Pixusvri® (Pixuvri®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substancePixantronPixantron
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  • Pixusvri®
    lyophilizate d / infusion 
    Servier Laboratories     France
    • Dosage form: & nbsplyophilizate for the preparation of concentrate for the preparation of a solution for infusions
    Composition:

    1 bottle contains:

    Active substances: pixantrone dimaleate 50.0 mg, in terms of pixantron 29.0 mg,

    Excipients: sodium chloride 92.5 mg, lactose monohydrate 300 mg, sodium hydroxide 1H 0.135 ml, hydrochloric acid 1 H 0.135 ml, water for injection q.s., nitrogen q.s.
    Description:

    Medicinal preparation

    Dark blue compressed powder, without any external signs of consistency change (without destruction, reflow or visible foreign particles).

    Diluted solution: a solution of dark blue color.

    Pharmacotherapeutic group:Antineoplastic agents, anthracyclines and related substances
    ATX: & nbsp

    L.01.D.B.11   Pixantron

    Pharmacodynamics:

    Mechanism of action

    The active substance of the drug Pixusvri® is pixantrone, cytotoxic aza-anthracene dione.

    Unlike anthracyclines (doxorubicin and others) and anthracenedione (mitoxantrone), pixantrone is a weak inhibitor of topoisomerase II. In addition, unlike anthracyclines or anthracenedions, pixantrone directly alkylates DNA, forming stable DNA adducts and interchain breaks. Also, since pixantrone includes a heteroatom of nitrogen in a ring structure and does not have ketone groups, it has less potential for generating reactive oxygen species, binding of iron, and formation of alcohol derivatives that are known to cause cardiac toxicity in anthracyclines. Thanks to this unique structure, pixantrone causes minimal cardiotoxicity in animal experiments, in comparison with doxorubicin or mitoxantrone.

    A comprehensive retrospective population pharmacokinetic / pharmacodynamic analysis of phase 1 studies and combined studies (phase 1/2) demonstrated that the survival rate without signs of progression and development of grade 2 and 3 neutropenia was associated with exposure to the Pixusvri® drug.

    Pediatric Patient Group

    Non-Hodgkin's B-cell lymphomas are not found in the pediatric group from birth to 6 months. There are no data on the use of the medicinal product in children.

    Pharmacokinetics:

    Absorption

    After intravenous administration, the concentrations of pixanthron in the blood plasma reached a maximum value at the end of the infusion,and then decreased polyexponentially. The pharmacokinetics of the drug Pixusvri® did not depend on the dose in the range of 3 mg / m2 up to 105 mg / m2, and there were no significant differences in the administration of the drug in monotherapy or in combination therapy. The average exposure when used as a monotherapy was:

    Dosage Pixewri® (mg / m2)

    Number of patients

    Area under the curve "concentration-time" AUC (0-24 h) (ng.h / ml)

    33

    3

    982± 115

    49

    6

    1727 ±474

    88

    2

    3811

    Based on the analysis of pharmacokinetics data at a target dose of pixanthron 50 mg / m2 it was found that the median exposure during the 28-day cycle was 6320 ng.h / mL, for a cycle of 3 doses / 4 weeks.

    Distribution

    The drug Pixusvri® has a large volume of distribution at 25.8 liters and is approximately 50% bound to plasma proteins.

    Biotransformation

    Acetylated metabolites are the main products of biotransformation of pixantron. but in vitro conversion of pixanthron to acetylated metabolites by N-acetyltransferases NAT1 and NAT2, was very limited. In humans, the drug in the urine was mainly determined unchanged, and very small amounts of acetylated metabolites of phase I and phase II were detected.Therefore, biotransformation is not an important way of deducing a pixantron. Acetylated metabolites were pharmacologically inactive and metabolically stable.

