Tsitouvin - instructions for use, doses, side effects, contraindications

Pharmacodynamics:Vinorelbine is an antitumor agent of plant origin from the group of semisynthetic vinca alkaloids isolated from a plant of the genus Vinca Periwinkle. Violates the polymerization of tubulin in the process of cellular mitosis. It blocks the mitosis of cells at the stage of metaphase G2-M, causing cell death during interphase or subsequent mitosis. Acts mainly on mitotic microtubules; When used in high doses, it affects the axonal microtubules. The effect of spiral tubulin, caused by vinorelbine, is less pronounced than that of vincristine.

Pharmacokinetics:

Distribution. The volume distribution of vinorelbine is high, averaging 21.2 l / kg (range 7.5 - 39.7 l / kg), which indicates an extensive distribution of vinorelbine in tissues. Binding to plasma proteins is insignificant - 13.5%, vinorelbine in large quantities binds to blood cells, especially with platelets (78%). There is a significant seizure of vinorelbine with pulmonary tissue, where a concentration of 300 times higher than in plasma is achieved. Vinorelbine is not found in the brain tissues.

Metabolism. Vinorelbine is biotransformed in the liver under the action of an isoenzyme CYP ZA4 cytochrome P450. All metabolites are identified and inactive, with the exception of 4-O-deacetyl-vinorelbine, which is the main metabolite in the blood plasma. Sulfo- and glucuronic conjugates were not detected.

Excretion. The average half-life (T1 / 2) of vinorelbine in the final phase of elimination is about 40 hours (27.7-43.6). Systemic clearance of vinorelbine is high and approaches the rate of blood flow in the liver, averaging 0.72 l / h / kg (0.32 - 1.26 l / h / kg). Vinorelbine mainly excreted in the bile in unchanged form and in the form of metabolites. The kidneys excrete less than 20% of the intravenously administered dose, mainly mainly as a starting material

Indications:

- non-small cell lung cancer;

- common breast cancer;

- prostate cancer resistant to hormone therapy (in combination with treatment with oral glucocorticosteroids in small doses).

Contraindications:

- hypersensitivity to vinorelbine or other vinca alkaloids, as well as to other components of the drug;

- initial absolute number of neutrophils less than 1500 cells / μl of blood;

- initial number of platelets less than 100000 cells / μl of blood;

- Infectious diseases on the day of initiation of therapy or transferred during the last 2weeks;

- simultaneous application with phenytoin, itraconazole;

- simultaneous use with the yellow fever vaccine, as well as other live attenuated vaccines;

- pregnancy and the period of breastfeeding;

- children under 18 years of age (no data on effectiveness and safety).

Carefully:

- with ischemic heart disease in history;

- with hepatic insufficiency of moderate and severe degree;

- when used simultaneously with strong inhibitors or isoenzyme inducers CYP3A4.

Pregnancy and lactation:

The use of vinorelbine is contraindicated during the period of pregnancy in connection with embryotoxic action. Vinorelbine contraindicated during breastfeeding. Breastfeeding should be discontinued before use.

Dosing and Administration:

Strictly intravenously. Intrathecal injection can lead to death, it is strictly prohibited!

Dosing regimen, frequency of administration and duration of treatment are determined by the attending physician.

The drug CITUVIN® is administered strictly intravenously in the form of a 6-10 minute infusion.Preconcentrate of CITUVIN preparation is diluted in 20-50 ml of 0.9% solution of sodium chloride or in 5% solution of dextrose for injection. Immediately after administration of the drug, at least 250 ml of 0.9% sodium chloride solution should be injected to wash the vein.

Non-small cell lung cancer and advanced breast cancer

In the monotherapy regime, the usual dose of the drug is 25-30 mg / m² body surface once a week. With combined chemotherapy, the standard dose of the drug is 25-30 mg / m² body surface, but the frequency of administration decreases - on days 1 and 5 every 3 weeks or on days 1 and 8 every 3 weeks - depending on the protocol of antitumor therapy.

Prostate Cancer Resistant to Hormone Therapy

The usual dose of the drug is 30 mg / m² body surfaces on days 1 and 8 every 3 weeks in combination with a daily intake of oral glucocorticosteroids in low doses (for example, hydrocortisone in a dose of 40 mg / day).

Correction of the dosing regimen Hematological toxicity

With a decrease in the absolute number of neutrophils of less than 1500 cells / μl and / or platelets of less than 100,000 cells / μl of blood, the next administration of the drug is postponed until the number of neutrophils is restored> 1500 cells / μl and / or platelets> 100,000 cells / μl.

Use in special patient groups

Patients with impaired hepatic function

The pharmacokinetics of vinorelbine does not change in patients with hepatic insufficiency. However, as a precautionary measure, it is recommended to reduce the dose to 20 mg / m body surface and carefully monitor hematological parameters in patients with moderate or severe hepatic insufficiency. Patients with impaired renal function

The effect of renal dysfunction on the pharmacokinetic properties of vinorelbine has not been investigated. However, due to the low level of renal elimination, a decrease in vinorelbine dose in the case of decreased renal function is not indicated.

