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

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 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:

Distribution

The volume of vinorelbine distribution 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 (about 78%). There is a significant seizure of vinorelbine with a pulmonary tissue, where a concentration of 300 times higher than in the blood plasma is achieved. Vinorelbine is not found in the brain tissues.

Metabolism

Vinorelbine is biotransformed in the liver under the action of the cytochrome P450 isoenzyme CYP3A4. All metabolites are identified and inactive, with the exception of 4-O-deacetyl-vinorelbine, which is the main active metabolite in the blood plasma. Sulfo- and glucuronic conjugates were not detected.

Excretion

The average half-life of vinorelbine in the final phase of elimination is about 40 (27.7-43.6) hours. Systemic clearance of vinorelbine is high and approaches the rate of blood flow in the liver, is on average

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 produce less than 20% of the intravenously administered dose, mainly as a starting material. Pharmacokinetics in specific patient groups

Patients with impaired hepatic function

The pharmacokinetics of vinorelbine does not change in patients with hepatic insufficiency. Nevertheless, as a precautionary measure, it is recommended to reduce the dose to 20 mg / m2 of the body surface and carefully monitor hematological parameters in patients with moderate or severe hepatic impairment.

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 vinorelbin in elderly patients (≥ 70 years) does not change. However, since elderly patients may be weakened, precautions should be taken when increasing the dose of vinorelbine.

Indications:

- non-small cell lung cancer;

- common breast cancer;

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

Contraindications:

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

- initial absolute number of neutrophils <1,500 cells / μl of blood;

- initial number of platelets <100 000 cells / μl of blood;

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

- simultaneous use with a yellow fever vaccine;

- pregnancy and the period of breastfeeding;

- Children under 18 years of age (safety and efficacy of vinorelbin in children have not been studied).

Carefully:

Carefully Navelbin should be used in patients with coronary heart disease in history, with moderate and severe hepatic insufficiency, while using with strong inhibitors or inducers of isoenzyme CYP3A4.

Pregnancy and lactation:

Drug Navelbin is contraindicated during pregnancy due to embryotoxic effects.

Drug Navelbin is contraindicated in the period of breastfeeding. Breastfeeding should be discontinued before taking the drug.

Dosing and Administration:

Strictly intravenously.

Intrathecal injection may result in death, categorically

forbidden!

Dosing regimen, frequency of administration and duration of treatment

are determined by the attending physician.

The drug is administered as a 6-10 minute infusion. Pre-concentrate

dilute in 20-50 ml of 0.9% solution of sodium chloride for injection or in 5% solution of dextrose for injection. Immediately after the administration of the drug should be introduced at least 250 ml of 0.9% sodium chloride solution to flush the veins.

Non-small cell lung cancer and common breast cancer.

In the monotherapy regimen, the standard dose of the drug is 25-30 mg / m

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

antitumor therapy.

Prostate Cancer Resistant to Hormone Therapy

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

Correction of the dosing regimen for hematological toxicity

With a decrease in the absolute number of neutrophils of less than 1500 cells / μl of blood and / or thrombocytopenia <100,000 cells / μl of blood, the next injection of Navelbin is postponed until their original amount is restored.

Correction of the dosing regimen in specific 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 recommendedreduce the dose to 20 mg / m "of the body surface and carefully monitor hematological parameters in patients with moderate or severe hepatic impairment.

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 elderly patients may be weakened, care should be taken when increasing the dose of Navelbin.

Side effects:

Adverse reactions are systematized according to the system-organ classes and are listed according to the following gradation: very frequent - 1/10 appointments (≥ 10%); frequent - 1/100 appointments (≥1% but <10%); infrequent - 1/1000 appointments (≥0.1% but <1%); rare - 1/10000 prescriptions (≥0.01% but <0,1%); very rare - less than 1 / 10,000 appointments (<0.01%), post-marketing messages, the frequency can not be estimated from available data.

Infectious and parasitic diseases

Often: bacterial, viral and fungal infections without neutropenia, various localizations.

Often: bacterial, viral or fungal infections resulting from myelosuppression and / or immunosuppression (neutropenic infections) are usually reversible with appropriate treatment.

Frequency unknown: neutropenic sepsis.

Violations of 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 hematotoxicity 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 unknown: syndrome of inadequate secretion of antidiuretic hormone.

Disorders from the metabolism and nutrition

Rarely: severe hyponatremia.

Frequency unknown: anorexia.

Disturbances from the nervous system

Often: Neurological disorders, including a decrease or loss of tendon reflexes.