    Excretion

    The plasma clearance of the pixantron varies from moderate to high (72.7 l / h), and the degree of excretion of the drug by the kidneys is low - less than 10% of the administered dose in the interval from 0 to 24 hours. The final half-life was 14.5 to 44.8 hours with an average value of 23.3 ± 8.0 h (n=14, coefficient of variation 34%) and median 21.2 hours. Due to limited renal excretion, plasma clearance is largely unrelated to renal function. Pixusvri® medication can be metabolized in the liver and / or excreted in the bile. Since the metabolism appears to be limited, the isolation of the pixantron in an unchanged form with bile can be the main way of excretion. Hepatic clearance is approximately equal to the hepatic plasmacy, indicating a high proportion of hepatic extraction and effective excretion of the original active substance. Hepatic absorption of pixantron is probably due to active organic cation transporters (OST1), and excretion with bile - involving P-glycoprotein and breast cancer resistance protein (BCRP). Pixantrone does not inhibit or weakly inhibit the transport mechanism of the P-glycoprotein, the breast cancer resistance protein (BCRP) and exporting bile acids (BSEP) in vitro.

    Pixantron inhibition of the mediated OST1 transport of metformin in vitro, but there is no reason to believe that it will inhibit OCT1 in therapeutic concentrations in vivo.

    It was shown that pixantrone is a weak inhibitor of the capture of the transport polypeptide of the organic anions OATP1B1 and OATP1B3 in vitro.

    Linearity / nonlinearity

    The pharmacokinetics of pixantron was linear over a wide dose range, from 3 mg / m2 up to 105 mg / m2.

    Pharmacokinetic / pharmacodynamic relationships

    A relationship was observed between the concentration of the pixantron in the plasma and the number of neutrophils.

    Indications:

    The drug Pixusvri® is indicated as a monotherapy for the treatment of adult patients with repeatedly relapsing or resistant to treatment aggressive non-Hodgkin's B-cell lymphomas. On the fifth or later line, the advantage of using Pixusvri in patients with resistance to prior therapy is not established.

    Contraindications:

    - Hypersensitivity to pixantron dimaleate or any of the excipients

    - Immunization with live viral vaccines

    - Severe suppression of bone marrow function

    - Severe liver dysfunction

    - Pregnancy, the period of breastfeeding

    - Children under 18 years of age (efficacy and safety not studied).

    Carefully:

    With violations of kidney function, violations of liver function of mild and moderate severity, with the general condition of patients assessed on a WHO scale> 2, while using the drug with substrates and inducers of isoenzyme CYP2C8.

    Pregnancy and lactation:

    Women capable of childbearing

    Women who are fertile and their partners must comply with contraceptive measures.

    Women and men should use effective contraception during treatment and within 6 months after it.

    Pregnancy

    There is no data on the use of pixantrone in pregnant women. Studies in animals have shown reproductive toxicity.

    The drug Pixusvri® is contraindicated for use during pregnancy and for women capable of childbearing who do not use contraception.

    Breastfeeding period

    It is not known whether the drug Pixusvri® or its metabolites with human breast milk is excreted.

    Risk for newborns / infants can not be ruled out.

    During treatment with Pixusvri® medication, breastfeeding should be discontinued.

    Fertility

    After multiple administration of Pixusvri® drug at doses of 0.1 mg / kg / day, a dose-dependent testicular atrophy was detected in dogs. This effect has not been studied in humans. Like other drugs belonging to the class of damaging deoxyribonucleic acid (DNA), the drug Pixusvri® can cause impairment of fertility. Although the effect on fertility has not been proven, as a precautionary measure, male patients are recommended to use contraceptive methods (preferably barrier) during treatment and for 6 months after the end of treatment to develop new sperm. In view of the risk of long-term infertility, the possibility of pre-sperm storage should be considered.

    Dosing and Administration:

    Treatment with Pixusvri® should be performed by a doctor who has experience in using antitumor drugs,and having the opportunity to regularly monitor clinical, hematological and biochemical parameters during and after treatment (See "Special Patient Groups").

    Doses

    The recommended dose is 50 mg / m2 pixantrone at 1, 8 and 15 days of each 28-day cycle for up to 6 cycles.

    Important:

    The recommended dose is determined in terms of the basis of the active substance (pixantrone). The calculation of the individual dose for administration to the patient should be based on the content of the active substance in the reconstituted solution that contains 5.8 mg / ml pixanthron and the recommended dose of 50 mg / m2. In some studies and publications, the recommended dose is given in terms of salt (pixantrone dimaleate). However, the dose should be adjusted before the start of each cycle, based on the maximum reduction in hematological parameters or maximum toxicity during the previous treatment cycle. The amount of Pixusvri® in milligrams that must be administered to the patient should be determined based on the patient's body surface area (PPT). PPT should Determined by the institutional standard for the calculation of PPT, and the weight measured on the first day of each cycle should be used.

