Clinical studies included patients under the age of 93 years.The pharmacokinetics of dalbavancin did not change significantly with age, so dose adjustment, depending on age, is not required.

    Indications:

    The drug Ksidalba is indicated for the treatment of acute skin and soft tissue infections in adult patients, including treatment of bacteremia associated with these infections.

    It is necessary to take into account the current official guidelines on the rules for the use of antibacterial drugs.

    Contraindications:

    Hypersensitivity to the active substance or to any auxiliary substances.

    Children under 18 years of age (safety and efficacy of the drug for this age category is not installed).

    Carefully:

    Dilbavancin should be used with caution in patients with hypersensitivity to other glycopeptides, since there may be a cross-over hypersensitivity.

    DALBAVANCIN should be used with caution in patients with moderate or severe hepatic impairment.

    Pregnancy and lactation:

    Pregnancy

    Data on the use of dalbavancin in pregnant women are not available. Studies in animals have shown reproductive toxicity.

    Daltbavancin is contraindicated during pregnancy.

    Breastfeeding period

    It is not established whether the dalbavancin with breast milk of a woman. However, during preclinical studies it was established that dalbavancin is excreted with the milk of lactating rats and, therefore, can be excreted in human breast milk. Dalbavancin poorly absorbed orally; However, the effect on the flora of the oral cavity and the gastrointestinal tract of a child can not be ruled out. When deciding whether to treat dalbavancin or continue breastfeeding, consideration should be given to the benefits of breastfeeding for a child and the benefit of dalbavancin for a woman. If it is necessary to use the drug, breastfeeding should be discontinued.

    Dosing and Administration:

    The drug is administered intravenously infusion.

    The drug Ksidalba can be used as an initial therapy.

    Recommended dosage regimen of the drug Ksidalba in adult patients:

    1500 mg of dalbavancin once or in the form of a double infusion, namely 1000 mg of dalbavancin on the first day of treatment and 500 mg of dalbavancin on the eighth day of treatment.

    Renal insufficiency

    For patients with renal insufficiency of mild or moderate severity (creatinine clearance ≥30-79 ml / min), dose adjustments are not required. For patients undergoing regular hemodialysis procedures (3 times a week), dose adjustments are not required, and the Xidalba preparation can be taken without taking into account the time of hemodialysis.

    In patients with chronic renal failure, in which creatinine clearance <30 ml / min and who do not undergo regular hemodialysis procedures, the recommended regimen dosing of the drug Ksidalba should be reduced to 750 mg on the first day and 375 mg on eighth day.

    Liver failure

    For patients with mild liver failure (Child-Pugh A classification), dose adjustments are not required. Caution should be exercised in prescribing dalbavancin to patients with moderate or severe hepatic impairment (Child-Pugh B and C classification) because there is no data available to determine the appropriate dosage.

    Elderly people

    Dose adjustments are not required. Clinical studies included patients under the age of 93 years.

    Mode of application

    It is necessary to restore and dilute the drug Ksidalba before use. The drug should be diluted in aseptic conditions. The drug Ksidalba is intended for intravenous use and is administered intravenously infusion for 30 minutes. Dalbavancin it is necessary to dissolve in sterile water for injection and then dilute with 5% dextrose solution for infusions.

    Solution recovery:

    - Dissolve the contents of each bottle for one-time use, slowly adding 25 ml of water for injection.

    - To prevent foaming, alternate careful mixing with circular motions and turning the vial until its contents are completely dissolved.

    - Do not shake.

    - The reconstituted solution at a concentration of 20 mg / ml should be a clear, yellow solution with no visible particles.

    Dilution of the reconstituted solution:

    - The reconstituted solution of the drug Ksidalba should be diluted with a 5% solution of dextrose for infusion.

    - The solution for infusion should have a final concentration of dalbavancin from 1 to 5 mg / ml and should be transparent without visible particles.

    - At the end of the infusion, it is necessary to dispose of any portions of diluted solution that have not been used.

    Solutions of sodium chloride can cause precipitation and should NOT be used.

