Цитувин®

General characteristics. Structure:

Active ingredient: 10 mg of a vinorelbin in the form of a vinorelbin of ditartrate.

Vspomgatelny substance: water for injections.

Pharmacological properties:

Pharmacodynamics. Vinorelbin - antineoplastic means of a plant origin from group of semi-synthetic vinkaalkaloid, allocated from a plant of the sort Vinca (periwinkle). Breaks polymerization of a tubulin in the course of a cellular mitosis. Blocks a mitosis of cells at a stage of G2-M metaphase, causing death of cells during interphase or at the subsequent mitosis. Affects preferential mitotic microtubules; at use in high doses exerts impact on axonal microtubules. The effect of spiralling of a tubulin caused vinorelbiny is expressed more weakly, than at Vincristinum.

Pharmacokinetics. Distribution. Volume distribution of a vinorelbin high, averages 21,2 l/kg (range of 7,5 - 39,7 l/kg) that demonstrates extensive distribution of a vinorelbin in fabrics. Linkng with proteins of plasma insignificant - 13,5%, винорелбин in large numbers contacts blood cells, especially thrombocytes (78%). Considerable capture of a vinorelbin is observed by pulmonary fabric where concentration 300 times higher, than in plasma is reached. Vinorelbin is not found in brain tissues.
 
Metabolism. Vinorelbin biotransformirutsya in a liver under the influence of an isoenzyme of CYP ZA4 of P450 cytochrome. All metabolites are identified and are inactive, behind exception 4-O-deatsetil-vinorelbina, being the main metabolite in a blood plasma. Sulfo-and glucuronic conjugates are not revealed.
 
Removal. The average elimination half-life (T1/2) of a vinorelbin in a final phase of elimination makes about 40 hours (27,7-43,6). The system clearance of a vinorelbin high also approaches blood-groove speed in a liver, averages 0,72 l/h/kg (0,32 - 1,26 l/h/kg). Vinorelbin is preferential brought with bile in not changed look and in the form of metabolites. Kidneys remove less than 20% of the dose entered intravenously, generally generally in the form of initial substance

Indications to use:

- not small-celled cancer of a lung;
 
- widespread breast cancer;
 
- a prostate cancer, resistant to hormonal therapy (in a combination with treatment by peroral glucocorticosteroids in small doses).

Route of administration and doses:

Strictly intravenously. Intrathecal introduction can lead to a lethal outcome, it is strictly forbidden!
 
The dosing mode, frequency of introduction and duration of a course of treatment are defined by the treating doctor.
 
The drug TSITUVIN® is administered strictly intravenously in the form of 6-10 minute infusions. Previously a drug TsITUVIN concentrate" dissolve in 20 - 50 ml 0,9% of solution of sodium of chloride or in 5% dextrose solution for injections. At once after administration of drug it is necessary to enter not less than 250 ml of 0,9% of solution of sodium of chloride for washing of a vein.
 
Not small-celled cancer of a lung and widespread breast cancer. In the monotherapy mode the usual dose of drug makes 25-30 mg/sq.m of a body surface once a week. At the combined chemotherapy the standard dose of drug makes 25-30 mg/sq.m of a body surface, but the frequency of introduction decreases - in days of 1 and 5 each 3 weeks or in days of 1 and 8 each 3 weeks - depending on the protocol of antineoplastic therapy.
 
Prostate cancer, resistant to hormonal therapy. The usual dose of drug makes 30 mg/sq.m of a body surface in days of 1 and 8 each 3 weeks in combination with daily reception of peroral glucocorticosteroids in low doses (for example, a hydrocortisone in a dose of 40 mg/day).
 
Correction of the mode of dosing Hematologic toxicity. At decrease in absolute number of neutrophils less than 1500 cells / мкл and/or thrombocytes less than 100000 cells / мкл blood postpone the next administration of drug until recovery of number of neutrophils> 1500 cells / мкл and/or thrombocytes> 100000 cells / мкл.
 
