Javlor (Javlor)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceWinfluninWinflunin
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  • Javlor
    concentrate d / infusion 
    Pierre Fabre Medication Production     France
    • Dosage form: & nbspconcentrate for solution for infusion
    Composition:

    Name of substance

    Dosage per vial

    50 mg / 2ml

    100 mg / 4 ml

    250 mg / 10 ml

    Active substance:




    Vinflunine ditartrate

    (in terms of vinflunine base)

    68.35 mg

    50.0 mg

    136.70 mg

    100.0 mg

    341.75 mg

    250 mg

    Excipient:




    Water for injections

    up to 2 ml

    up to 4 ml

    up to 10 ml
    Description:Transparent solution from colorless to light yellow color.
    Pharmacotherapeutic group:Antitumor agent - alkaloid
    ATX: & nbsp

    L.01.C.A.05   Winflunin

    Pharmacodynamics:
    Vinflunine has a cytostatic effect associated with the inhibition of tubulin polymerization in the process of cellular mitosis.
    Pharmacokinetics:

    Vinflunine demonstrates linear pharmacokinetics when administered at standard dosages (from 30 mg / m2 up to 400 mg / m2).

    Exposure of vinflunin in the blood - the area under the concentration-time curve (AUC) significantly correlates with the severity of leukopenia, neutropenia, and the severity of asthenia.

    Distribution

    Vinflunine moderately binds to blood plasma proteins (67.2 ± 1.1%), the concentration ratio between plasma and total blood volume is 0.8 ± 0.12.

    The association with proteins is mainly carried out with high-density lipoproteins and serum albumin, does not reach saturation in the range of therapeutic concentrations of the drug.Interaction with alpha-1-acid glycoprotein and platelets is insignificant (<5%).

    The limiting volume of distribution is 2422 ± 676 l (about 35 l / kg), which confirms the wide distribution of the drug in the tissues.

    Metabolism

    The main active metabolite in the blood is 4-O-deacetylvinvinlunine, formed as a result of the action of various esterases. All other identified metabolites are formed by cytochrome CYP3A4 isoenzyme.

    Excretion

    The half-life of vinflunine (T½) is 40 hours.

    The formation and excretion of the metabolite 4-O-deacetylvinvlunine occurs more slowly, its half-life (T½) is about 120 hours.

    Isolation of vinflunine and its metabolites occurs with feces (2/3) and urine (1/3).

    Indications:Monotherapy of adult patients with advanced or metastatic urothelial transitional cell carcinoma after therapy with platinum preparations, which did not give a positive result.
    Contraindications:
    - hypersensitivity to the active substance or to vinca alkaloids;
    - infectious diseases within 2 weeks before the start of therapy or ongoing severe infectious diseases;
    - the absolute number of neutrophils is less than 1,500 cells / μl of blood at the first administration of the drug and less than 1,000 cells / μl of blood in subsequent injections of the drug or platelets less than 100,000 cells / μl of blood;
    - pregnancy and the period of breastfeeding;
    - children's age till 18 years.
    Carefully:

    Syndrome of congenital lengthening of the interval Q-T, heart disease (heart failure, myocardial infarction, bradycardia).

    Electrolyte imbalance (eg, hypokalemia, hypomagnesemia). Simultaneous reception of medicinal products extending the interval Q-T (including antiarrhythmic IA and III classes).

    Hepatic insufficiency of moderate and severe severity (the standard dose of the drug Zhavlor should be reduced).

    Renal failure of moderate to severe severity (the standard dose of the drug Zhavlor should be reduced).

    Age over 75 years (recommended standard doses of the drug Zhavlor should be reduced).

    Pregnancy and lactation:

    The drug Zhavlor should not be used during pregnancy due to the potential risk to the embryo and fetus.

    When pregnancy occurs during the use of the drug,the patient should be warned about the existence of a risk to the fetus, such patients need to be monitored more carefully. Consultation of a specialist in genetics is recommended. Genetic counseling is also recommended for patients planning to have children after the end of therapy.

    Breastfeeding during therapy with the drug Zhavlor contraindicated.

