Universal reference book for medicines
Name of the drug: NAVELBINE (NAVELBINE ® )

Active substance: vinorelbine

Type: Antitumor preparation

Manufacturer: PIERRE FABRE MEDICAMENT PRODUCTION (France)
Composition, form of production and packaging
Concentrate for the preparation of a solution for infusions is
transparent, from colorless to pale yellow.

1 ml

vinorelbine tartrate 13.85 mg,

which corresponds to the content of vinorelbine base 10 mg

Auxiliary substances: water d / and nitrogen (inert gas).

1 ml - bottles of colorless glass (10) - packages of foam plastic (thermo containers) (1) - packs of cardboard.

Concentrate for the preparation of a solution for infusions is transparent, from colorless to pale yellow.

5 ml

vinorelbine tartrate 69.25 mg,

which corresponds to the content of vinorelbine base 50 mg

Auxiliary substances: water d / and nitrogen (inert gas).

5 ml - bottles of colorless glass (10) - packages of foam plastic (thermo containers) (1) - packs of cardboard.

Capsules soft gelatinous, oval, size 3, light brown, with a red inscription "N20";
the contents of the capsules are a viscous solution from light yellow to orange-yellow.
1 caps.

vinorelbine tartrate 27.7 mg,

which corresponds to the content of vinorelbine 20 mg

Excipients: ethanol anhydrous - 5 mg, purified water - 12.5 mg, glycerol - 2 mg, macrogol 400 - qs up to 175 mg.

The composition of the capsule shell: gelatin, glycerol 85%, anhydrizor 85/70 (D-sorbitol, 1,4-sorbitan, mannitol, higher polyols), medium-chain triglycerides PHOSAL 53 MST (phosphatidylcholine, glycerides, ethanol), iron oxide yellow (E172) , titanium dioxide (E171).

1 PC.
- blisters (1) - packs of cardboard.
Capsules soft gelatinous, oblong, size 4, pink, with a red inscription "N30";
the contents of the capsules are a viscous solution from light yellow to orange-yellow.
1 caps.

vinorelbine tartrate 41.55 mg,

which corresponds to the content of vinorelbine 30 mg

Excipients: ethanol anhydrous - 7.5 mg, purified water - 18.75 mg, glycerol - 3 mg, macrogol 400 - qs up to 262.5 mg.

The composition of the capsule shell: gelatin, glycerol 85%, anhydrizor 85/70 (D-sorbitol, 1,4-sorbitan, mannitol, higher polyols), medium-chain triglycerides PHOSAL 53 MST (phosphatidylcholine, glycerides, ethanol), iron oxide red (E172) , titanium dioxide (E171).

1 PC.
- blisters (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2011.

PHARMACHOLOGIC EFFECT

An antitumor drug from the group of vincaalkaloids (alkaloid vinca pink, obtained semisynthetic way).
The drug blocks the mitosis of cells in the metaphase G2-M stage, causing cell death during interphase or subsequent mitosis. At the molecular level, it affects the dynamic equilibrium of tubulin in the microtubule apparatus of the cell. Navelbin inhibits the polymerization of tubulin, primarily binding to mitotic microtubules, and at higher concentrations also has an effect on axonal microtubules. The induction of spiral tubulin under the action of Navelbin is less pronounced than with vincristine.
PHARMACOKINETICS

Suction and distribution

After oral administration, it is rapidly absorbed from the digestive tract.
C max vinorelbine is reached after 1.5-3 hours. Absolute bioavailability averages 40%. Eating does not affect the degree of absorption.
After iv introduction, the kinetics of vinorelbine is a three-phase exponential process.

Binding to 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. High concentrations of vinorelbine are found in the spleen, liver, kidneys, lungs and thymus, moderate in the heart and muscles, minimal in the adipose tissue and bone marrow. Concentration in the lungs is 300 times higher than the concentration in the plasma. Does not penetrate the BBB.
Metabolism and excretion

Biotransformed in the liver, mainly under the action of the isoenzyme CYP3A4 with the formation of a number of metabolites;
The main one that is determined in the blood is diacetylvinorelbine, which retains antitumor activity. It is excreted mainly with bile. The mean T 1/2 in the terminal phase is 40 h (27.7-43.6 h).
Pharmacokinetics in special clinical cases

The pharmacokinetic parameters of Navelbin (administered at a dose of 20 mg / m 2 weekly) do not depend on the age of the patients and do not change with moderate or severe hepatic insufficiency.

INDICATIONS

- non-small cell lung cancer;

- mammary cancer;

- Prostate cancer, resistant to hormone therapy (in combination with small doses of GCS for oral administration).

DOSING MODE

Navelbin 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.
Concentrate Navelbina is administered strictly IV in the form of a 6-10-minute infusion.

Capsules are taken whole by mouth, washed down with water without chewing and dissolving them in the mouth.