Use for special groups of patients. Patients with an abnormal liver function. The pharmacokinetics of a vinorelbin does not change at patients with a liver failure. Nevertheless, as a precautionary measure the dose decline to 20 mg/m of a body surface and careful control of hematologic indicators at patients with a liver failure of average or heavy degree is recommended. Patients with a renal failure
 
Influence of a renal failure on pharmacokinetic properties of a vinorelbin was not investigated. However, thanks to the low level of renal elimination, reduction of a dose of a vinorelbin in case of reduced function of kidneys is not shown.
 
Elderly patients. The pharmacokinetics of a vinorelbin at elderly patients does not change. However, as elderly patients can be weakened, it is necessary to observe precautionary measures at increase in a dose of drug.

Features of use:

Pregnancy and lactation. Use of a vinorelbin is contraindicated during the pregnancy period in connection with embriotoksichesky action. Vinorelbin is contraindicated during breastfeeding. Breastfeeding should be stopped prior to drug use.

Drug is intended only for intravenous administration. Intrathecal introduction leads to a lethal outcome and is strictly forbidden!
 
Treatment by the drug TSITUVIN® should be carried out under observation of the doctor having experience with antineoplastic drugs. During treatment careful hematologic monitoring - definition of number of leukocytes, neutrophils, thrombocytes and hemoglobin in day of each introduction has to be carried out.
 
At suspicion on existence of the accompanying infection in day of the beginning of therapy it is necessary to inspect the patient and to estimate a ratio of advantage and risk at making decision on administration of drug.
 
At emergence of an asthma, cough or hypoxia of the obscure etiology it is necessary to inspect the patient for an exception of pulmonary toxicity.
 
In case of development of paralytic intestinal impassability it is necessary to stop administration of drug. Treatment can be continued after recovery of level of normal motility of intestines.
 
Hit of a concentrate on skin, mucous membranes or in eyes can lead to a burn. If it occurred, affected sites it is necessary to wash out immediately and carefully 0,9% chloride sodium solution.
 
Vinorelbin it is not necessary to apply at the same time with carrying out the roentgenotherapy which is especially occupying the area of a liver.
 
Drug should be used with care with strong inhibitors and inductors of an isoenzyme CYPZA4; simultaneous use with Phenytoinum, itrakonazoly, live attenuirovanny vaccines is not recommended.
 
Men and women have to use reliable methods of contraception during treatment by the drug TSITUVIN®, and also within 3 months after the termination of chemotherapy. Genetic consultation is recommended to the patients planning the birth of children after completion of treatment.
 
Owing to possible development of irreversible loss of fertility as a result of treatment vinorelbiny, to patients the recommendation about preservation of sperm prior to the beginning of a course of treatment has to be made by the drug TSITUVIN®.
 
Instructions for administration of ready solution. Preparation for introduction and administration of the drug TSITUVIN® have to be carried out by the medical personnel trained in work with chemotherapeutic drugs. The personnel should use protection for eyes, one-time gloves, a mask and an apron. The drug should be administered strictly intravenously: it is very important to be convinced that the needle or a catheter are precisely established in a vein, prior to administration of drug TsITUVIN. At an ekstravazation it is necessary to stop immediately introduction, to wash out a vein of 0,9% chloride sodium solution, to enter the rest of a dose into other vein. In case of an ekstravazation for reduction of risk of phlebitis it is necessary to enter immediately intravenously glucocorticosteroids.
 
Unused solution or waste have to be utilized according to regulations of treatment and prevention facility.

Influence on ability to manage vehicles and mechanisms. Special researches on influence of drug on ability to driving of motor transport and control of mechanisms were not conducted. Nevertheless, patients are not recommended to manage vehicles and to be engaged in other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions in case of development of the side reactions capable to influence performance of this activity.

