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

Active substanceDaptomycinDaptomycin

Similar drugsTo uncover

Kubitsin

lyophilizate d / infusion

Novartis Pharma AG Switzerland

Dosage form: & nbsplyophilizate for solution for infusion

Composition:

10 ml of lyophilizate for the preparation of a solution for infusions (1 bottle) contain:

active substance: daptomycin 300 mg or 500 mg;

Excipients: sodium hydroxide solution 3H.

Description:

Lyophilizate from light yellow to light brown in color.

Pharmacotherapeutic group:cyclic antibiotic lipopetide

ATX: & nbsp

J.01.X.X Other antibacterial drugs

J.01.X.X.09 Daptomycin

Pharmacodynamics:

Daptomycin is a naturally occurring cyclic lipopeptide active against aerobic Gram-positive bacteria, including antibiotic-resistant strains (methicillin-resistant strains, vancomycin and linezolid). In vitro the spectrum of daptomycin activity covers the majority of clinically significant Gram-positive bacteria.

Daptomycin binds to the cell membrane of the bacterial cell and causes its depolarization, which leads to a rapid inhibition of the synthesis of DNA, RNA, protein and cell death.

At present, there is no mechanism of development of resistance to daptomycin. Possible changes in the genome of the bacterial cell, which confirm the development of resistance, are also not established.There was no evidence of the development of cross-resistance to daptomycin, based on the mechanisms of resistance development inherent in other classes of antibiotics.

Of the 160 000 patients who received daptomycin therapy (condition for 2007), 31 isolates of resistant strains Staphylococcus aureus, y 2 - Enterococcus faecalis, in 3 - Enterococcus faecium. When daptomycin is used in studies in vitro and in vivo the drug had a fast, dose-dependent bactericidal action.

In vitro daptomycin had a synergistic antibacterial effect when used together with aminoglycosides, β-lactam antibiotics and rifampicin for a number of strains Staphylococcus (including some methicillin-resistant strains) and Enterococcus (including some vancomycin-resistant strains). Daptomycin did not have an antagonistic effect when interacting with other antibiotics.

Sensitive microorganisms:

Staphylococcus aureus *

Staphylococcus haemolyticus

Staphylococcus spp. coagulase-negative strains

Streptococcus agalactiae *

Streptococcus dysqalactiae *

Streptococcus pyogenes *

Streptococcus spp. groups G

Clostridium perfringens

Peptostreptococcus spp.

Natural-resistant microorganisms:

Gram-negative microorganisms.

* species with proven sensitivity to daptomycin according to the results of clinical studies.

Pharmacokinetics:

When daptomycin is administered in doses of 4-12 mg / kg once a day by intravenous infusion of 30 minutes for 14 days, the pharmacokinetics is mostly linear (dose-dependent); equilibrium concentration is achieved after the administration of 3 daily daptomycin doses.

Distribution

In healthy volunteers, the volume of distribution of daptomycin in the equilibrium state is about 0.1 l / kg, regardless of the dose of the drug.

In experimental studies with a single or repeated application of daptomycin, its penetration through the blood-brain and placental barriers was minimal.

Daptomycin reversibly binds to human plasma proteins regardless of its concentration. In healthy volunteers and patients with mild to moderate liver function impairment (<8 on the Child-Pugh scale), the association with plasma proteins is approximately 90-93%. In patients with severe renal dysfunction (creatinine clearance <30 ml / min) or who are on hemodialysis or continuous ambulatory peritoneal dialysis, daptomycin binds to plasma proteins to a lesser degree (84-88%).

Metabolism

In studies in vitro Daptomycin is not metabolized in the liver by microsomal oxidation. Since the preparation does not exert any influence on the cytochrome P450 isoenzyme system (isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4), the interaction of daptomycin with drugs metabolized by this system is unlikely.

In the blood plasma metabolites of daptomycin are not detected. In urine, 4 inactive metabolites of daptomycin are determined: 3 products of oxidative metabolism and 1 product, the pathway of metabolism of which is not established. At present, it is not known where daptomycin is metabolized.

