Composition, form of production and packaging
Concentrate for solution for infusion 1 ml
vinflunine 25 mg
2 ml - bottles of glass (1) - packs of cardboard.
4 ml - bottles of glass (1) - packs of cardboard.
10 ml - bottles of glass (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2013.
PHARMACHOLOGIC EFFECT
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 / m 2 to 400 mg / m 2 ).
Exposure of vinflunin in the blood - AUC significantly correlates with the severity of leukopenia, neutropenia and severity of asthenia.
Distribution
Vinflunine moderately binds to blood plasma proteins (67.2 В± 1.1%), the concentration ratio between plasma and total blood volume is 0.8 В± 0.12. The connection 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 В± 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
T 1/2 vinflunine is 40 hours.
The formation and excretion of the 4-O-deacetylvinvinlunine metabolite occurs more slowly, its T 1/2 is approximately 120 hours. The excretion 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.
DOSING MODE
Intravenously.
The recommended dose is 320 mg / m 2 of vinflunin in the form of a twenty-minute intravenous infusion every 3 weeks.
When assessing the general condition on a WHO / ECOG scale of 0 or 1, and after preliminary irradiation of the pelvic area, treatment should begin at a dose of 280 mg / m 2 . In the absence of hematologic toxicity during the first cycle, requiring delay in treatment or dose reduction, the dose should be increased to 320 mg / m 2 for subsequent cycles (1 every 3 weeks).
1.Temporary suspension or discontinuation of treatment in case of toxicity
Types of toxicity Day of planned infusion
Neutropenia (ANC * < 1,000 cells / Ојl) or Thrombocytopenia (platelet count <100,000 cells / Ојl) - Suspension of treatment before recovery (ANC> 1,000 cells / ОјL and platelets> 100,000 cells / Ојl), adjust the dose if necessary (see Table 2 ); - Termination of treatment if the indicators did not return to normal within 2 weeks
Toxicity of 2-4 degree - Suspension of treatment before the appearance of toxicity of 1-2 degrees, if necessary, adjust the dose (see Table 2); - Termination of treatment if the reduction in toxicity did not occur within 2 weeks
Ischemia of the myocardium in patients with a history of myocardial infarction or angina pectoris - Treatment termination
* ANC - absolute number of neutrophles
2. Correction of the dose in case of toxicity:
Types of toxicity
(NCI CTC v. 2.0) * Initial dose 320 mg / m 2 Initial dose 280 mg / m 2
first episode of toxicity second subsequent episode of toxicity third subsequent episode of toxicity first episode of toxicity second subsequent episode of toxicity
Neutropenia 4 degrees (ANC <500 cells / ОјL> 7 days) 280 mg / m 2 250 mg / m 2 treatment discontinuation 250 mg / m 2 discontinuation of treatment
Febrile neutropenia (ANC <1,000 cells / ОјL and body temperature> 38.5 В° C)
Mucositis or constipation of 2nd degree lasting more than 5 days or 3-4 degrees of any duration
Any other toxicity of grade 3 or 4 (except nausea or vomiting of grade 3)
* National Cancer Research Institute, General Toxicity Criteria (NCI-CTC).
Patients with impaired hepatic function
The following doses are recommended:
in patients with prothrombin index more than 70% and one of the following indices:
- the concentration of total bilirubin exceeds the VGN by no more than 1.5 times;
- and / or the activity of transaminases exceeds ILV from 1.5 to 2.5 times;
- and / or the activity of gamma-glutamyl transferase (GGT) exceeds the VGN no more than 5 times - dose adjustment is not required (recommended dose of vinflunin is 320 mg / m 2 - 1 every 3 weeks);
in patients with mild liver failure (Class A on the Child-Pugh scale) or in patients with a prothrombin index> 60% and a concentration of total bilirubin exceeding the VLN from 1.5 to 3 times;
- and / or with the activity of transaminases exceeding the VGN;
- and / or activity of GGT exceeding VGN 5 times - the recommended dose of vinflunine is 250 mg / m 2 (1 every 3 weeks);
in patients with moderate hepatic insufficiency (class B on the Child-Pugh scale) or in patients with a prothrombin index? 50%;
- and if the bilirubin concentration exceeds the VGN more than 3 times;
- and the activity of transaminases and GGT exceeds HHV - the recommended dose of vinflunine is 200 mg / m 2 (1 every 3 weeks).