    Care should be taken for patients with obesity. Dose-based dose determination data are very limited for this group of patients.

    Guidelines for dose adjustment

    The dose change and the time of administration of subsequent doses should be determined on the basis of the clinical state, and also depending on the extent and duration of myelosuppression. For subsequent courses, in usual cases, the previous dosage can be used if the white blood cell and platelet counts returned to an acceptable level.

    If on the first day of any cycle the absolute number of neutrophils (AFN) is <1.0 x 109/ l or the number of platelets is <75 x 109/ l, it is recommended to postpone the treatment until the ASC is restored to the level ≥ 1.0 x 109/ l, and the number of platelets is ≥ 75 x 109/ l.

    Table 1 and Table 2 are recommended as guidelines for dose adjustment on days 8 and 15 within the 28-day cycle.

    Table 1

    Dose changes depending on hematological toxicity on days 8 and 15 of any cycle

    Power

    Number

    platelets

    Index

    ASC

    Dose change

    1-2

    NGN * - 50 x 109/ l

    NGN - 1.0 х 109/ l

    No change in dose or dosing regimen is required.

    3

    <50-25 x 109/ l

    <1.0 -0.5 x 109/ l

    Delay treatment until the platelet count is restored ≥50 x 109/ л and АЧН ≥ 1,0 х 109/ l.

    4

    <25 x 109/ l

    <0.5 x 109/ l

    Delay treatment until the platelet count is restored ≥50 x 109/ l and АЧН ≥ 1,0 х 10%. Reduce the dose by 20%.

    * NGN: the lower limit of the normal range

    table 2

    Treatment changes for nonhematological toxicity

    Toxicity

    Change

    Any manifestation of non-cardial toxicity of grade 3 or 4, except for nausea or vomiting

    Delay treatment until recovery to 1 degree of toxicity. Reduce the dose by 20%.

    Any manifestation of cardiotoxicity of degree 3 or 4 according to the criteria NYHA* or persistent decline in LVEF **

    Delay treatment and monitor before recovery. Consider discontinuation of treatment in the event of a sustained reduction in LVEF ** by ≥ 15% of the baseline value.

    * NYHA: New York Heart Association

    ** LVEF: Left ventricular ejection fraction

    Special patient groups

    Children and teens

    The safety and efficacy of Pixusvri® in children under the age of 18 have not been established to date.No data.

    Elderly patients

    For elderly patients (≥65 years of age), no special dose adjustment is required.

    Patients with impaired renal function

    The safety and efficacy of the Pixusvri® drug has not been established in patients with impaired renal function. Patients with serum creatinine levels exceeding 1.5 times the upper limit of the norm (VGN) were excluded from the randomized study. Therefore, the Pixusvri® drug should be used with caution in patients with impaired renal function.

    Patients with impaired hepatic function

    The safety and efficacy of the use of the Pixusvri® drug has not been established in patients with impaired hepatic function. Pixusvri® drug should be used with caution in patients with mild to moderate liver function disorder. The drug Pixusvri® is contraindicated in patients with severe hepatic impairment (See section "Contraindications").

    Patients with a poor general condition

    At present, there is no information on the safety and efficacy of the drug for patients with a poor general condition (scale index ECABOUTG-B3> 2).Care should be taken when treating such patients.

    Mode of application

    The drug Pixusvri® is for intravenous use only. The safety of intrathecal application is not established.

    The Pixusvri® drug is administered only intravenously slowly using a filter (for at least 60 minutes), only after reconstitution with 5 ml of isotonic sodium chloride solution (0.9%) for injection, and after further dilution with isotonic sodium chloride solution (0 , 9%) for injections up to a final volume of 250 ml.

    Application

    Restoration and breeding

    The drug should not be mixed with any drugs other than those specified in this section below.

    In each vial containing 29 mg of pixantrone, inject 5 ml of a solution for injection of sodium chloride 9 mg / ml (0.9%) under aseptic conditions. Powder should completely dissolve in 60 seconds with shaking. As a result, a dark blue solution with a pixantrone concentration of 5.8 mg / ml should be obtained.