Side effects:

The side reactions which are found more often than in isolated cases are listed according to the following gradation: very often (> 10%); often (> 1% and <10%); infrequently (> 0,1% and <1%); seldom (> 0,01 and 0,1); very seldom (0,01%), frequency is unknown - single post-marketing messages, frequency cannot be estimated according to the available data.

Infectious and parasitic diseases: often - bacterial, viral or fungal infections respiratory, urinary and digestive tract from easy to moderate severity, usually reversible at the corresponding treatment; infrequently - heavy sepsis with multiorgan insufficiency, a septicaemia; very seldom - the complicated septicaemia, sometimes with a lethal outcome.

Disturbances from blood and lymphatic system: very often - the miyelosupressiya leading to a neutropenia (the smallest number of neutrophils is observed for 7-10 day from the beginning of therapy, recovery happens in the next 5-7 days, the kumulirovaniye of hematologic toxicity is noted), anemia; often - thrombocytopenia; frequency is unknown - a febrile neutropenia.

Disturbances from immune system: frequency is unknown - system allergic reactions (an anaphylaxis, an acute anaphylaxis or reactions of anaphylactoid type).

Disturbances from endocrine system: frequency is unknown - a syndrome of inadequate secretion of antidiuretic hormone.

Disturbances from a metabolism and food: seldom - a heavy hyponatremia; frequency is unknown - anorexia.

Disturbances from a nervous system: very often - neurologic disturbances, including decrease or loss of tendon jerks; infrequently - heavy paresthesias with touch and motor symptoms, usually reversible; frequency is unknown - weakness of the lower extremities at long chemotherapy.

Disturbances from heart: seldom - coronary heart disease (stenocardia, a myocardial infarction); very seldom - tachycardia, fibrillation, disturbance of a cordial rhythm, a heart consciousness.

Disturbances from vessels: infrequently - arterial hypotension, arterial hypertension, feeling of "inflows", a cold snap of extremities; seldom - heavy arterial hypotension, a collapse.

Disturbances from respiratory system, bodies of a thorax and a mediastinum: infrequently - an asthma, a bronchospasm; seldom - intersticial pneumonia.

Disturbances from digestive tract: very often - stomatitis, nausea, vomiting, a lock; often - diarrhea (usually moderate or moderate severity); seldom - paralytic intestinal impassability, pancreatitis.

Disturbances from a liver and biliary tract: very often - tranzitorny increase in activity of hepatic transaminases without clinical symptomatology.

Disturbances from skin and hypodermic fabrics: very often - an alopecia (usually moderate degree); seldom - generalized skin reactions; frequency is unknown - an erythema on palms and feet.

Disturbances from musculocutaneous system and connecting fabric: often - an arthralgia, a temporal and mandibular joint pain, a mialgiya.

The general frustration and disturbances in an injection site: very often - reactions in an injection site can include an erythema, a thermalgia, discoloration of a vein and phlebitis in an injection site; often - an adynamy, weakness, fever, pain of various localization, including thorax pain and areas of a tumor; seldom - a necrosis in an injection site.

Interaction with other medicines:

Pharmaceutical interaction. It is not necessary to use alkaline solutions for dilution of a concentrate (possibly loss of a deposit).
 
It is not necessary to mix ready solution for infusions of the drug TSITUVIN® with other medicines for intravenous administration.
 
Pharmakodinamichesky interaction. Vaccination: in connection with immunosuppressive effect of drug and a possibility of development of heavy infections, it is not recommended to perform during chemotherapy vaccination by the live (weakened) vaccines.
 
Itrakonazol: increase in a neurotoxicity of a vinorelbin owing to increase in concentration of a vinorelbin in a blood plasma as a result of decrease in his metabolism in a liver.

 
Phenytoinum: decrease in anticonvulsant action of Phenytoinum, decrease in efficiency and increase in toxicity of a vinorelbin is possible.
 
Cisplatinum: there is no mutual influence at the combined use
 
vinorelbin and Cisplatinum during several cycles of treatment. However, the frequency of cases of a granulocytopenia when using a combination of a vinorelbin with Cisplatinum is higher, than in case of monotherapy vinorelbiny.
 