In patients with hepatic insufficiency class C on the Child-Pugh scale with a prothrombin index <50% or with a bilirubin concentration exceeding the VGN by a factor of 5, or with a transaminase activity exceeding the VGN by a factor of 6, or with GGT activity, exceeding the VGN by 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 CK> 60 mL / min.
For patients with impaired renal function of moderate severity (CK 40-60 ml / min), the recommended dose is 280 mg / m 2 (1 every 3 weeks);
For patients with severe renal dysfunction (CC 20-40 ml / min) the recommended dose is 250 mg / m 2 (1 every 3 weeks).
Elderly patients (over 75 pet)
For patients from 75 to 80 years, the recommended dose is 280 mg / m 2 (1 every 3 weeks).
For patients 80 years and older, the recommended dose is 250 mg / m 2 (1 every 3 weeks).
For subsequent treatment cycles, the dose should be adjusted according to the toxicity.
3. Correction of dose in case of toxicity in patients with impaired renal function or in elderly patients
Types of toxicity
(NCI CTC v. 2.0) * Initial dose 280 mg / m 2 Initial dose 250 mg / m 2
first episode of toxicity second subsequent episode of toxicity first episode of toxicity second subsequent episode of toxicity
Neutropenia 4 degrees (ANC <500 cells / Ојl> 7 days) 250 mg / m 2 treatment discontinuation 225 mg / m 2 discontinuation of treatment
Febrile neutropenia (ANC <1,000 cells / ОјL and body temperature> 38.5 В° C)
Mucositis or constipation of 2nd degree lasting more than 5 days or 3-4 degrees of any duration
Any other toxicity of grade 3 or 4 (except nausea or vomiting of grade 3)
* National Cancer Research Institute, General Toxicity Criteria (NCI-CTC).
Pediatric Use
There is no experience of using the drug Zhavlor children.
Dilution of concentrate
To dilute the concentrate use 0.9% infusion solution of sodium chloride or 5% infusion solution of glucose. 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:
в„–1: 500 ml infusion bag with 0.9% infusion solution of sodium chloride or 5% infusion solution of glucose;
в„–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 veins 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 0.9% solution of sodium chloride or 5% glucose solution;
- The infusion of the drug Zhavlor is carried out for 20 minutes;
- during the infusion it is necessary to frequently check the patency of the venous duct and carefully follow the measures to prevent extravasation;
- after the administration of the solution of the drug Zhavlor, the remaining 250 ml of 0.9% sodium chloride infusion solution or 5% glucose infusion solution (300 ml / h flow rate) is administered.
SIDE EFFECT
Adverse reactions are systematized according to the system-organ classes and listed according to the following gradation: very 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)
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.
Disorders from the metabolism: very often - anorexia; often - dehydration.
Disorders of the psyche: often - insomnia.
Violations from the nervous system: very often - peripheral sensory neuropathy; often - fainting, headache, dizziness, neuralgia, eating disorders, neuropathy;infrequent peripheral motor neuropathy.
Disorders from the side of the organ of vision: infrequently - disturbances of visual perception.
Hearing disorders and labyrinthine disorders: often - pain in the ear; infrequent - dizziness, sensation of ringing in the ears.
Disturbances from the heart: often - tachycardia; infrequently - myocardial ischemia, myocardial infarction.
Disorders from the vessels: often - arterial hypertension, venous thrombosis, arterial hypotension.
Disturbances from the respiratory system, chest and mediastinal organs: often - shortness of breath, cough; infrequently - acute respiratory distress syndrome, pain in the larynx and pharynx.
Disorders from the digestive 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.