    Dosing and Administration:
    The recommended dose is 320 mg / m2 vinflunine as an intravenous infusion for 20 minutes once every 3 weeks.
    When assessing the overall status on a WHO / ECOG scale of 0 or 1, and after preliminary irradiation of the pelvic area,
    treatment should begin with a dose of 280 mg / m2 . In the absence of hematologic toxicity during the first cycle, requiring deferment of treatment or dose reduction, the dose should be increased to 320 mg / m2 for subsequent cycles (1 every 3 weeks).

    Table 1. Temporary suspension or cessation of treatment in the event of toxicity

    Types of toxicity

    Day of planned infusion

    Neutropenia (ANC* <1,000 cells / μl) or Thrombocytopenia (platelets <100,000 cells / μl)

    - Suspension of treatment before recovery (ANC ≥1000 cells / μl and platelets> 100,000 cells / μl), adjust the dose as necessary (see Table 2);

    - Termination of treatment if the indicators did not return to normal within 2 weeks

    Organotoxicity: mild, severe or life threatening

    - Suspension of treatment to the level of weak or zero toxicity or to the initial level (see Table 2);

    - Discontinuation of treatment if the reduction in toxicity did not occur within

    2 weeks

    Myocardial ischemia in patients with a history of myocardial infarction or angina

    - Termination of treatment

    * ANC - absolute number of neutrophils

    Table 2. Correction of dose in case of toxicity

    Types of toxicity

    Dosing regimen

    (NCI ITS V. 2.0)*

    The initial dose of 320 mg /m2

    Initial dose 280 mg / m2


    first episode of toxicity

    second subsequent episode of toxicity

    third consecutive episode of toxicity

    first episode of toxicity

    second subsequent episode of toxicity

    Neutropenia of the 4th degree (ANC< 500 cells / mcl> 7days

    280

    mg / m2

    250

    mg / m2

    The End

    sweep

    treatment

    250

    mg / m2

    The End

    sweep

    treatment

    Febrile neutropenia (ANC<1,000 cells / μL and body temperature ≥38.5 ° C)

    Mucositis or constipation of 2nd degree lasting more than 5 days or 3-4 degrees of any duration1

    Any other toxicity of grade 3 or 4 (except for nausea or vomiting 3 degree)2

    * National Cancer Research Institute, General toxicity test (NCI-CTC).
    [1] In the case of constipation of the 2nd degree in the NCI ITS, laxatives are required, grade 3 is an obstruction requiring the evacuation of the intestinal contents by manual or enema, with grade 4 obstruction or toxic megacolon. Mucositis 2 degrees is considered "moderate", 3 degrees - "heavy", 4 degrees - life-threatening.
    [2] Nausea of ​​grade 3 NCI CTC is defined as insignificant, does not require intravenous fluids. Vomiting of 3 degrees ≥ 6 times a day requires premedication or the need for intravenous fluids.

    Special patient groups

    Patients with impaired hepatic function

    The following doses are recommended:

    - in patients with prothrombin index more than 70% and, at least, with one of the following indicators: the concentration of total bilirubin exceeds the upper limit of the norm (VGN) no more than 1.5 times; and / or transaminase activity is more than 1.5 times higher than IGN, but no more than 2.5 times; and / or the activity of gamma-glutamyltransferase (GGT) exceeds HHV, but not more than 5 times; or the activity of transaminases exceeds IGN 2.5 times (up to 5 times only in the presence of metastases in the liver) - dose adjustment is not required,the recommended dose of vinflunine is 320 mg / m (1 every 3 weeks);

    - in patients with mild hepatic insufficiency (class A on the Child-Pugh scale) or in patients with a prothrombin index ≥ 60% and the concentration of total bilirubin more than 1.5 times higher than VGN, but not more than 3 times and one of the following:

    • the activity of transaminases exceeding HHV;
    • and / or the activity of GGT exceeding VGN 5-fold - the recommended dose of vinflunine is 250 mg / m2 (Once in 3 weeks);
    • in patients with hepatic insufficiency of medium degree (class B on the Child-Pugh scale) or in patients with a prothrombin index ≥ 50%;

      and if the bilirubin concentration exceeds the VGN by more than 3 times;

      and the activity of transaminases and GGT exceeds IGN - the recommended dose of vinflunine is 200 mg / m 2 (Once in 3 weeks).