Elderly patients

The pharmacokinetics of vinorelbine in elderly patients does not change. However, since older patients may be weakened, care should be taken when increasing the dose of the drug.

Side effects:

Adverse reactions occurring more often than in single cases are listed according to the following gradation: very often (> 10%); often (> 1% and <10%); infrequently (> 0.1% and <1%); rarely (> 0.01 and 0.1); very rarely (0.01%), the frequency is unknown - single post-marketing messages, the frequency can not be estimated from available data.

Infectious and parasitic diseases: often - bacterial, viral or fungal infections of the respiratory, urinary and gastrointestinal tract from mild to moderate severity, usually reversible with appropriate treatment; infrequently - severe sepsis with multiple organ failure, septicemia; very rarely - complicated septicemia, sometimes fatal.

Violations from the blood and lymphatic system: Often -

myelosuppression, leading to neutropenia (the smallest number of neutrophils is observed on the 7-10th day from the start of therapy, recovery occurs in the next 5-7 days, cumulation of hematologic toxicity is not observed), anemia; often - thrombocytopenia; frequency unknown - febrile neutropenia.

Immune system disorders: frequency unknown - systemic allergic reactions (anaphylaxis, anaphylactic shock or anaphylactoid type reactions).

Disorders from the endocrine system: frequency is unknown - syndrome of inadequate secretion of antidiuretic hormone.

Disorders from the metabolism and nutrition: rarely severe hypnasatremia; frequency is unknown - anorexia.

Impaired nervous system: very often - neurological disorders, including a decrease or loss of tendon reflexes; infrequently - severe paresthesias with sensory and motor symptoms, usually reversible; frequency is unknown - weakness of the lower extremities with prolonged chemotherapy.

Heart Disease: rarely - ischemic heart disease (angina pectoris, myocardial infarction); very rarely - tachycardia, fibrillation, heart rhythm disturbance, palpitation.

Vascular disorders: infrequently - arterial hypotension, arterial hypertension, sensation of "hot flushes", cold extremities; rarely - severe arterial hypotension, collapse.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently - shortness of breath, bronchospasm; rarely - interstitial pneumonia.

Disorders from the gastrointestinal tract: very often - stomatitis, nausea, vomiting, constipation; often diarrhea (usually moderate or moderate severity); rarely - paralytic intestinal obstruction, pancreatitis.

Disorders from the liver and bile ducts: very often - a transient increase in the activity of hepatic transaminases without clinical symptoms.

Disturbances from the skin and subcutaneous tissues: very often - alopecia (usually a moderate degree); rarely - generalized skin reactions; frequency is unknown - erythema on the palms and feet.

Disturbances from the musculoskeletal system and connective tissue: often - arthralgia, pain in the temporomandibular joint, myalgia.

General disorders and disorders at the site of administration: very often - reactions at the site of administration may include erythema, burning pain, vein discoloration and phlebitis at the site of administration; often - asthenia, weakness, fever, pain of different localization, including pain in the chest and tumor area; rarely - necrosis at the injection site.

Overdose:

Symptoms: the main toxic effect due to an overdose is the suppression of bone marrow function, sometimes in combination with infection, fever, dynamic intestinal obstruction and impaired liver function.

Treatment: a specific antidote is not known. In case of an overdose, the patient should be hospitalized and closely monitor the functions of vital organs. The following measures should be taken: blood transfusion, administration of antibiotics, growth factors. Monitoring of liver function is recommended.

Interaction:

Pharmaceutical interaction

Do not use alkaline solutions to dilute the concentrate (precipitation may occur).

Do not mix ready-made solution for infusions of CITUVIN® with other medications for intravenous administration.

Pharmacodynamic interaction

Vaccination: in connection with the immunosuppressive effect of the drug and the possibility of developing severe infections, it is not recommended during the period of chemotherapy to carry out vaccination with live (weakened) vaccines.

Itraconazole: an increase in the neurotoxicity of vinorelbine due to an increase in the concentration of vinorelbine in the blood plasma as a result of a decrease in its metabolism in the liver.

Phenytoin: it is possible to reduce the anticonvulsant effect of phenytoin, decrease the efficacy and increase the toxicity of vinorelbine.

Cisplatinum: there is no mutual influence in combined use

vinorelbine and cisplatin for several treatment cycles. However, the incidence of granulocytopenia when using a combination of vinorelbine with cisplatin is higher than in the case of monotherapy with vinorelbine.

Cytotoxic agents: while using the drug CITUVIN ® with other cytostatics, mutual aggravation of side effects is possible, first of all - myelosuppression.

Oral anticoagulants: the mutual aggravation of side effects is possible, the INR (international normalized relationship) should be systematically monitored, as well as careful monitoring of the patient's general condition.