    Breeding: In aseptic conditions, select the volume required for the required dose (based on a concentration of 5.8 mg / ml) and transfer it to an infusion bag of 250 ml with an isotonic sodium chloride solution (0.9%) for injection.The final concentration of pixantrone in the infusion set should be less than 580 μg / ml after the addition of the reconstituted drug. Compatibility with other dilution solutions is not established. After the transfusion, carefully mix the contents of the infusion set. The mixture should be a clear dark blue solution.

    When a diluted Pixusvri drug solution is administered, polyether sulfone filters with a pore size of 0.2 μm should be used.

    The drug Pixusvri® is a cytotoxic drug. Avoid contact with eyes and skin. It is necessary to use gloves, masks and goggles when carrying out procedures with Pixusvri® medicinal preparation, as well as decontamination procedures.

    Special precautions for disposal

    The drug Pixusvri® is intended for single use only. Any unused medicinal product or waste, including materials used for reconstitution, dilution and administration, should be disposed of in accordance with local requirements for cytotoxic drugs.

    Side effects:

    General security profile

    The safety of the Pixusvri® drug was evaluated for 407 patients. The most frequent manifestation of toxicity was the suppression of bone marrow function, in particular the neutrophil cell line. Although the incidence of severe myelosuppression with clinical consequences was relatively low, patients treated with Pixusvri® were under constant monitoring with frequent monitoring of blood counts, in particular neutropenia. The incidence of severe infections was low, and infections caused by conditionally pathogenic microorganisms against the background of immune deficiency did not occur. Although the frequency of cardiotoxicity manifested in the form of congestive heart failure (CHF) appears to be lower than would be expected with the use of related medications such as anthracyclines, monitoring LVEF with multi-projection radionuclide examination of the heart or Echo-CG is recommended for evaluating subclinical cardiotoxicity. The experience of using pixantrone is limited to patients with LVEF ≥ 45%, and in most patients these values ​​were ≥ 50%.The experience of prescribing the Pixusvri® drug to patients with a more severe degree of heart failure is limited, and such appointments can only be done as part of a clinical trial. Other manifestations of toxicity, such as nausea, vomiting and diarrhea, were usually not frequent, mild, reversible, amenable to, and expected in patients undergoing cytotoxic treatment. Effects on liver or kidney function were minimal or not observed.

    List of unwanted reactions in the form of a table

    The undesirable drug reactions (NLR) detected when taking the Pixusvri® drug are taken from the final data of all completed studies. The NLRs are listed in Table 3 below, in the MedDRA system-organ classes and in frequency: 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); very rarely (<1 / 10,000), the frequency is unknown (can not be estimated from the available data). In each group of frequencies, undesirable effects are presented in order of severity.

    Table 3

    Undesirable drug reactions associated with the use of Pixusvri®, reported in the completed studies with Pixusvri®, in frequency

    Classes and systems of organs

    Frequency

    Undesirable effect

    Infectious and parasitic diseases

    Often

    Neutropenic infection, respiratory tract infection, infection

    Infrequently

    Bronchitis, candidiasis, inflammation of the subcutaneous tissue, herpes zoster (shingles), meningitis, nail infection, fungal infection of the oral cavity, oral cavity herpes, pneumonia, salmonella gastroenteritis, septic shock.

    Benign, malignant and unspecified neoplasms (including cysts and polyps)

    Infrequently

    Progression of the neoplasm. Secondary neoplasms (including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)

    Disturbances from the blood and lymphatic system *

    Often

    Neutropenia, leukopenia, lymphopenia, anemia, thrombocytopenia

    Often

    Febrile neutropenia, impaired blood

    Infrequently

    Insufficiency of bone marrow function, eosinophilia

    Immune system disorders

    Infrequently

    Hypersensitivity to the drug

    Disorders from the metabolism and nutrition

    Often

    Anorexia, hypophosphataemia

    Infrequently

    Hyperuricemia, hypocalcemia, hyponatremia.