    In patients with severe hepatic insufficiency (class C on the Child-Pugh scale) or in patients with a prothrombin index <50%, or with a bilirubin concentration exceeding the VGN by more than 5 times, or with transaminase activity exceeding the IGN of more than 2, 5 times (from 5 or more times only in the presence of metastases in the liver), or with GGT activity exceeding the VGN by more than 15 times, the study of vinflunin was not carried out.

    Patients with impaired renal function

    In clinical trials, standard doses were used in patients with creatinine clearance> 60 mL / min.

    For patients with impaired renal function of moderate severity (creatinine clearance 40-60 ml / min), the recommended dose is 280 mg / m2 (Once in 3 weeks).

    For patients with severe renal impairment (creatinine clearance 20-39 mL / min), the recommended dose is 250 mg / m2 (Once in 3 weeks).

    For subsequent treatment cycles, the dose should be adjusted according to the toxicity (see Table 3).

    Elderly patients (75 years and older):

    - for patients younger than 75 years, dose adjustment is not required;

    - for patients from 75 to 79 years, the recommended dose is 280 mg / m2 (Once in 3 weeks);

    - for patients from 80 years and older the recommended dose is 250 mg / m2 (Once in 3 weeks).

    For subsequent treatment cycles, the dose should be adjusted according to toxicity.

    Table 3. Correction of dose in case of manifestation of toxicity in patients with impaired renal function or in elderly patients

    Types of toxicity

    Dosing regimen

    (NCI ITS v. 2.0)*

    Initial dose 280 mg / m2

    Initial dose of 250 mg / m2

    first episode of toxicity

    second subsequent episode of toxicity

    first episode of toxicity

    second subsequent episode of toxicity

    Neutropy of the 4th degree (ANC< 500 cells / μl > 7 days

    250

    mg / m2

    The End

    sweep

    treatment

    225

    mg / m2

    The End

    sweep

    treatment

    Febrile neutropenia (ANC <1,000 cells / μl and body temperature ≥ 38.5 ° C)

    Mucositis or constipation of 2nd degree lasting more than 5 days or 3-4 degrees of any duration1

    Any other toxicity of grade 3 or 4 (except nausea or vomiting of grade 3) 2

    * National Cancer Research Institute, General toxicity test (NCI-CTC).

    1 In case of constipation of the 2nd degree in the NCI CTC, laxatives are required, grade 3 is an obstruction requiring the evacuation of the intestinal contents by the manual method or with the use of an enema, and at 4 degrees there is obstruction or toxic megacolon. Mucositis 2 degrees is considered "moderate", 3 degrees - "heavy", 4 degrees - life-threatening.

    2 Nausea of ​​grade 3 NCI is defined as minor, does not require intravenous fluids. Vomiting of 3 degrees ≥ 6 times a day requires premedication or the need for intravenous fluids.

    Pediatric Use

    There is no experience of using Javlor in children.

    Dilution of concentrate

    To dilute the concentrate use 0.9% solution of sodium chloride for infusion or 5% solution of dextrose for infusion. The volume of concentrate corresponding to the calculated dose of vinflunine is diluted in 100 ml of the solvent in the infusion bag. The prepared solution must be protected from exposure to light before the introduction procedure.