Excretion

The drug is excreted mainly through excretion through the kidneys. There is no active tubular secretion of daptomycin in the kidneys. After intravenous injection, the plasma clearance of daptomycin was about 7-9 ml / h / kg. Kidney clearance - 4-7 ml / h / kg. With a single application, 78% of daptomycin is excreted through the kidneys and 6% through the intestine. About 52% of the dose is excreted unchanged by the kidneys.

Pharmacokinetics in special clinical cases

Patients aged ≥ 65 years old

When using the drug at a dose of 4 mg / kg intravenously for 30 minutes, the total clearance of daptomycin averaged 35% lower, and the area under the concentration-time curve (AUC) was an average of 58% higher compared with healthy volunteers aged less than 65 years. The maximum concentration (C_m_Oh) did not change daptomycin.

Patients aged < 18 years

Pharmacokinetic parameters of the drug in adolescents aged 12 to 17 years were similar to those in healthy adult patients, except for reducing systemic bioavailability. Children aged 2 to 11 years had a decrease in systemic bioavailability (FROM_m_Oh and AUC) and duration of the period elimination half-life of daptomycin (as a result of increased clearance) compared with adolescents.

Floor

The sex of patients did not affect the pharmacokinetics of daptomycin.

Patients with excessive body weight (obesity)

In patients with moderate (Body Mass Index (BMI) 25-40 kg / m²) and pronounced (BMI> 40 kg / m²) there was an increase in obesity AUC by 28% and 42%, respectively, compared with patients with normal body weight.

Patients with impaired renal function

When using the drug at a dose of 4 or 6 mg / kg in the form of intravenous infusion for 30 minutes in patients with varying degrees of renal dysfunction, a decrease in clearance and an increase AUC daptomycin.

Patients with hepatic impairment

Since the pharmacokinetics of daptomycin did not change in patients with mild to moderate liver function impairments (5-8 points on the Child-Pugh scale) compared to healthy volunteers.

In patients with severe impairment of liver function (> 9 on the Child-Pugh scale), the pharmacokinetics of daptomycin have not been studied.

Indications:

Treatment of infectious and inflammatory diseases caused by aerobic gram-positive microorganisms sensitive to the drug:

- complicated skin and soft tissue infections in adults caused by sensitive Gram-positive bacteria.

- bacteremia caused by Staphylococcus aureus, including right-sided infective endocarditis in adults.

Contraindications:

Hypersensitivity to daptomycin or excipients.

Carefully:

Patients with mild to moderate renal impairment (CK 30-80 mL / min), obesity, severe impaired liver function (> 9 on the Child-Pugh scale), and patients aged ≥65 years should be cautious about prescribing Kubitsin .

The drug should be used with caution along with potentially nephrotoxic drugs,providing additional regular monitoring of kidney function in all patients (regardless of the initial state of renal function). Patients with severe renal dysfunction (CK <30 mL / min), and concomitantly with drugs that cause myopathy, should be prescribed only when the expected benefit from therapy exceeds the possible risk.

Pregnancy and lactation:

Application of the drug Kubitsin in pregnant women not studied. In preclinical studies daptomycin did not adversely affect fertility, the course of pregnancy, the formation and maturation of the fetus, childbirth and postnatal development. Data on the effect of the drug Kubitsin on the fertility of men and women are absent. Use the drug in pregnancy should be only in cases where the expected benefit of therapy for the mother exceeds the potential risk to the fetus.

When using the drug Kubitsin during lactation at a dose of 500 mg / day intravenously for 28 days the concentration of daptomycin in breast milk was low, not more than 0.045 μg / ml. If you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

The drug Kubitsin is administered by intravenous infusion for at least 2 minutes or for 30 minutes.

The drug can not be used more than once a day.

Complicated skin and soft tissue infections in adults caused by sensitive Gram-positive bacteria

The recommended adult dose is 4 mg / kg intravenously (in sodium chloride solution 0.9%) once a day for 7-14 days or until the signs of infection disappear.