    Disorders of the psyche

    Infrequently

    Anxiety, insomnia, sleep disorders

    Disturbances from the nervous system

    Often

    Disturbances of taste sensations, paresthesia, headache, drowsiness

    Infrequently

    Dizziness, lethargy

    Vision disorders

    Often

    Conjunctivitis

    Infrequently

    Dryness of the mucous membranes of the eyes, keratitis

    Hearing disorders and labyrinthine disorders

    Infrequently

    Vertigo

    Heart Disease *

    Often

    Left ventricular dysfunction, cardiac dysfunction, congestive heart failure, bundle bundle blockage, tachycardia

    Infrequently

    Arrhythmia

    Vascular disorders

    Often

    Pallor, discoloration of veins, hypotension

    Infrequently

    Venous disorder

    Disturbances from the respiratory system, chest and mediastinal organs

    Often

    Shortness of breath, cough

    Infrequently

    Pleural effusion, pneumonitis, rhinorrhea

    Disorders from the gastrointestinal tract

    Often

    Nausea, vomiting

    Often

    Stomatitis, diarrhea, constipation, abdominal pain, dry mouth, indigestion

    Infrequently

    Esophagitis, oral paresthesia, rectal bleeding

    Disturbances from the liver and bile ducts

    Infrequently

    Hyperbilirubinemia

    Disturbances from the skin and subcutaneous tissues *

    Often

    Skin discoloration, alopecia

    Often

    Erythema, changes from the nails, itching

    Infrequently

    Night sweats, petechial hemorrhages, macular rash, skin ulcers

    Disturbances from musculoskeletal and connective tissue

    Often

    Pain in the bones

    Infrequently

    Arthralgia, arthritis, back pain, muscle weakness, musculoskeletal pain in the chest, musculoskeletal stiffness, neck pain, pain in the extremities

    Disorders from the kidneys and urinary tract

    Often

    Chromaturia (change of color of urine)

    Often

    Proteinuria, hematuria

    Infrequently

    Oliguria

    Violations of the genitals and mammary gland

    Infrequently

    Spontaneous erection of the penis

    Common symptoms and disorders, disorders at the site of administration

    Often

    Asthenia

    Often

    Fatigue, inflammation of the mucous membranes, fever, chest pain, swelling

    Infrequently

    Chills, cold at the injection site, local reaction

    Laboratory and instrumental data

    Often

    An increase in the level of alanine aminotransferase, an increase in the level of aspartate aminotransferase, an increase in the level of alkaline phosphatase in the blood, an increase in the concentration of creatinine in the blood

    Infrequently

    Bilirubinuria, an increase in the concentration of phosphorus in the blood, an increase in the concentration of urea in the blood, an increase in the concentration of gamma-glutamyltransferase, an increase in the number of neutrophils, a decrease in body weight.

    * The NLRs described below

    Description of individual adverse reactions

    Hematologic toxicity and complications of neutropenia

    Hematologic toxicity was the most commonly observed manifestation of toxicity, but usually this condition was easily controlled by immunostimulants and blood transfusion, if necessary. Although a randomized trial of grade 3 and 4 neutropenia was more common in patients receiving Pixusvri®, in most cases it was without complications, was not cumulative, and was rarely accompanied by febrile neutropenia or infection. Importantly, growth factor support was generally not required, and transfusion of erythrocyte and platelet masses was rare (See "With caution").

    Cardiotoxicity

    In a clinical study, a reduction in the ejection fraction was observed in 13 patients (19.1%) in the Pixusvri® drug group.In 11 patients who received Pixusvri® medication, these events had a degree of 1-2, and in 2 patients - grade 3; these phenomena were transient and not associated with the dose of Pixusvri®. Cases of heart failure (MedDRA: heart failure and congestive heart failure) were observed in 6 patients (8.8%) who received the Pixusvri® medication (2 patients with a grade of 1-2, 1 patient with a grade of 3 and 3 patients with a grade of 5 ). In three patients receiving Pixusvri® (4.4%), tachycardia, arrhythmia, sinus tachycardia, or bradycardia were noted.

    A baseline cardiac examination using a multi-projected radioisotope examination of the heart or Echo-CG is recommended, especially for patients with risk factors for severe cardiac toxicity. It should be considered the possibility of repeated multi-projected radioisotope examination of the heart or Echo-CG for the determination of LVEF for patients with risk factors such as high cumulative exposure to previously obtained anthracyclines or a history of severe heart disease (See "With caution").

    Other common types of toxicity

    Changes in skin color and chromaturia are known effects associated with taking Pixusvri®, due to the color of the preparation (blue). Skin discoloration usually disappears within a few days or weeks, as the drug is removed from the body.