    Method of administration

    - in the infusion system, two infusion bags:

    №1: 500 ml infusion bag with 0.9%

    solution of sodium chloride for infusions

    or 5% dextrose solution for infusion;

    №2: 100 ml infusion bag with the prepared solution of the preparation Zhavlor;

    • it is necessary to provide venous access in the vein area of ​​the upper part of the forearm or the central vein of the hand, the introduction of the drug into the vein of the back of the hand and into the veins located close to the joints should be avoided;
    • infusion begins with the introduction of 250 ml of a 0.9% solution of sodium chloride for infusion or a 5% solution of dextrose for infusion;
    • the infusion of the drug Zhavlor is carried out for 20 minutes;
    • during the infusion it is necessary to frequently check the permeability of the venous duct and carefully follow the measures to prevent extravasation;
    • after administration of the Javlor drug solution, the remaining 250 ml of a 0.9% sodium chloride solution for infusion or 5% dextrose solution for infusion (300 ml / h flow rate) is administered.
    Side effects:
    Adverse reactions are systematized according to the system-organ classes and are listed according to the following gradation:
    Often (≥ 1/10),
    often (≥ 1/100 to <1/10),
    infrequently (≥ 1/1000 to <1/100),
    rarely (≥ 1/10000 to <1/1000),
    very rarely (<1/10000)
    frequency is unknown (can not be estimated from available data).

    Infectious and parasitic diseases: often: infectious diseases against neutropenia, infectious complications (viral, bacterial, fungal); infrequently: bacterial sepsis on the background of neutropenia.

    Violations from the blood and lymphatic system:very often: neutropenia, leukopenia, anemia, thrombocytopenia; often: febrile neutropenia.

    Immune system disorders: often: hypersensitivity.

    Metabolic disorders: very often: hyponatremia, decreased appetite; often: dehydration.

    Disorders of the psyche: often: insomnia.

    Impaired nervous system: Often: peripheral sensory neuropathy; fainting, headache, dizziness, neuralgia, eating disorders,Neuropathy; infrequently: peripheral motor neuropathy; rarely: reverse reversible encephalopathy syndromea.

    Disorders from the side of the organ of vision: infrequently: visual impairment.

    Hearing disorders and labyrinthine disturbances: often: pain in the ear; infrequently: dizziness, ringing in the ears.

    Heart Disease: often: tachycardia; infrequently: ischemia myocardium, infarction myocardium.

    Vascular disorders: often: increased blood pressure, venous thrombosis, phlebitis, decreased blood pressure.

    Disturbances from the respiratory system, chest and mediastinal organs:often: dyspnea, cough; infrequently: acute respiratory distress syndrome, pain in the larynx and pharynx.

    Disorders from the gastrointestinal tract:very often: constipation, abdominal pain, vomiting, nausea, stomatitis, diarrhea; often: intestinal obstruction, dysphagia, mucous membrane disorders of the oral cavity, dyspepsia; infrequently: pain when swallowing, gastritis,esophagitis, gingivitis.

    Disorders from the endocrine system: infrequently: a syndrome of inadequate secretion of an antidiuretic hormone (SNA ADH)a

    Neoplasms: benign, malignant and unknown etiology; infrequent: tenderness in the tumor a.

    Disturbances from the skin and subcutaneous tissues: very often: alopecia, often: skin reactions (rash, urticaria), itching, hyperhidrosis; infrequently: erythema, dry skin.

    Disturbances from the musculoskeletal system and connective tissue:very often: myalgia; often: muscle weakness, arthralgia, musculoskeletal pain of various locations, pain in the chest, back pain, pain in the jaw, pain in the limbs.

    Disorders from the kidneys and urinary tract: infrequently: renal failure.

    General disorders and disorders at the site of administration: very often: asthenia, fatigue, reaction at the injection site, fever; often: chest pain, chills, pain and / or swelling at the injection site; infrequently: extravasation.

    Laboratory and instrumental data: very often: weight loss; infrequently: increased activity of transaminases, weight gain.

    Note:

    a The undesirable reaction recorded after the release of the drug on the market

    Overdose:

    The main toxic effect due to overdose is the suppression of bone marrow function with the risk of subsequent development of severe infection.

    The specific antidote is not known.

    In case of an overdose, it is necessary to hospitalize the patient and carefully monitor the functions of vital organs. Appropriate measures should be taken such as, blood transfusion, administration of antibiotics, growth factors.
    Interaction:

    In vitro studies have shown that vinflunine does not have an inducing effect on the activity of CYP1A2, CYP2B6 or CYP3A4 isozymes and does not inhibit the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 isoenzymes.