Bacteremia caused by Staphylococcus aureus, including right-sided infective endocarditis in adults

The recommended dose for adults is 6 mg / kg intravenously (in 0.9% sodium chloride solution) once a day for 2-6 weeks at the discretion of the treating doctor.

Patients with impaired renal function

Given the limited clinical experience in patients with CC <80 ml / min, Kubitsin can only be used if the expected clinical effect exceeds possible risks.

In patients with complicated skin and soft tissue infections with CC less than 30 ml / min or patients on hemodialysis or continuous outpatient peritoneal dialysis, the drug Kubitsin should be administered at a dose of 4 mg / kg once every 48 hours (when possible after completion of hemodialysis, the day of hemodialysis).

In patients with bacteraemia caused by Staphylococcus aureus, including right-sided infective endocarditis in adults with terminal renal failure with QC less than 30 ml / min or patients on hemodialysis or continuous outpatient peritoneal dialysis drug Kubitsin should be administered at a dose of 6 mg / kg 1 time per 48 hours (when possible after hemodialysis, on the day of hemodialysis).

In patients with QC ≥30 ml / minute correction of the dosing interval is not required.

Patients with hepatic impairment

Have patients with mild and moderate degree violations of liver function (5-8 points on the scale Child-Pugh) dose adjustment is not required.

Since patients with severe impairment of liver function (> 9 on the Child-Pugh scale), the pharmacokinetic parameters of daptomycin have not been studied, Care should be taken when prescribing the drug in this category of patients.

Patients ≥65 years of age

Patients older than 65 years in the absence of severe renal dysfunction with CK> 30 ml / min dose adjustment is not required.

Patients aged ≤18 years

Since the effectiveness and safety of the drug Kubitsin in children and adolescents is not established, the drug is not recommended for use in this category of patients.

Floor

Correction of the dose of the drug according to the sex of the patient is not required.

Obesity

An additional dose adjustment in patients with obesity is not required.

Rules for the preparation of the drug Kubitsin

One vial of the preparation contains 350 mg or 500 mg of sterile lyophilizate for the preparation of a solution for infusions. The drug does not contain preservatives or bacteriostatic substances.

Preparation of the drug solution is carried out under aseptic conditions.

Before the introduction of the drug Kubitsin should visually control the quality of dissolution of the drug and the color of the solution. The drug solution should be from pale yellow to light brown in color. If the color changes or the appearance of undissolved visible particles, the solution of the preparation can not be used.

To prevent foaming during the preparation of the solution, the vial should not be shaken!

To obtain a solution for intravenous infusion within 2 minutes, you should:

1. Remove polypropylene "flip off" Cap for detecting the central part of the rubber plug.

2. A 0.9% solution of sodium chloride is injected into the vial through the center of the rubber stopper, directing the needle to the wall of the vial.

a) 350 mg of the lyophilizate is dissolved in 7 ml of 0.9% sodium chloride solution;

(b) 500 mg of the lyophilizate is dissolved in 10 ml of a 0.9% solution of sodium chloride to prepare a solution with a daptomycin concentration of 50 mg / ml.

3. The bottle should be gently rotated to ensure complete dissolution of the drug, then leave it for 10 minutes.

To obtain a solution for intravenous infusion for 30 minutes, you should:

4. Remove polypropylene "flip off" Cap for detecting the central part of the rubber plug.

5. A 0.9% solution of sodium chloride is injected into the vial through the center of the rubber stopper, directing the needle to the wall of the vial.

a) 350 mg of the lyophilizate is dissolved in 7 ml of 0.9% sodium chloride solution;

(b) 500 mg of the lyophilizate is dissolved in 10 ml of a 0.9% solution of sodium chloride to prepare a solution with a daptomycin concentration of 50 mg / ml.

6. The bottle should be gently rotated to ensure complete dissolution of the drug, then leave it for 10 minutes.

7. The vial is then gently shaken for a few minutes until the desired clear, reconstituted solution is obtained.

8. The resulting solution is brought to a final volume of 50 ml with a 0.9% solution of sodium chloride.

Rules for the introduction and storage of the drug Kubitsin

The drug solution should be injected into the vein immediately after its preparation!