    Overdose:

    No overdose of Pixusvri® was reported.

    Single doses of pixantrone to 158 mg / m were introduced in clinical studies with dose escalation, with no signs of dose-related toxicity.

    In case of an overdose, maintenance therapy is recommended.

    Interaction:

    No interactions were reported with other medications in humans, and no interaction with other drugs with human participation was also conducted.

    Inhibition studies in vitro

    Research in vitro with the most common isoforms of human cytochrome P450 (including CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) showed possible inhibition of a mixed type of isoenzymes CYP1A2 and CYP2C8, which can be of clinical importance.Other Significant Clinical Interactions with Cytochrome P450s it was not revealed.

    Theophylline: with the simultaneous use of the medicinal product theophylline with a narrow therapeutic index, which is metabolized primarily by isoenzyme CYP1A2, there is a theoretical danger that theophylline concentration may increase with subsequent manifestation of its toxic effects. The level of theophylline should be carefully monitored in the first weeks after the initiation of co-therapy with the Pixusvri® drug.

    Warfarin partially metabolized by isoenzyme CYP1A2, so with a simultaneous appointment, there are theoretical concerns about the effect that the inhibition of warfarin metabolism on its expected effect may have. The coagulation parameters, especially the international normalized ratio (INR), should be monitored in the first days after the initiation of simultaneous therapy with Pixusvri® drug.

    Amitriptyline, haloperidol, clozapine, ondansetron and propranolol metabolized by isoenzyme CYP1A2, therefore there is a theoretical danger,that with the simultaneous therapy with the drug Piksvri®, the content of these drugs in the blood can increase.

    Although the risk of inhibiting isoenzyme CYP2C8 pixantrone has not been proven, caution should be exercised while concurrently administering substances that are primarily metabolized by CYP2C8, such as repaglinide, rosiglitazone or paclitaxel, for example, through careful monitoring of side effects.

    In studies in vitro it was found that pixantrone is a substrate for the membrane transport of proteins P-gp/BRCP and OCT1, and drugs that inhibit these transport proteins may possibly decrease the efficiency of absorption and excretion of pixantron by the liver. Careful monitoring of blood indicators when co-prescribing with drugs that inhibit these transport proteins, such as ciclosporin A or tacrolimus (which are often used in the chronic "graft versus host" reaction) and drugs for HIV therapy (ritonavir, saquinavir or nelfinavir).

    Care should be taken when using the drug with inducers (rifampicin, carbamazepine) isoenzyme CYP2C8.

    Special instructions:

    Before starting treatment with Pixusvri®, a thorough initial check of blood counts, the concentration of total bilirubin and total serum creatinine, and assessment of cardiac function, as determined by LVEF, should be performed.

    Myelosuppression

    Possible development of severe myelosuppression. Patients treated with Pixusvri® may develop myelosuppression (neutropenia, leukopenia, anemia, thrombocytopenia, and lymphopenia), with neutropenia as the predominant symptom. When the recommended dosage and administration regimen are followed, neutropenia is usually transient and manifests itself as much as possible between the 15th and 22nd day when the drug is administered on a "day 1, day 8 and day 15" schedule, with normal recovery usually occurring to The 28th day.

    Careful monitoring of blood counts is required, including the number of leukocytes, erythrocytes, platelets and the absolute number of neutrophils. Recombinant factors of hematopoietic growth can be used in accordance with the recommendations of the institution or the European Medical Society.oncology (ESMO). Consider the possibility of changing the dose (see "Method of administration and dose").

    Cardiotoxicity

    Impaired cardiac function, including reduced LVEF or lethal CHF, may occur during or after treatment with Pixusvri®. Cardiovascular disease in active or latent form, prior therapy with anthracyclines or aptracenedione, previous or concomitant X-ray therapy of the mediastinum or concomitant use of other cardiotoxic drugs may increase the risk of cardiotoxicity. Cardiotoxicity on the background of taking Pixusvri® medication can manifest independently of the presence of cardiac risk factors.

    For patients with heart disease or risk factors, such as baseline LVEF <45% according to radionuclide angiography (multi-projection radioisotope study of the heart), clinically significant cardiovascular disorders (corresponding to grades III or IV on the scale of the New York Heart Association [NYHA]), myocardial infarction, suffered during the last 6 months, severe arrhythmia, uncontrolled hypertension,uncontrolled angina, or previous administration of doxorubicin or an equivalent in a cumulative dose of more than 450 mg / m2, a careful evaluation of the risk-benefit ratio before administration of Pixusvri® medication is necessary.