    Research in vitro showed that vinflunine, like other vinca alkaloids, is a substrate for Pgp, but with less affinity, so the risk of clinically significant interaction is unlikely.

    When combined use of vinflunine with cisplatin, carboplatin, capecitabine or gemcitabine was not observed pharmacokinetic interactions of drugs.

    With the combined use of vinflunine with doxorubicin, no pharmacokinetic interactions drugs, but this combination is associated with an increased risk of hematological toxicity.

    Joint application with ketoconazole (400 mg dose orally for 8 days) leads to an increase in the exposure of vinflunine in the blood (by 30%) and to an increase in the exposure of its metabolite 4-O-deacetyl-vinflunine (by 50%).

    Avoid joint use of vinflunine and strong inhibitors of isoenzyme CYP3A4 (ritonavir, ketoconazole, itraconazole, grapefruit juice) or its inducers (rifampicin, the herb of St. John's wort perfumed), since these substances can change the concentration of vinflunin.

    Avoid joint use with drugs that extend the interval Q-T/Q-Tc.

    Joint use with opioids increases the risk of constipation. The pharmacokinetic interaction between vinflunine and liposomal doxorubicin was noted, which caused a 15% to 30% increase in the exposure of vinflunin and a 2-3 times decrease in the area under the concentration-time curve (AUC) doxorubicin, while the concentrations of doxorubicinol metabolite remained unchanged.

    Research in vitro showed that such changes may be due to absorption of vinflunine by liposomes and an altered distribution both compounds in the blood. Therefore, combinations of this type should be used with caution.

    Possible interaction of vinflunine with paclitaxel and docetaxel (CYP3 substrates) was studied in the study in-vitro (slight inhibition of vinflunin metabolism), but no special clinical studies have been conducted to interact with these drugs.

    Special instructions:

    The drug Zhavlor is intended exclusively for intravenous administration.

    Intrathecal injection leads to death, is strictly prohibited!

    Treatment with the drug Zhavlor should be conducted under the supervision of a doctor who has experience with antitumor drugs.

    Therapy is performed under strict hematological control, determining the number of leukocytes, neutrophils, platelets, as well as the concentration of hemoglobin before each regular infusion.

    After the introduction of vinflunine, there were several cases of prolongation of the Q-T interval, which increases the risk of ventricular arrhythmia.Despite the fact that with the use of vinflunine, ventricular arrhythmias were not observed, vinflunine should be used with caution in patients at risk of developing proarhythmy (eg, heart failure, prolongation of the QT interval in history, hypokalemia). It is not recommended simultaneous administration of two or more drugs extending the interval Q-T / Q-Tc.

    Particular caution should be exercised when vinflunine is administered to patients with a history of cardiovascular disease. There may be ischemic cardiovascular complications, especially in patients who have a major cardiovascular disease.

    Patients receiving Zhavlor should be carefully observed by the doctors for the development of cardiovascular complications. Regularly carry out a thorough analysis of the relationship between risk and benefit! The possibility of reversing vinflunin should be considered for patients who developed myocardial ischemia.

    After the introduction of vinflunine, cases of reverse reversible encephalopathy syndrome (ZOO) were observed. Typical clinical symptoms to varying degrees include the following manifestations: neurological (headaches, confusion,convulsive seizures, visual disorders), systemic (arterial hypertension) and gastrointestinal (nausea, vomiting).

    Radiological signs consist in the presence of changes in the white matter of the posterior parts of the brain. Patients with emerging symptoms of ZOO should monitor blood pressure. To confirm the diagnosis, it is recommended to perform a brain imaging.

    Clinical and radiological signs, as a rule, are reversible and quickly disappear after drug withdrawal.

    It should be considered the possibility of withdrawal of vinflunin in patients who have neurological signs of ZoE.

    After the introduction of vinflunine, pronounced hyponatremia was observed, including cases due to the syndrome of inadequate secretion of the antidiuretic hormone (SNH ADH). Therefore, regular monitoring of serum sodium levels during treatment with vinflunin is recommended.