In the monotherapy regime, the usual dose of the drug for intravenous administration is 25-30 mg / m 2 of the body surface once a week.
Navelbin is diluted in 0.9% solution of sodium chloride or 5% dextrose solution to a concentration of 1.0-2.0 mg / ml (average 50 ml). After the administration of the drug, the vein should be washed by additionally adding at least 250 ml of a 0.9% solution of sodium chloride or a 5% solution of dextrose.
For patients with a body surface area of ​​2 m 2 or more, a single dose of Navelbin for IV administration should not exceed 60 mg.

The recommended one-time initial dose of Navelbina for oral administration is 60 mg / m 2 of the body surface once a week.
After the third dose, it is recommended to increase the dose to 80 mg / m 2 .
An increase in the dose from 60 mg / m 2 to 80 mg / m 2 can be achieved if there was no grade 4 neutropenia (less than 500 / μl) during the three weeks of Navelbin, or there was one episode of grade 3 neutropenia (less than 1000 / μl, but more than 500 / μl), and the number of neutrophils before the next intake is not lower than 1500 / μl.

The minimum number of neutrophils (cells / μl) recorded in the first 3 weeks of Navelbin intake in a dose of 60 mg / m 2 per week> 1000?
500 and <1000 (1 case)?500 and <1000 (2 cases) <500
The recommended dose, starting at the fourth dose of 80 mg / m 2 60 mg / m 2

If Naevelbina at a dose of 80 mg / m 2 has a grade 4 neutropenia (less than 500 / mm3) or 2 cases of grade 3 neutropenia (less than 1000 / μl but more than 500 / μl), then in the subsequent 3 doses Navelbina dose should be reduced from 80 up to 60 mg / m 2 per week.

The minimum number of neutrophils (cells / μl) recorded in the first 3 weeks of Navelbin intake inside at a dose of 80 mg / m 2 per week> 1000?
500 and <1000 (1 case)? 500 and <1000 (2 cases) <500
The recommended dose, starting at the fourth dose of 80 mg / m 2 60 mg / m 2

If the number of neutrophils did not decrease less than 500 / μl, or more than one decrease in the number of neutrophils in the range of 500 to 1000 / μL was observed within three weeks of Navelbin administration at a dose of 60 mg / m 2 (according to the recommendations above), the dose of the drug from 60 to 80 mg / m 2 per week.

Recommended doses of Navelbin for oral administration depending on the body surface area of ​​the patient (BSA) are given in the following table.

Body surface area (m 2 ) 60 mg / m 2 80 mg / m 2

Dose (mg) per week

0.95 to 1.0 60 80

From 1.05 to 1.14 70 90

1.15 to 1.24 70,100

From 1.25 to 1.34 80 100

1.35 to 1.44 80 110

From 1.44 to 1.54 90 120

1.55 to 1.64 100 130

From 1.65 to 1.74 100 140

1.75 to 1.84 110 140

1.85 to 1.94 110 150

1.95 and more 120 160

For patients with a BSA of 2 m 2 or more, the total single dose of Navelbin for oral ingestion should never exceed 120 mg per week when administered at a dose of 60 mg / m 2 and 160 mg per week at a dose of 80 mg / m 2 .

The use of Navelbin in doses of 60 mg / m 2 and 80 mg / m 2 corresponds to the administration of Navelbin in doses of 25 mg / m 2 and 30 mg / m 2 .

With polychemotherapy, the dose and frequency of Navelbin administration (both for intravenous administration and for oral administration) depend on a specific program of antitumor therapy.

With a decrease in the number of neutrophils less than 1500 / μL or platelets less than 75,000 / μL (with IV) or less than 100,000 / μL (ingestion), another injection or ingestion of Navelbina is postponed for 1 week.
If due to hematologic toxicity had to refrain from 3 weekly injections or drug administration, it is recommended that Navelbin be discontinued.
Patients with severe hepatic impairment Navelbin should be administered with caution, in a dose reduced by 33%.

Safety and efficacy of Navelbina in children have not been studied.

Special correction of the dosage regimen Navelbina in the elderly is not required.

SIDE EFFECT

The following side effects were more common than in isolated cases.
The following criteria were used to estimate the incidence of adverse events: very often (> 1/10);often (> 1 / 100.1 / 10); sometimes (> 1/1000, 1/100); rarely (> 1/10 000, 1/1000); extremely rare (1/10 000).
From the hemopoietic system: very often - neutropenia, anemia, thrombocytopenia, the attachment of secondary infections against the background of oppression of bone marrow hematopoiesis;
often - a fever (38 ° C) against neutropenia; sometimes - 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 side of the peripheral nervous system: very often - paresthesia, hyperesthesia, reduction or loss of deep tendon reflexes;
often - weakness in the legs;sometimes - severe paresthesia with sensory and motor symptoms, usually reversible.
From the cardiovascular system: sometimes - increase or decrease in blood pressure, hot flashes and cold extremities;
rarely - ischemic heart disease (angina, myocardial infarction), pronounced hypotension, collapse; extremely rarely - tachycardia, palpitation, heart rhythm disturbance.
From the respiratory system: sometimes - shortness of breath, bronchospasm;
rarely - interstitial pneumonia (with combined therapy with mitomycin), acute respiratory distress syndrome.
On the part of the digestive system: very often - nausea, vomiting, stomatitis, constipation, diarrhea, transient increase in functional liver samples (ALT, ACT);
rarely - pancreatitis, increased bilirubin level, intestinal paresis.
From the immune system: rarely - anaphylactic shock, angioedema.