Infrequently: severe paresthesia with sensory and motor symptoms, usually reversible.

Frequency unknown: weakness of the lower extremities with prolonged chemotherapy.

Heart Disease

Rarely: ischemic heart disease (angina pectoris, myocardial infarction).

Rarely: tachycardia, fibrillation, heart rhythm disturbances, palpitation.

Vascular disorders

Infrequently: Arterial hypotension, arterial hypertension, sensation of "hot flashes", 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

Often: stomatitis, nausea, vomiting, constipation.

Often: diarrhea (usually moderate or moderate severity).

Rarely: paralytic intestinal obstruction, pancreatitis.

Disturbances from the side of baked and bile ducts

Often: transient increase in the activity of hepatic transaminases without clinical symptoms.

Disturbances from the skin and subcutaneous tissues

Often: alopecia (usually moderate degree).

Rarely: generalized skin reactions.

Frequency 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

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 various localizations, including pain in the chest and in the area of the tumor.

Rarely: necrosis of tissues at the site of administration.

Overdose:

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

The specific antidote is unknown.

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: 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 Navelbin infusions with other medications for intravenous administration.

Pharmacodynamic interaction

Vaccines: 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 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: possibly mutual aggravation of side effects, in the first place - 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 CYP AP4 (eg, 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 CYP AP4 (eg, rifampicin): decreased efficacy and increased toxicity of vinorelbine due to increased metabolism in the liver.

Inductors and inhibitors of cytochrome P450: a change in the pharmacokinetics of vinorelbine is possible.

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 it is known that vinca alkaloids are a substrate for P-glycoprotein, caution should be exercised when using the drug Navelbin together with preparations that modify the function of this transport protein.

Special instructions:

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

- Treatment should be conducted under the supervision of a physician with experience

work with antitumor drugs. During the treatment, a thorough haematological monitoring should be performed to determine the number of leukocytes, neutrophils, platelets and hemoglobin on the day of each injection.

- In case of suspected co-infection on the day of initiation of therapy, the patient should be examined and the benefit-risk ratio should be evaluated when deciding whether to administer the drug.

- If there is shortness of breath, coughing, or hypoxia of unexplained etiology

should be examined to exclude pulmonary toxicity.

- In case of paralytic intestinal obstruction,

stop the drug. can be continued after restoration of normal intestinal motility.

- If the concentrate is on the skin, mucous membranes or in the eyes,

lead to burns. If this happens, the affected areas should be washed immediately and thoroughly with 0.9% sodium chloride solution.

- Navelbin should not be used concomitantly with X-ray therapy, which is especially exciting for the liver area.

- Navelbin should be used with caution with strong inhibitors or inductors of the CYP3A4 isoenzyme; simultaneous use of the drug with phenytoin, itraconazole, live attenuated vaccines is not recommended.

Instructions for the introduction of ready-made mortar and waste management

Preparation for the introduction and administration of the drug Navelbin should

be carried out by medical personnel trained in working 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 drug starts.

When extravasation should stop the infusion, wash the vein with 0.9% solution

sodium chloride, the remainder of the dose to enter into another vein. In the case of extravasation for

reduce the risk of phlebitis should be immediately administered intravenously

glucocorticosteroids.

Storage of a ready-made solution for infusions

From a microbiological point of view, the ready-made solution for infusions follows

use immediately. If the drug has not been injected immediately, the health care 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 2 ° C to 8 ° C in a dark place.

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 hazardous activities requiring increased concentration and speed of psychomotor reactions if they experience adverse reactions that may affect the performance of this activity.

Form release / dosage:

Concentrate for the preparation of a solution for infusions of 10 mg / 1 ml.

Packaging:

1 ml (10 mg) or 5 ml (50 mg) of the drug in a vial of colorless glass (type 1). The bottles are sealed with a stopper made of butyl- or chlorobutyl rubber (elastomer), rolled with an aluminum cap with a plastic lid.

For 10 vials in a thermo-container of foam plastic with instructions for use. 1 thermo container in a carton box box.

Storage conditions:

At a temperature of 2 ° C to 8 ° C,

in a place protected from light.

Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N011707 / 01

Date of registration:04.02.2011

The owner of the registration certificate:Pierre Fabre Medication ProductionPierre Fabre Medication Production France

Manufacturer: & nbsp

PIERRE FABRE MEDICAMENT PRODUCTION France

Representation: & nbspPIER FABR PIER FABR France

Information update date: & nbsp24.10.15

Illustrated instructions

Instructions

Navelbin (Navelbine)