    Cardiac function monitoring should be performed before starting treatment with Pixusvri® and then periodically. If, during treatment, signs of cardiotoxicity are detected, it is necessary to evaluate the risk-benefit ratio of continuing Pixusvri® therapy.

    Secondary malignant neoplasm

    The development of secondary hematologic diseases, for example, secondary AML or MDS, has been described as complications of chemotherapy regimens containing anthracyclines and other topoisomerase II inhibitors. Such secondary hematological oncological diseases, including AML and MDS, can develop both during and after the treatment with Pixusvri.

    Infection

    Clinical studies have reported infections, including pneumonia, inflammation of the subcutaneous tissue, bronchitis and sepsis. Infections could lead to hospitalization, septic shock and death.Patients with neutropenia are more likely to be infected, although there has been no increase in the incidence of atypical, difficult-to-treat infections, such as systemic fungal infections or infections caused by opportunistic microorganisms, in particular Pneumocystis jiroveci.

    Pixusvri® medication should not be given to patients with active infection, severe infection, patients with recurrent or chronic infections in the anamnesis, or to conditions that predispose to the development of severe infection.

    Tumor lysis syndrome

    Pixantrone can cause hyperuricemia due to the massive catabolism of purines that accompanies drug-induced rapid disintegration of tumor cells (tumor lysis syndrome), and can lead to electrolyte imbalance that can cause kidney damage. After treatment, it is necessary to determine the concentration of uric acid, potassium, calcium phosphate and creatinine in the blood in patients with a high risk of tumor lysis (elevated levels of low-density lipoproteins, high tumor volume, high initial serum uric acid or phosphate concentrations).Hydration, alkalinization of urine and prevention of allopurinol or other drugs designed to prevent hyperuricemia may reduce potential complications of tumor lysis syndrome.

    Vaccination

    Vaccination may be ineffective if conducted during the treatment with Pixusvri®. Vaccination with live viral vaccines is contraindicated because of the suppression of immunity associated with Pixusvri® therapy (See section "Contraindications").

    Extravasation of the drug

    If the drug penetrates from the vessel into the surrounding tissue, then its administration should be stopped immediately and again begin to inject the drug into another vein. The drug Pixusvri® does not cause skin abscesses, which reduces the risk of local reaction after its extravasation.

    Prevention of photosensitivity reactions

    Photosensitivity is a potential risk, based on research data in vitro and preclinical research in vivo. During the clinical research program, confirmed cases were not reported. As a precaution, patients should be advised to follow the sun protection measures,wear protective clothing from the sun and use sunscreen. Since most drug-induced photosensitivity reactions are caused by light wavelengths within the UV-A range, sunscreens are recommended that effectively absorb UVA.

    Patients on a diet low in sodium

    After dilution of the drug, a single dose contains approximately 1000 mg (43 mmol) of sodium. This need to be taken into account by patients on a diet with controlled sodium content.

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

    Because of the likelihood of side effects when taking the drug, in particular, such as drowsiness, dizziness, caution should be exercised when engaging in potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

    Form release / dosage:

    Lyophilizate for the preparation of concentrate for the preparation of a solution for infusions, 29 mg.

    Packaging:

    The amount of the drug, equivalent to 29 mg pixantron, in a bottle of borosilicate glass (or glass 1 of hydrolytic class) of 20 ml with a gray plug of butyl rubber and an aluminum cap,coated with a colorless varnish, with a red safety cap (20 mm Flip-Off ®seal).

    1 bottle together with instructions for medical use in a cardboard box.

    Storage conditions:

    At a temperature of 2 to 8 ° C.

    Keep out of the reach of children. Store in a cardboard box to protect from light.

    Shelf life:

    5 years.

    Do not use after expiry date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004439
    Date of registration:01.09.2017
    Expiration Date:01.09.2022
    The owner of the registration certificate:Servier LaboratoriesServier Laboratories France
    Manufacturer: & nbsp
    Representation: & nbspServier Laboratories Servier Laboratories France
    Information update date: & nbsp04.10.2017
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