Vinorelbine - instructions for use, dose, side effects, contraindications

Vinorelbine (pink vinca alkaloid, obtained semi-synthetically) is an antitumor agent from the group of vinca alkaloids. Disrupts the polymerization of tubulin in phases G2 and M of the cell cycle. It blocks mitosis, causes destruction of cells in the interphase or subsequent mitosis. Acts mainly on mitotic microtubules; when high doses are applied, it also affects axonal microtubules. The effect of spiral tubulin, caused by vinorelbine, is less pronounced than that of vincristine.

Pharmacokinetics:

After intravenous administration of the preparation, three-phase kinetics can be traced. The average half-life in the final phase is 40 (27.7-43.6) hours. The connection with plasma proteins is 13.5%. Intensively binds to blood cells and especially to platelets (78%). It penetrates well into tissues and lingers in them for a long time.

Large quantities are found in the spleen, liver, kidneys, lungs and thymus, moderate in the heart and muscles, minimal in the adipose tissue and bone marrow. Does not penetrate the blood-brain barrier. Concentration in the lungs is 300 times higher than the concentration in the plasma.Metabolised in the liver, mainly by the action of the isoform of the enzyme CYP3A4, related to the system of cytochromes P₄₅₀. Forms a number of metabolites; one of the metablets - diacetylvinorelbine retains antitumor activity. It is excreted mainly with bile.

Pharmacokinetics of vinorelbine administered at a dose of 20 mg / m² weekly in patients with moderate or severe hepatic impairment, does not change.

The pharmacokinetics of vinorelbine does not depend on the age of the patients.

Indications:

- Common inoperable non-small cell lung cancer.

- Common breast cancer, refractory or progressing after chemotherapy involving anthracyclines.

Contraindications:

- Hypersensitivity to vinca alkaloids or other components of the drug.

- The initial content of neutrophils is <1500 cells / μl of blood and platelets <75,000 cells / μl of blood.

- Severe infectious diseases during the initiation of therapy or transferred during the last 2 weeks.

- Severe liver failure, not associated with the tumor process.

- Pregnancy and the period of breastfeeding.

- Child age (lack of safety and efficacy data).

Carefully:With respiratory failure, oppression of bone marrow hematopoiesis (including after previous chemotherapy or radiation treatment), constipation or phenomena of intestinal obstruction in anamnesis, neuropathy in anamnesis, simultaneous intake of inhibitors of isoenzyme CYP3A4.

Dosing and Administration:

Vinorelbin is injected strictly intravenously slowly (within 5-10 minutes) or drip (within 20-30 minutes).

Vinorelbin is used both in the form of monotherapy, and in combination with other antitumor drugs. When choosing a dose and mode of administration in each individual case, you should refer to the special literature.

In the monotherapy regime, the usual dose of the drug is 25-30 mg / m² body surface once a week. The drug is diluted in 0.9 % solution of sodium chloride or 5% solution of dextrose to a concentration of 1.5-3.0 mg / ml. After the introduction of the drug, the vein should be washed by additionally adding at least 250 ml of a 0.9% solution of sodium chloride.

For patients with body surface area ≥2 m² a single dose of VINORELBIN should not exceed 60 mg.

Correction of dosing regimes

Correction of the dosing regimen with hematotoxicity (depending on hematological parameters)

The number of neutrophils on the day of administration. of the preparation (cells / μl)	The percentage of starting dose of the drug - VINORELBIN
≥1500	100%
1499-1000	50%
<1000	The drug is not injected. Repeat the determination of the number of neutrophils after 1 week. If due to granulocytopenia had to refrain from 3 weekly injections of the drug, the use of vinorelbine is recommended to be discontinued.
In patients with fever and / or sepsis with a background of neutropenia during treatment or when two weekly injections of the drug are missed in a row, due to the low content of neutrophils, the doses for subsequent administration should be as a percentage of the previous doses:
≥1500	75%
1499-1000	37,5%
<1000	The drug is not injected.

Correction of dosing regimen VINORELBIN with hepatic impairment

Patients with hepatic impairment VINORELBIN should be administered with caution. When there is hyperbilirubinemia on the background of drug treatment VINORELBIN subsequent doses should be reduced according to the below recommendations.

Concentration of total bilirubin (μmol / L)	Percentage of starting dose of vinorelbine
≤34,2	100%
35,9-51,3	50%
>51,3	25%

Children: safety and efficacy of the drug VINORELBIN in children not studied.

Aged people: any special instructions for the use of the drug VINORELBIN the elderly are absent.

Side effects:

From the hematopoiesis: neutropenia, anemia, thrombocytopenia; against the background of oppression of bone marrow hematopoiesis joining of secondary infections, fever (> 38 ° С), sepsis, septicemia; extremely rare - complicated septicemia, in some cases leading to death.

The smallest number of neutrophils is observed on the 7-10th day from the beginning of therapy, recovery occurs in the next 5-7 days. Cumulation of hematotoxicity was not observed.

From the immune system: rarely anaphylactic shock or angioedema.