Cyclosporin, tacrolimus: marked immunosuppression with risk of lymphoproliferation. Inhibitor inhibitors CYPAP4 (for example, ketoconazole): an increase in the neurotoxicity of vinorelbine due to an increase in vinorelbine concentration in the blood plasma as a result of a decrease in its metabolism in the liver.

Inductors of isoenzyme CYPAP4 (for example, rifampicin): decreased efficacy and increased toxicity of vinorelbine due to increased metabolism in the liver. Inductors and inhibitors of cytochrome P450. possibly changing the pharmacokinetics of vinorelbine;

Mitomycin C: increased pulmonological toxicity mitomycin (risk of bronchospasm, acute respiratory failure, there were rare cases of interstitial pneumonia).

Inductors and inhibitors of P-glycoprotein: since vinca alkaloids are known to be a substrate for P-glycoprotein, therefore caution should be exercised when the preparation of CITUVIN® is used together with preparations having the function of this transport protein.

Special instructions:

The drug is intended exclusively for intravenous administration. Intrathecal injection leads to death and is strictly prohibited!

Treatment with CITUVIN® should be performed under the supervision of a doctor who has experience with antitumor drugs. During the treatment should be a thorough hematological monitoring - the number of leukocytes, neutrophils, platelets and hemoglobin on the day of each injection.

If a concomitant infection is suspected on the day of initiation of therapy, the patient should be examined and the benefit-risk ratio is determined when deciding whether to administer the drug.

When there is shortness of breath, coughing or hypoxia of unexplained etiology, the patient should be examined to exclude pulmonary toxicity.

In the case of paralytic intestinal obstruction, the drug should be discontinued.Treatment can be continued after restoration of the level of normal intestinal motility.

The contact of the concentrate with skin, mucous membranes or in the eyes can lead to burns. If this happens, the affected areas should be washed immediately and thoroughly with 0.9% sodium chloride solution.

Vinorelbine should not be used simultaneously with X-ray therapy, which is especially exciting for the liver region.

The drug should be used with caution with strong inhibitors and isoenzyme inducers CYPZA4; simultaneous use with phenytoin, itraconazole, live attenuated vaccines is not recommended.

Men and women should use reliable methods of contraception during the treatment with the drug CITUVIN®, and also within 3 months after the end of chemotherapy. Patients who plan to have children after treatment are recommended for genetic counseling.

Due to the possible development of irreversible loss of fertility as a result of treatment with vinorelbine, patients should be given a recommendation on the preservation of sperm before the start of the course of treatment with the drug CITUVIN®.

Instructions for the introduction of a ready-made solution

Preparation for the introduction and administration of the drug CITUVIN® should be carried out by medical personnel trained in the work with chemotherapeutic drugs. Personnel should wear eye protection, disposable gloves, a mask and apron. The drug should be administered strictly intravenously: it is very important to make sure that the needle or catheter is accurately set in the vein, before the introduction of the drug CITUVIN. When extravasation should immediately stop the injection, wash the vein with 0.9% solution of sodium chloride, the remainder of the dose to enter another vein. In the case of extravasation, to reduce the risk of phlebitis, glucocorticosteroids should be injected intravenously.

Unused solution or waste must be disposed of in accordance with the regulations of the treatment and prophylactic establishment.

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

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 dangerous activities,requiring increased concentration of attention and speed of psychomotor reactions in the event of development of adverse reactions that could affect the performance of this activity.

Form release / dosage:

Concentrate for solution for infusion, 10 mg / ml.

Packaging:

1 ml or 5 ml of the drug into the bottles of colorless neutral glass I of the hydrolytic class, hermetically sealed with rubber stoppers with the rolling of aluminum caps.

For each bottle stick the label self-adhesive.

For 1 bottle (1 ml of the drug) in the contour cell packaging of the polymer film. On 1 contour acheikova packing together with the instruction on application in a pack from a cardboard.

For 1 bottle (5 ml of the drug), together with instructions for use in a pack of cardboard.

5 bottles in a contour cell box from a polymer film. 1 or 2 contour packs with instructions for use in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of 2 to 8 ° C. Do not freeze.

Keep out of the reach of children.

After further dilution of the drug in a 0.9% solution of sodium chloride or 5% solution of dextrose at concentrations of 1.0 mg / ml and 2.0 mg / ml vinorelbine(in each solution, respectively) in glass vials or polymer bags for infusion solutions, the stability of the prepared infusion solutions (physical, chemical and biological) is maintained at room temperature (25 ± 2 ° C) or in a refrigerator (at a temperature of 5 ± 3 ° C) for 8 days.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002558

Date of registration:04.08.2014

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

BIOCAD, CJSC Russia

Representation: & nbspBIOCAD CJSC BIOCAD CJSC Russia

Information update date: & nbsp12.10.15

Illustrated instructions

Instructions

Cituvin® (Cytuvin® )