    Compatibility of dissolved dalbavancin with intravenous substances, auxiliary substances or drugs, except 5% solution dextrose for infusion is not established.

    Infusion

    Before starting the infusion, it is necessary to evaluate the prepared solution visually for the presence of suspended particles and discoloration. If suspended particles or discoloration are detected, the solution should not be used.

    The drug Ksidalba is administered intravenously infusion for 30 minutes.

    Flasks of the drug Ksidalba are intended exclusively for one-time use. Any unused or contaminated product should be disposed of in accordance with local requirements.

    Side effects:

    Security Profile Characteristics

    In phases II and III of clinical trials, 2,473 patients received Xidalba once in a dosage of 1500 mg or as a double infusion, namely 1000 mg of dalbavancin on the first day of treatment and 500 mg of dalbavancin on the eighth day of treatment.The most frequent adverse reactions that occurred in ≥1% of patients treated with Xidalba were nausea (2.4%), diarrhea (1.9%) and headache (1.3%), which were mainly light and moderate severity.

    The list of undesirable side reactions

    The following undesirable adverse reactions were established in Phase II and III clinical trials of the Ksidalba preparation. Undesirable adverse reactions are classified according to the system-organ class and frequency of occurrence. Frequency categories are defined as follows: very often (≥1/10), often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1,000 to <1/100), rarely (from ≥1 / 10 000 to <1/1 000).

    System-Organic

    grade

    Often

    Infrequently

    Rarely

    Infectious and parasitic diseases

    Candida vulvovaginitis, urinary tract infections, fungal infection, colitis caused by Clostridium difficile, candidiasis of the oral cavity

    Violations of the blood and lymphatic system

    Anemia, thrombocytosis, eosinophilia, leukopenia, neutropenia

    Immune system disorders

    Anaphylactic reactions

    Disorders of metabolism and nutrition

    Decreased appetite, hypoglycemia

    Disorders of the psyche

    Insomnia

    Disturbances from the nervous system

    Headache

    Perversion of taste, dizziness

    Vascular disorders

    Hyperemia, phlebitis

    Disturbances from the respiratory system, chest and mediastinal organs

    Cough

    Bronchospasm

    Disturbances from the organs of the gastrointestinal tract

    Nausea, diarrhea, vomiting

    Constipation, abdominal pain, indigestion, discomfort in the abdomen

    Disturbances from the liver and bile ducts

    Hepatotoxicity

    Disturbances from the skin and subcutaneous tissues

    Rash

    Itching, urticaria

    Violations of the genitals and mammary gland

    Vulvovaginal itching

    Are common disorders and disorders at the site of administration

    Infusion reactions

    Impact on the results of laboratory and instrumental studies

    Increase in gamma-glutamyl transferase

    Increased serum LDH, increased alanine aminotransferase, aspartate aminotransferase increase, increase in blood uric acid, disorders biochemical indicators of liver function, increased transaminases, increased serum alkaline phosphatase, an increase in the platelet count, fever, elevated liver enzymes, increased gamma glutamyl transferase

    Undesirable side reactions of the class of antibiotics-glycopeptides:

    Glycopeptides (especially Vancomycin) can cause ototoxicity; in patients receiving co-treatment with other drugs with ototoxic side effects (eg, aminoglycosides), the risk of ototoxicity is increased.

    Overdose:

    Specific information on the treatment of an overdose of Xidalba is absent, since dose-related toxicity in clinical studies has not been studied. In phase 1 studies, healthy volunteers took a single dose of up to 1500 mg with cumulative dose up to 4500 mg for a period of up to 8 weeks without signs of toxicity or significant laboratory changes.

    When using higher doses of Xidalbul preparation, observation and general therapeutic measures. Although there is no specific information on the use of hemodialysis for overdose treatment, it is worth noting that in Phase 1 of the clinical trial in patients with renal insufficiency less than 6% of the recommended dose of dalbavancin was removed after 3 hours of hemodialysis.

    Interaction:

    The results of a screening study of receptors in vitro Do not demonstrate the possible interaction with other therapeutic targets or the possibility of clinically significant pharmacodynamic interactions. Clinical studies of drug-drug interaction with dalbavancin have not been conducted.