Dermatological reactions: often - alopecia;
rarely - skin rashes.
Local reactions: often - pain / burning or redness at the injection site, change in vein color, phlebitis;
when extravasation - cellulite; possibly - necrosis of surrounding tissues.
Other: often - increased fatigue, myalgia, arthralgia, fever, pain of different localization, including chest pain, pain in the lower jaw and in the area of ​​tumor formations;
rarely - hyponatremia; very rarely - hemorrhagic cystitis and the syndrome of inadequate secretion of ADH.
CONTRAINDICATIONS

- the number of neutrophils is less than 1500 / μL;

- the number of platelets is less than 75,000 / μL (for intravenous administration) and less than 100,000 / μL (for oral administration);

- severe infectious diseases during the initiation of therapy or transferred during the last two weeks;

- severe liver failure, not associated with the tumor process;

- the need for continuous oxygen therapy in patients with a lung tumor;

- diseases and conditions leading to a decrease in absorption from the digestive tract (for oral administration);

- Pregnancy;

- the period of lactation (breastfeeding);

- hypersensitivity to the drug and to other vinaalkaloids.

With caution, prescribe the drug for respiratory failure, oppression of bone marrow hematopoiesis (including after previous chemotherapy or radiation therapy), constipation or phenomena of intestinal obstruction in the history, neuropathy in the anamnesis.

PREGNANCY AND LACTATION

Navelbin is contraindicated in pregnancy and lactation (breastfeeding).

APPLICATION FOR FUNCTIONS OF THE LIVER

If the kidney function is impaired, it is necessary to monitor the patient's condition.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Patients with severe hepatic impairment Navelbin should be administered with caution, in a dose reduced by 33%.

SPECIAL INSTRUCTIONS

Treatment with Navelbin should be performed under the supervision of a doctor who has experience with antitumor drugs.

If there is a marked violation of the liver, the dose of Navelbina should be reduced by 33%.

If the kidney function is impaired, it is necessary to monitor the patient's condition.

If there are signs of neurotoxicity of 2 or more, use of Navelbin should be discontinued.

If dyspnoea, cough or hypoxia of unexplained etiology appears, 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.

If nausea or vomiting occurs after taking Navelbin capsules, do not take the same dose again.

During and for at least three months after discontinuation of therapy, it is necessary to use reliable contraceptive methods.

If the active substance gets into the oral cavity, it is recommended to rinse the mouth with water or any saline solution.

When Navelbin hits the eyes, they should be washed and rinsed thoroughly with water.

Because
the composition of the drug is sorbitol, Navelbin should not be used in patients with hereditary intolerance to fructose.
Control of laboratory indicators

The drug is administered under strict hematological control, determining the number of leukocytes, neutrophils, platelets and hemoglobin level before each next injection or ingestion.
With a decrease in the number of neutrophils less than 1500 / μL and / or platelets less than 75,000 / μL (for intravenous administration) or less than 100,000 / μL (for oral administration), the next dose of the drug is postponed until the parameters are normalized, while monitoring the patient's condition.
OVERDOSE

Symptoms: suppression of bone marrow function, neurotoxic reactions.

Treatment: in case of an overdose, the patient should be hospitalized;
conduct symptomatic therapy with careful monitoring of the functions of vital organs. The specific antidote is unknown.
DRUG INTERACTION

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

When combined with mitomycin C, 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 Navelbin after radiotherapy can lead to the reappearance of radiation reactions.
Simultaneous use of the drug with inducers and inhibitors of cytochrome P450 isoenzymes may lead to a change in the pharmacokinetics of vinorelbine.

TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

List B. Concentrate for the preparation of solution for infusion should be stored out of reach of children, protected from light at a temperature of 2 ° to 8 ° C.

Capsules should be stored out of the reach of children at a temperature of 2 ° to 8 ° C.

After additional dilution of the concentrate, its physical and chemical stability is maintained for 8 days at room temperature (20 ° ± 5 ° C) or in a refrigerator (at a temperature of 2 ° to 8 ° C).

From a microbiological point of view, the drug should be used immediately after reconstitution.
If the drug has not been injected immediately, the health care provider assumes responsibility for the conditions and duration of storage prior to administration. Typically, the duration of such storage should not exceed 24 hours at a temperature of 2 ° to 8 ° C, unless dilution was performed in controlled and validated aseptic conditions.
Shelf life of the concentrate is 3 years.
After further dilution with physiological saline or glucose solution, the shelf life is 24 hours at room temperature.
The shelf life of the capsules is 2.5 years.

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