The introduction of the solution of the drug Cubicin into the vein is carried out under aseptic conditions.

The chemical and physical stability of the dissolved drug in the vial is maintained up to 12 hours at a temperature of up to 25 ° C; up to 48 hours at 2-8 ° C.

The chemical and physical stability of the diluted solution in the infusion bag is maintained for 12 hours at a temperature of up to 25 ° C or for 48 hours at 2-8 ° C.

The total shelf life of the solution of daptomycin in the vial and diluted solution of the drug in the infusion bag should not exceed 12 hours at a temperature of 25 ° C or 48 hours at 2-8 ° C.

After a single administration of the drug Kubitsin, the unused solution of the drug remaining in the vial can not be re-applied.

After using the product, disposal of all materials should be carried out properly.

Side effects:

When using the drug Kubitsin in clinical studies, the following undesirable phenomena were listed, listed below for organs and systems, indicating the frequency of their occurrence: very often ≥ 1/10 (> 10%), often ≥1 / 100 and <1/10 (≥ 1% and <10%), infrequently ≥1 / 1,000 and <1/100 (≥0, 1% and 1%); rarely ≥ 1/10000 and <1/1 000 (≥ 0.01% and <0.1%), very rarely ≤ 1 / 10,000 (<0.01%).

Infectious diseases:

Often: fungal infections (including candidiasis), urinary tract infections;

Infrequent: fungal sepsis.

From the system of blood and organs hematopoiesis:

Often: anemia;

Infrequent: thrombocytosis, eosinophilia.

Metabolic and nutritional disorders:

Infrequent: decreased appetite, hyperglycemia; violation of electrolyte balance.

Mental disorders:

Often: anxiety, insomnia;

From the nervous system and sensory organs:

Often: headache, dizziness;

Infrequently: paresthesia, taste disorders, tremor, vertigo.

From the cardiovascular system:

Often: decrease or increase in blood pressure (BP);

Infrequently: supraventricular arrhythmia, "tides" of blood to the face.

From the digestive system:

Often: abdominal pain, constipation, nausea, vomiting, diarrhea, bloating and painful abdominal tension;

Infrequent: indigestion.

From the liver and bile ducts:

Rarely: jaundice;

From the skin and subcutaneous tissue:

Often: rash, itching;

Infrequently: urticaria.

From the musculoskeletal system:

Often: pain in the limbs;

Infrequently: muscle pain, muscle weakness, arthralgia.

From the side of the urinary system:

Infrequent: impaired renal function, including renal failure.

On the part of the reproductive system:

Infrequently: vaginitis.

On the part of the body as a whole and the reaction together with the administration of the drug:

Often: reactions at the injection site, increased body temperature, asthenia;

Infrequent: increased fatigue, chills.

Change in laboratory indicators

Often: increased activity of creatinine phosphokinase (CPK), violations of laboratory parameters of liver function (increased activity of aspartate aminotransferase (ACT), alanine aminotransferase (ALT) and alkaline phosphatase (AFP);

Infrequent: increased blood lactate dehydrogenase activity, increased creatinine concentration in the blood plasma, an increase in the international normalized ratio (INR);

Rarely: increased prothrombin time.

When using the drug Kubitsin in clinical practice, the following undesirable phenomena (the frequency of which is unknown) were noted:

From the immune system: hypersensitivity reactions, including eosinophilic infiltrates in the lungs, anaphylaxis, angioedema,Rash with eosinophilia and systemic manifestations (DRESS-syndrome)

From the musculoskeletal system: rhabdomyolysis.

From the nervous system: peripheral neuropathy.

Infections and infestations: diarrhea caused by Clostridium difficile.

From the skin and subcutaneous tissue: Vesiculo-bullous rash with / without lesions of mucous membranes.

On the part of the respiratory system, the organs of the thorax and the mediastinum: eosinophilic pneumonia, cough.

Overdose:

In case of an overdose of the drug, medical supervision and symptomatic therapy are recommended.

