2010/06/16

Navelbine

Composition, structure and packing

Soft gelatin capsules, oval, size, number 3, light brown color, with red inscription "N20"; contents of capsules - viscous solution from light yellow to orange-yellow color.

1 capsule. vinorelbina tartrate 27.7 mg, which corresponds to the content vinorelbina 20 mg.

Excipients: ethanol anhydrous, purified water, glycerol, macrogol 400.

The composition of the shell capsules: gelatin, glycerol 85%, anidrisorb 85/70 (D-sorbitol and 1,4-sorbitan), triglycerides srednetsepochechnye PHOSAL 1953 MST (phosphatidylcholine, glycerides, ethanol), iron oxide red (E172), iron oxide yellow ( E171

Soft gelatin capsules, oblong, size, number 4, pink, red-labeled "N30"; contents of capsules - viscous solution from light yellow to orange-yellow color.

1 capsule. vinorelbina tartrate 41.55 mg, which corresponds to the content vinorelbina 30 mg.

Excipients: ethanol anhydrous, purified water, glycerol, macrogol 400.

The composition of the shell capsules: gelatin, glycerol 85%, anidrisorb 85/70 (D-sorbitol and 1,4-sorbitan), triglycerides srednetsepochechnye PHOSAL 1953 MST (phosphatidylcholine, glycerides, ethanol), iron oxide red (E172), iron oxide yellow ( E171

Concentrate for solution for infusion is transparent, from colorless to pale yellow.

1 ml vinorelbina tartrate 13.85 mg, which corresponds to the content vinorelbina base 10 mg.

Excipients: Water d / and nitrogen (inert gas).

Concentrate for solution for infusion is transparent, from colorless to pale yellow.

5 ml vinorelbina tartrate 69.25 mg, which corresponds to the content vinorelbina base 50 mg.

Excipients: Water d / and nitrogen (inert gas).

Clinico-pharmacological group: The antitumor drug.

Pharmacological action

The antitumor drug from the group vinkaalkaloidov (pink periwinkle alkaloid obtained by semi-synthetic). The drug blocks the mitosis of cells at metaphase G2-M, causing cell death during interphase or during the subsequent mitosis. At the molecular level affect the dynamic equilibrium of tubulin in the microtubule apparatus of the cell. Navelbin inhibits polymerization of tubulin by binding predominantly to the mitotic microtubules, but in higher concentrations also affects the axonal microtubules. Induction of helix tubulin under the influence Navelbina less pronounced than with vincristine.

Pharmacokinetics

Absorption and distribution

After ingestion rapidly absorbed from ZhKT.Smax vinorelbina achieved through 1.5-3 h. The absolute bioavailability averaging 40%. Eating does not affect the degree of suction.

After i / v administration kinetics vinorelbina a three-phase exponential process.

Binding to plasma proteins is 13.5%. Intensive contacts with cells of blood and especially platelets (78%). Well into the tissue and delayed them for a long time. High concentrations vinorelbina determined in the spleen, liver, kidneys, lungs and thymus, moderate - in the heart and muscles, minimum - in the adipose tissue and bone marrow. Concentration in the lungs is 300 times higher than the concentration in plasma. Do not cross the BBB.

Metabolism and excretion

Biotransformiruetsya in the liver, mainly under the influence of CYP3A4 isoenzyme with the formation of several metabolites, mostly determined in the blood is diatsetilvinorelbin which retains antitumor activity. Derive mainly from the bile. The average T1 / 2 in the terminal phase is 40 h (27.7-43.6 h).

Pharmacokinetics in special clinical situations

Pharmacokinetic parameters Navelbina (introduced in a dose of 20 mg/m2 weekly) does not depend on the age of patients and did not change with moderate or severe hepatic insufficiency.

Statement
non small cell lung cancer of the lung;
breast cancer;
prostate cancer resistant to hormone therapy (in combination with low doses of GCS for oral).

Dosage regimen

Navelbin used as a monotherapy and in combination with other anticancer agents. When choosing the dose and mode of administration in each individual case should be referred to special literature.

Concentrate Navelbina introduced strictly in / as the 6-10 minute infusion.

The capsules are inside entirely, drinking water, not liquid and not rassasyvaya them in his mouth.

In monotherapy the usual dosage for a / in the introduction of 25-30 mg/m2 body surface once a week. Navelbin diluted in 0.9% sodium chloride or 5% dextrose to a concentration of 1.0-2.0 mg / ml (average 50 ml). After drug administration the vein should be flushed by introducing an additional minimum of 250 ml 0.9% sodium chloride or 5% dextrose.

For patients with body surface area 2 m2 and a single dose for Navelbina in / introduction must not exceed 60 mg.

Recommended single initial dose Navelbina Oral 60 mg/m2 body surface once a week. After receiving the third dose is recommended to increase to 80 mg/m2.

If the number of neutrophils did not decrease less than 500 cells / mm, or more than one was observed to reduce the number of neutrophils in the range from 500 to 1000/mkl within three weeks of Navelbina dose of 60 mg/m2 (in accordance with the above recommendations), we can again increase the dose from 60 to 80 mg/m2 per week.

Recommended doses Navelbina Oral depending on body surface area (BSA) are given in the following table.