Cytostatics: at simultaneous use of the drug TSITUVIN® with other cytostatics perhaps mutual aggravation of side effects, first of all - miyelosupressiya.
 
Peroral anticoagulants: perhaps mutual aggravation of side effects, it is necessary to make systematic control INR (the international normalized relation), and also careful control of the general condition of the patient.

Cyclosporine, такролимус: the expressed immunosuppression with risk of a limfoproliferation. CYPZA4 isoenzyme inhibitors (for example, кетоконазол): increase in a neurotoxicity of a vinorelbin owing to increase in concentration of a vinorelbin in a blood plasma as a result of decrease in his metabolism in a liver.
 
CYPZA4 isoenzyme inductors (for example, rifampicin): decrease in efficiency and increase in toxicity of a vinorelbin owing to strengthening of his metabolism in a liver. Inductors and inhibitors of P450 cytochrome. change of pharmacokinetics of a vinorelbin is possible;
 
Mitomitsin With: strengthening of pulmonary toxicity of a mitomitsin (risk of development of a bronchospasm, acute respiratory insufficiency, exceptional cases of development of intersticial pneumonia were observed).
 
Inductors and inhibitors of the R-glycoprotein: as it is known that alkaloids of a periwinkle are substrate for the R-glycoprotein, thus, it is necessary to be careful at combined use of the drug TSITUVIN® with the drugs having function of this transport protein.

Contraindications:

- hypersensitivity to a vinorelbin or other alkaloids of a periwinkle, and also other components of drug;
- initial absolute number of neutrophils less than 1500 cells / мкл blood;
- initial number of thrombocytes less than 100000 cells / мкл blood;
- infectious diseases in day of the beginning of therapy or postponed within the last 2 weeks;
- simultaneous use with Phenytoinum, itrakonazoly;
- simultaneous use with a vaccine against yellow fever, and also other live attenuirovanny vaccines;
- pregnancy and period of feeding by a breast;
 - children's age up to 18 years (there are no data on efficiency and safety).

With care:
- at coronary heart disease in the anamnesis;
- at a liver failure of average and heavy degree;
- at simultaneous use with strong inhibitors or inductors of an isoenzyme CYP3A4.

Overdose:

Symptoms: the main toxic effect owing to overdose is suppression of function of marrow, sometimes - in combination with an infection, fever, dynamic intestinal impassability and an abnormal liver function.
 
Treatment: the specific antidote is not known. In case of overdose of the patient it is necessary to hospitalize and to carefully control functions of vitals. The following measures have to be taken: hemotransfusion, introduction of antibiotics, growth factors. Monitoring of function of a liver is recommended.

Storage conditions:

In the place protected from light at a temperature from 2 to 8 °C. Not to freeze. To store in the place, unavailable to children. After additional cultivation of drug in 0,9% solution of sodium chloride or 5% dextrose solution in concentration of 1,0 mg/ml and 2,0 mg/ml of a vinorelbin of the basis (in each solution, respectively) in glass bottles or polymeric packages for infusion solutions, stability of the prepared solutions for infusion (physical, chemical and biological) remains at the room temperature (25 ± 2 °C) or in the refrigerator (at a temperature of 5 ± 3 °C) within 8 days.

Issue conditions:

According to the recipe

Packaging:

On 1 ml or 5 ml of drug in the bottles of colourless neutral glass I of a hydrolytic class which are hermetically corked by rubber bungs with a running in aluminum caps. On each bottle paste the label self-adhesive. On 1 bottle (on 1 ml of drug) in a blister strip packaging from a film polymeric. On 1 blister strip packaging together with the application instruction in a pack from a cardboard. On 1 bottle (on 5 ml of drug) together with the application instruction in a pack from a cardboard. On 5 bottles in a blister strip packaging from a film polymeric. 1 or 2 blister strip packagings together with the application instruction in a pack from a cardboard.