Disturbances from the skin and subcutaneous tissues: very often - alopecia; often - skin reactions (rash, urticaria), itching, hyperhidrosis; infrequently - erythema, dry skin.
Disorders from the musculoskeletal system and connective tissue: very often - myalgia; often - muscle weakness, arthralgia, musculoskeletal pain of various locations, including pain in the chest, back pain, jaw, limbs.
Disorders from the kidneys and urinary tract: infrequent - renal failure.
General disorders and disorders at the injection site: 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, increase in body weight.
CONTRAINDICATIONS
- hypersensitivity to the active substance or to vinca alkaloids;
- infectious diseases for 2 weeks before the start of therapy;
- the absolute number of neutrophils is less than 1,500 cells / Ојl of blood at the first administration of the drug and less than 1,000 cells / Ојl of blood in subsequent injections of the drug or platelets less than 100,000 cells / Ојl of blood;
- Pregnancy and the period of breastfeeding;
- Children under 18 years.
Carefully
Syndrome of congenital prolongation of the QT interval, heart disease (heart failure, myocardial infarction, bradycardia).
Electrolyte imbalance (eg, hypokalemia, hypomagnesemia).
Simultaneous reception of drugs extending the QT interval (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. If 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.
APPLICATION FOR FUNCTIONS OF THE LIVER
Use with caution in renal failure of moderate to severe severity (the standard dose of Javlor should be reduced).
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Use with caution in liver failure of moderate to severe severity (the standard dose of Javlor should be reduced).
APPLICATION FOR CHILDREN
Contraindicated for children under 18 years.
APPLICATION IN ELDERLY PATIENTS
Use with caution in individuals over 75 years of age (the standard dose of Javlor should be reduced).
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.
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.
When the drug is administered through the peripheral vein, vinflunin can cause its phlebitis.
Men and women should use reliable contraceptive methods 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 for preserving the sperm before starting treatment with the drug Zhavlor.
The efficacy and safety of the drug is not defined for patients of equal or more than 2 functional class.
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 personnel are advised to use gloves, goggles and protective clothing.
If the drug solution gets on the skin or mucous membranes, immediately rinse them thoroughly with soap and 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 drugs.
Impact on the ability to drive vehicles and manage mechanisms
Special studies on the effect of the drug on the ability to drive vehicles and control mechanisms have not been conducted. However, patients are not advised to drive vehicles and engage in other potentially hazardous activities requiring increased concentration, attention and speed of psychomotor reactions if they experience adverse reactions that can affect the performance of this activity (eg, dizziness, fainting).
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.
DRUG INTERACTION
With the combined use of vinflunine with cisplatin, carboplatin, capecitabine, doxorubicin, or gemcitabine, pharmacokinetic interactions of the drugs were not observed.
Co-administration with ketoconazole (400 mg orally every 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 potential inhibitors of the isoenzyme CYP3A4 (ritonavir, ketoconazole, itraconazole, grapefruit juice) or its inducers (rifampicin, St. John's wort marrow), since these substances can alter the concentration of vinflunine.
Avoid joint use with drugs that extend the QT / Q-Tc interval.
Joint use with opioids increases the risk of constipation.
The possible interaction of vinflunine with paclitaxel and docetaxel (CYP3 substrates) was studied in an in vitro study (a slight inhibition of vinflunine metabolism), but no special clinical studies on the interaction with these drugs have been conducted.
TERMS OF RELEASE FROM PHARMACY
On prescription.
TERMS AND CONDITIONS OF STORAGE
Store at temperatures between + 2 В° and + 8 В° C, in a place protected from light. Keep out of the reach of children. Shelf life - 3 years.
During the transport of the drug it is allowed to store the drug at a temperature of up to + 30 В° C in a place protected from light for no longer than 7 days.
From a microbiological point of view, the ready-made solution for the infusions of the drug Zhavlor should be used immediately. If the drug was not introduced immediately, the provider assumes responsibility for the conditions and duration of storage prior to administration. The duration of such storage should not exceed 24 hours at a temperature of from + 2 В° to + 8 В° C, protected from light.