    In order to prevent constipation, from the first to the fifth or the seventh day after each use of the drug, Zhavlor should use laxatives, as well as a diet rich in fiber and abundant drink.Patients with high risk of constipation (simultaneous reception opiates, peritoneal carcinoma, tumors of the abdominal cavity, prior extensive abdominal surgery) should be administered osmotic laxatives once a day in the morning before breakfast 1 to 7 days after application ditartrate.

    In the presence of constipation 2 degrees, which requires the use of laxatives for at least 5 days, or constipation ≥ 3 degrees for any duration should adjust the dose ditartrate (see. Table 2 of "Dosage and Administration").

    Constipation is 3 degrees obstruction requiring evacuation of intestinal contents by manual aids or enemas using, when there is obstruction of 4 degrees or toxic megacolon.

    When gastrointestinal toxicity ≥ 3 degrees (excluding nausea and vomiting) or mucositis (grade 2 for 5 days or more, 3 or ≥ extent of any duration) is required to dose adjustment. 2 degree is "average", 3 degree is "severe", and 4 degree is "life-threatening" (see Table 2 of the section "Method of administration and dose").

    The drug should be injected into a large vein,preferably in the area of ​​the vein of the upper part of the forearm or the central vein of the arm.

    When the drug is administered through the peripheral vein vinflunine can cause her phlebitis.

    To avoid extravasation or hemorrhage, you need to make sure that the needle is correctly inserted before starting the infusion.

    For veins of small diameter or veins with a tight wall, lymphatic edema or a recent puncture of the same vein, it is preferable to use a central catheter.

    Men and women should use reliable methods of contraception during the treatment period, and also within three months after the end of therapy.

    Due to the possibility of irreversible loss of fertility as a result of treatment with vinflunin, patients should be given a recommendation but preservation of sperm before the start of treatment with the drug Zhavlor.

    General precautions for preparation and use.

    The preparation and administration of the solution is performed by medical personnel, properly trained in the handling of cytotoxic substances.

    All procedures for preparing a solution for infusion require compliance with aseptic conditions. Medical staff are advised to use gloves, goggles and protective clothing.

    If you get a solution of the drug on the skin, immediately rinse them thoroughly with soap and water. If the solution of the drug hits the mucous membranes, immediately rinse thoroughly with water.

    Pregnant women are prohibited from working with the drug Zhavlor.

    Recycling

    The drug Zhavlor is intended only for single use.

    All unused material and waste must be disposed of in accordance with the requirements for handling cytotoxic drug preparations.

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

    Patients should not be administered vehicles and other potentially hazardous activities that require increased concentration, attention and speed of psychomotor reactions if they experience adverse reactions that may affect the performance of this activity (for example, frequent fatigue, dizziness, fainting).

    Form release / dosage:
    Concentrate for the preparation of a solution for infusions of 25 mg / ml.
    Packaging:
    50 mg / 2 ml, 100 mg / 4 ml, 250 mg / 10 ml in vials of colorless glass with a black stopper made of chlorobutyl or a laminated rubber stopper of gray color,sealed with aluminum caps gray, with a plastic protective cover type "flip - off" yellow for a vial of 50 mg / 2 ml, of pink color for a vial of 100 mg / 4 ml vial orange to 250 ml / 10 ml. 1 bottle in a plastic pallet along with the instruction for use is placed in a cardboard pack.
    Storage conditions:

    At temperatures from + 2 ° to + 8 ° C in the dark place.

    Keep out of the reach of children.

    Storage during transport

    During transportation of the drug it is allowed to store it at a temperature of up to + 30 ° C in a place protected from light for no more than 7 days.

    Shelf life:

    3 years.

    Do not use after the expiry date.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-001721
    Date of registration:02.07.2012
    Expiration Date:Unlimited
    The owner of the registration certificate:Pierre Fabre Medication ProductionPierre Fabre Medication Production France
    Manufacturer: & nbsp
    Representation: & nbspPIER FABR PIER FABR France
    Information update date: & nbsp17.05.2017
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