    Pre-clinical studies have shown that dalbavancin does not inhibit or induce cytochrome P450 enzymes. Clinically significant drug-drug interactions between dalbavancin and substances metabolized by cytochrome P450 isoenzymes are not expected. Correction of dalbavancin doses when combined with substrates, inhibitors or inducers of cytochrome P450 is not required.

    Special instructions:

    Hypersensitivity reactions

    Dilbavancin should be used with caution in patients with hypersensitivity to other glycopeptides, since there may be cross-over hypersensitivity.

    In patients who received dalbavancin, cases of hypersensitivity reactions (anaphylactic reactions) and skin reactions were recorded. In case of development of allergic reactions, it is necessary to abolish dalbavancin and prescribe specific therapy.

    Infusion reactions

    The drug Ksidalba is intended for parenteral administration by intravenous infusion, to minimize the risk of infusion reactions, the administration time should be 30 minutes. Rapid intravenous infusions of glycopeptide antibiotics can cause reactions similar to the "red man" syndrome, which include hyperemia of the upper half of the body, hives, itching and / or rash. The termination or slowdown of infusion may lead to the cessation of these reactions.

    Renal insufficiency

    Information on the efficacy and safety of dalbavancin in patients with creatinine clearance <30 mL / min that do not undergo regular hemodialysis procedures is limited. Dose adjustment is necessary in patients with chronic renal disease insufficiency, with creatinine clearance <30 ml / min and not receiving regular hemodialysis procedures. In patients with creatinine clearance <30 ml / min treated with dalbavancin, the incidence of adverse reactions is similar to that in of patients with creatinine clearance> 30 mL / min.

    Laboratory indicators

    When using dalbavancin, an increase in the level of hepatic enzymes is possible (see the "Adverse Reactions" section)

    Resistant microorganisms

    The use of antibiotics can contribute to the excessive reproduction of resistant microorganisms. If superinfection occurs during treatment, appropriate measures should be taken.

    Mixed Infections

    In the treatment of patients with mixed gram-negative and Gram-positive infections, additional use of antibiotics active against the corresponding Gram-negative microorganisms is necessary.

    Clostridium difficile-Associated diarrhea

    Antibiotic-associated colitis and pseudomembranous colitis are noted with almost all antibiotics and can vary in severity from mild to life-threatening. In this connection, it is important to consider such a diagnosis in patients with diarrhea who fidgeted during or after the administration of dalbavancin. In such cases, it is necessary to interrupt treatment with dalbavancin and begin the application of general therapeutic measures in conjunction with the appointment of specific treatment Clostridium difficile. Contraindicated use of drugs that inhibit intestinal peristalsis.

    Limited clinical data

    The experience of dalbavancin in the treatment of patients with necrotizing fasciitis, gas gangrene, gangrene,ulcers with diabetic foot syndrome, peri-rectal abscess, bedsores or severe immunodeficiency is limited or absent.

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

    Studies of the impact on the ability to drive vehicles and work with mechanisms have not been carried out. There may be dizziness, which can affect the ability to drive vehicles and work with mechanisms.

    Form release / dosage:Liofilizate for the preparation of concentrate for the preparation of a solution for infusions 500 mg.
    Packaging:

    500 mg of the active ingredient in a 48 ml vial of a colorless sulfonated glass type I with a rubber stopper and an aluminum cap with breaking off.

    1 bottle with instructions for use in a cardboard box.

    Storage conditions:

    At a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years. Do not use after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004255
    Date of registration:20.04.2017
    Expiration Date:20.04.2022
    The owner of the registration certificate:Aziande Kimike Riounite Angelini Francesco AKR.A.A. SpAAziande Kimike Riounite Angelini Francesco AKR.A.A. SpA Italy
    Manufacturer: & nbsp
    Representation: & nbspANGELINI PHARMA РУС, ОООANGELINI PHARMA РУС, ОООRussia
    Information update date: & nbsp10.05.2017
    Illustrated instructions
      Instructions
      Up