From the nervous system: paresthesia, hyperesthesia, reduction or loss of deep tendon reflexes, peripheral neuropathy, autonomic neuropathy, weakness in the legs, pain in the jaw region, headache, intestinal paresis; rarely - severe paresthesia with sensory and motor symptoms, usually reversible, paralytic intestinal obstruction.

From the cardiovascular system: increase or decrease in blood pressure, "hot flushes" of blood to the face and cold extremities, coronary heart disease (angina pectoris, myocardial infarction), severe hypotension, collapse, pulmonary edema; extremely rarely - tachycardia, palpitation and heart rhythm disturbance.

On the part of the respiratory system: dyspnea, bronchospasm, interstitial pneumonia (with combined therapy with mitomycin), acute respiratory distress syndrome.

On the part of the digestive system: nausea, vomiting, anorexia, stomatitis, constipation, diarrhea, pancreatitis, transient increase in bilirubin concentration and increased activity of "liver" transaminases.

From the skin and skin appendages: alopecia, skin rashes.

Local reactions: pain / burning or redness at the injection site, change in vein color, phlebitis; when extravasation - inflammation of subcutaneous fat, perhaps necrosis of surrounding tissues.

Other: allergic reactions, weakness, fever, pain of various locations, including abdominal pain, pain in the bones, joints and muscles, back pain, in the area chest and in the field of tumor formations, increase in creatinine concentration, hyponatremia, hemorrhagic cystitis and syndrome of inadequate secretion of antidiuretic hormone.

Overdose:

The main expected overdose manifestations include suppression of bone marrow function with a risk of developing superinfection and manifestations of neurotoxicity. The specific antidote is not known. In case of an overdose, the patient should be hospitalized and closely monitor the functions of vital organs.

Treatment is symptomatic.

Interaction:

When combined with other cytostatics, mutual aggravation of side effects is possible, first of all - myelosuppression.

When combined with mitomycin, acute respiratory failure may develop.

When combined with paclitaxel, the risk of neurotoxicity increases.

Application on the background of radiation therapy leads to radiosensitization. The use of vinorelbine after radiation therapy can lead to the re-emergence of radiation reactions.

Simultaneous use of the drug with inducers and inhibitors of cytochrome P450 may lead to a change in the pharmacokinetics of vinorelbine.

Special instructions:

Treatment with drug VINORELBIN should be carried out under the supervision of a doctor who has experience working with antitumor drugs.

Treatment with drug VINORELBIN conducted under strict hematological control, determining the number of leukocytes, neutrophils, platelets and hemoglobin level before each injection. If the neutrophil count is less than 1500 cells / μl and / or platelets below 75,000 cells / μl, the administration of the next dose should be postponed until the normal level is restored.

If there is a marked violation of liver function, the dose of the drug VINORELBIN should be reduced.

If there is a violation of the kidneys, it is necessary to monitor the patient more closely.

If there are signs of neurotoxicity of the 2nd and more degree, the use of the drug VINORELBIN should be discontinued.

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

When extravasation, the infusion of the drug should be stopped immediately, the remaining dose is injected into another vein.

During and for at least three months after cessation of therapy, reliable methods of contraception should be used.

If the drug is ingested VINORELBIN In their eyes, they should be washed and rinsed thoroughly with water.

Form release / dosage:

Concentrate for the preparation of a solution for infusions of 10 mg / 1 ml and 50 mg / 5 ml (10 mg / ml).

Packaging:

Producer of PJSC "PHARMSTANDART-BIOLEC".

5 ml vials of glass tube or 1 ml or 5 ml vials of glass, sealed with rubber stoppers with aluminum caps or caps with a combination of aluminum and plastic.

10 vials of 1 ml, 5 ml or 1 vial of 1 ml, 5 ml, together with instructions for use in a stack of cardboard.

Packaging of 10 packs per film is allowed.

Producer LLC ONKO JENERICS ".

1 ml or 5 ml vials of glass, sealed with rubber stoppers with aluminum caps or caps with a combination of aluminum and plastic.

For 1 bottle of 1 ml, 5 ml each, along with instructions for use in a pack of cardboard.

10 packs of 1 ml or 5 ml bottles are packed in a film.

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

Concentrate for the preparation of solution for infusions VINORELBIN in the original packaging - 2 years.

Concentrate for solution for infusion after opening the package, as well as for infusion solutions prepared by dilution of vinorelbine 0.9% sodium chloride or 5% dextrose solution,are physically and chemically stable for 24 hours if stored in a glass bottle or polyvinyl chloride bag at room temperature in an unprotected area. From the microbiological point of view, the drug should be used immediately.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-000932

Date of registration:18.10.2011 / 18.12.2015

Expiration Date:18.12.2020

The owner of the registration certificate:FARM STANDART, OJSC FARM STANDART, OJSC Russia

Manufacturer: & nbsp

PHARMSTANDART-BIOOLEK, PAO Ukraine

ONKO DZHENERIKS, LLC Ukraine

Representation: & nbspPHARMSTANDART JSC PHARMSTANDART JSC Russia

Information update date: & nbsp16.02.2017

Illustrated instructions

Instructions

Vinorelbine (Vinorelbine)