Daptomycin is slowly excreted from the body by hemodialysis (about 15% of the dose taken is withdrawn after 4 hours) or by peritoneal dialysis (about 11% of the administered dose is removed after 48 hours).

Interaction:

Since the preparation does not have an inducing or inhibitory effect on the cytochrome P450 system (CYP450), development CYP450-dependent interactions in humans are unlikely.

When daptomycin was used together with aztreonam, warfarin and probenecid, there was no significant change in the pharmacokinetic parameters of the drugs.

The experience of simultaneous use of daptomycin with warfarin is limited.Studies of the interaction of daptomycin with other anticoagulants have not been conducted. When prescribing the drug Kubitsin along with warfarin, it is necessary to control the coagulability of the blood during the first days of use.

When daptomycin (at a dose of 2 mg / kg) was administered together with tobramycin by intravenous infusion for 30 minutes, slight changes in pharmacokinetic parameters (statistically unreliable) were observed. However, there is no experience of the combined use of daptomycin in therapeutic doses (4 mg / ml and 6 mg / ml) and tobramycin. Care should be taken when using the drug Kubitsin simultaneously with tobramycin.

The experience of using daptomycin together with inhibitors of HMG-CoA reductase (lipid-lowering drugs) is limited. Therefore, when administering daptomycin in combination with HMG-CoA reductase inhibitors, it is recommended that the time interval between the intake of HMG-CoA reductase inhibitors and the intravenous administration of the Kubitsin preparation be recommended.

When combined with non-steroidal anti-inflammatory drugs, NSAIDs, including cyclooxygenase inhibitors 2 types (COX-2), it is possible to increase the concentration of daptomycin in the blood serum.

In clinical practice, there have been cases of interaction of daptomycin with a specific reagent used in the determination of prothrombin time / international normalized ratio (MI / INR) - recombinant thromboplastin. This interaction resulted in a pronounced dose-dependent lengthening of the PV and an increase in INR. In detecting the deviation of MI / INR in patients receiving treatment with Kubitsin, the possibility of interaction between daptomycin in vitro with a laboratory reagent. The probability of an error in the determination of PV or INR can be minimized by taking blood at the lowest possible concentration of daptomycin in the blood plasma.

If patients with Kubitsin showed a marked increase in MI / INR in patients with a drug, it should be:

1. Repeated determination of MI / INR, while taking blood at the lowest possible concentration of daptomycin in the blood plasma. If, during a re-determination, MI and INR values are higher than the expected value, it is necessary to determine the MI / INR by an alternative route (without the use of recombinant thromboplastin).

2. Conduct an assessment of all other cases of increased rates of MI and INR.

Pharmaceutical incompatibility

Do not mix the drug Kubitsin with solutions containing dextrose.

Currently, there are limited data on the compatibility of the drug with other drugs for intravenous administration, so do not mix the drug Kubitsin in a vial or in the infusion system with any drugs, with the exception of 0.9% sodium chloride solution (see section "Method application "). If it is necessary to administer the drug and another drug through one infusion system, it is necessary to rinse this system before and after the administration of the drug Kubitsin.

If necessary, the drug can be administered through one infusion system together with aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin and lidocaine.

Special instructions:

If suspected of developing a mixed infection (including Gram-negative and / or anaerobic microorganisms), the Cubicin preparation should be combined with appropriate antibacterial drugs effective against gram-negative and / or anaerobic bacteria.

When using the drug Kubitsin, development of anaphylactic reactions / hypersensitivity reactions was noted. In the case of development of allergic reactions against the background of the drug, treatment should be discontinued and appropriate therapy prescribed.

The use of the drug Cubicin is not effective in patients with community-acquired pneumonia, since daptomycin binds to the pulmonary surfactant in the alveoli and is inactivated by it.

With the use of almost all antibacterial drugs, including the drug Kubitsin, there was a development of diarrhea caused by Clostridium difficile. In case of development of diarrhea caused by Clostridium difficile, on the background of the drug, treatment should be discontinued and, if necessary, appropriate therapy should be prescribed.

If the background of the use of the drug Kubitsin there are worsening of the course or recurrence of bacteremia / endocarditis caused by Staphylococcus aureus, or there is a low clinical efficacy of the drug, it is necessary to re-isolate the pathogen from the patient's blood. If this is repeatedly allocated Staphylococcus aureus, it is necessary to establish the sensitivity of the pathogen to antibiotics (to determine the minimum inhibitory concentration), as well as to conduct a patient examination to identify hidden foci of infection.To achieve a clinical effect, appropriate surgical interventions (including wound repair, prosthesis removal, valve prosthetics) or the administration of another antibacterial drug may be required.

In patients receiving antibiotic treatment, including the drug Kubitsin, the development of resistance to the drug is possible. With the development of antibiotic resistance to daptomycin, appropriate measures must be taken.

Disturbances from the musculoskeletal system

When using the drug Kubitsin, there were cases of increased activity of CKK, development of muscle pain, weakness and / or rhabdomyolysis, therefore:

- fromIt is advisable to inform patients receiving treatment with Kubitsin about the need to immediately inform the doctor about the development of muscle pain or weakness, especially in the legs;

- the activity of CKD of blood plasma should be determined before the initiation of therapy and during treatment with Cubicin at regular intervals (at least 1 time per week) in all patients. When prescribing the drug with HMG-CoA reductase inhibitors, the determination of CK should be performed more often;

- when increasing activity of CKF it is necessary to monitor the activity of CKK more than once a week;

- when the symptoms of myopathy develop and the activity of CK is increased more than 1000 IU / L (approximately ≥ 5 times higher than the upper limit of the norm, ≥ 5 × VLN), and also when increased activity of CK more than 2000 IU / l (≥10xVGN), in the absence of symptoms of myopathy, drug treatment should be discontinued;

- when daptomycin is administered in combination with HMG-CoA reductase inhibitors that can cause rhabdomyolysis, it is recommended that the time interval between the intake of inhibitors of HMG-CoA reductase and intravenous administration of the drug Kubitsin.

Peripheral Neuropathy

When using the drug Kubitsin should monitor the status of patients in order to identify signs of peripheral neuropathy.

Eosinophilic pneumonia

Against the background of the use of the drug Kubitsin during the first 2-4 weeks, cases of eosinophilic pneumonia, accompanied by fever, dyspnoea with hypoxic respiratory failure and diffuse pulmonary infiltrates, were noted. With the withdrawal of the drug Kubitsin and the beginning of glucocorticosteroid therapy, clinical improvement was noted. There were reports of repeated occurrence of eosinophilic pneumonia with the resumption of Kubitsin therapy.

With the development of eosinophilic pneumonia on the background of the use of the drug Kubitsin, the drug should be immediately canceled, the patient needs to conduct a medical examination, including, if necessary, bronchoalveolar lavage to exclude other causes of the disease (including bacterial, fungal, parasitic infections, and effects of other drugs). The patient should be urgently assigned systemic glucocorticosteroid therapy.

Renal impairment

In patients with renal insufficiency, kidney function and the activity of CK should be determined more than once a week.

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

The effect of the drug on the ability to drive vehicles and work with mechanisms has not been studied. However, considering the undesirable phenomena associated with the use of the drug Kubitsin, the possibility of a negative impact on the ability to drive vehicles and / or work with mechanisms

Form release / dosage:

Lyophilizate for the preparation of a solution for infusions, 350 mg and 500 mg.

Packaging:

For 350 mg and 500 mg per bottle of colorless glass with a capacity of 10 ml, Corked with a rubber stopper, covered with an aluminum cap with a flip cover yellow (for a dosage of 350 mg) and blue (for a dosage of 500 mg) of color.

One bottle together with instructions for use in a cardboard tutu.

Storage conditions:

Store at 2-8 ° C.

The drug should be stored out of the reach of children.

Shelf life:

3 years.

The drug should not be used after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-005067/09

Date of registration:26.06.2009

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS PHARMACEUTICALS UK, Ltd. United Kingdom

NOVARTIS PHARMA, GmbH Germany

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp27.12.2015

Illustrated instructions

Instructions

Kubitsin (Cubicin)