Body surface area (m2) 60 mg/m2 80 mg/m2 dose (mg) per week

From 0.95 to 1.0 60 80

From 1.05 to 1.14 70 90

From 1.15 to 1.24 70 100

From 1.25 to 1.34 80 100

From 1.35 to 1.44 80 110

From 1.44 to 1.54 90 120

From 1.55 to 1.64 100 130

From 1.65 to 1.74 100 140

From 1.75 to 1.84 110 140

From 1.85 to 1.94 110 150

1.95 and more than 120 160

For patients with a BSA 2 m 2 and the more general single dose Navelbina Oral should never exceed 120 mg per week in the appointment of the drug in a dose of 60 mg/m2 and 160 mg per week at a dose of 80 mg/m2.

Application Navelbina inside at doses of 60 mg/m2 and 80 mg/m2 corresponds to / in the introduction Navelbina at doses of 25 mg/m2 and 30 mg/m2.

When chemotherapy dose and frequency of administration Navelbina (as in in / in the introduction, and ingestion) depend on the specific program of anticancer therapy.

By reducing the number of neutrophils, or platelets less 1500/mkl least 75 000/mkl (with a / in the introduction), or less than 100 000/mkl (ingestion), the next administration or ingestion Navelbina set aside for 1 week. If, due to hematological toxicity had to abstain from 3 weekly injections or a drug-use Navelbina be discontinued.

Patients with severe hepatic insufficiency Navelbin be used with caution in doses, decreased by 33%.

Safety and effectiveness in Navelbina in children has not been studied.

Special correction Navelbina dosing regimen in the elderly is not required.

Side effect

The following side effects occurred more frequently than in isolated cases. We used the following criteria for evaluating the frequency of occurrence of undesirable effects: very common (> 1 / 10), frequently (> 1 / 100, 1 / 10), sometimes (> 1 / 1000, 1 / 100), rare (> 1 / 10000, 1 / 1000), rarely (1 / 10000).

On the part of the hemopoietic system: very often - neutropenia, anemia, thrombocytopenia, secondary infections accession against the oppression of bone marrow hematopoiesis and often - fever (38 ° C) in the presence of neutropenia, sometimes - sepsis, septicemia, very rarely - is complicated by septicemia, in some cases leading to death. The smallest number of neutrophils observed at 7-10 days of therapy, recovery occurs in the next 5-7 days. Cumulation gematotoksichnosti not observed.

On the part of the peripheral nervous system: very often - paresthesia, hyperesthesia, reduction or loss of deep tendon reflexes, and often - a weakness in the legs, sometimes - hard paresthesia with sensory and motor symptoms are usually reversible.

Since the cardiovascular system: sometimes - increase or decrease blood pressure, hot flushes and cold extremities; rare - CHD (angina, myocardial infarction), expressed as hypotension, collapse, very rarely - tachycardia, palpitations, heart rhythm disturbances.

In the respiratory system: sometimes - shortness of breath, bronchospasm, rarely - interstitial pneumonia (in combination therapy with mitomycin), acute respiratory distress syndrome.

On the part of the digestive system: very often - nausea, vomiting, stomatitis, constipation, diarrhea, transient increase in liver function tests (ALT, ACT); rarely - pancreatitis, raising the level of bilirubin, paresis of the intestine.

On the part of the immune system: rare - anaphylactic shock, angioedema.

Dermatological reactions: often - alopecia, rarely - skin rashes.

Local reactions: often - pain / burning or redness at the injection site, change in color of the veins, phlebitis, with extravasation - Cellulite possible - necrosis of the surrounding tissues.

Other: often - fatigue, myalgia, arthralgia, fever, pain, various locations, including chest pain, pain in the lower jaw and in the field of tumor formation; rare - hyponatremia, very rarely - hemorrhagic cystitis and the syndrome of inappropriate secretion of ADH.

Contraindications
number of neutrophils less 1500/mkl;
platelet count less than 75 000/mkl (for in / in the introduction) and less than 100 000/mkl (Oral);
serious infectious disease during the beginning of therapy or deferred in the past two weeks;
marked deficiency of liver function, not related to the neoplastic process;
need for constant oxygen therapy in patients with tumors of the lung;
diseases and conditions that lead to a decrease in absorption from the gastrointestinal tract (for oral);
Pregnancy - Lactation (breastfeeding);
Hypersensitivity to the drug and other vinkaalkaloidam.

Be wary prescribers with respiratory failure, inhibition of bone marrow hematopoiesis (including after previous chemotherapy or radiation therapy), constipation, or intestinal obstruction phenomena in history, a history of neuropathy.

Pregnancy and lactation

Navelbin contraindicated during pregnancy and lactation (breastfeeding).

Application for violations of liver function

Patients with severe hepatic insufficiency Navelbin be used with caution in doses, decreased by 33%.

Application for violations of renal function

In case of violation of renal function is necessary to monitor the patient's condition.

Cautions

Treatment Navelbinom should be under the supervision of a physician who has experience working with anticancer agents.

In marked abnormal liver function Navelbina doses should be reduced by 33%.

In case of violation of renal function should be monitored the patient's condition.

If signs of neurotoxicity of 2 or more degrees Navelbina use should be discontinued.

If you have shortness of breath, cough, or hypoxia of unknown etiology should examine the patient to avoid pulmonary toxicity.

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

In the case of nausea or vomiting after taking the capsules Navelbina again the same dose should not be accepted.

During and for at least three months after cessation of therapy, you must use reliable methods of contraception.

After contact with the active substance in the oral cavity is recommended to rinse your mouth with water or any saline solution.

In case of contact Navelbina in their eyes should be abundantly and thoroughly rinse with water.

Since the substance is formulated sorbitol, Navelbin should not be used in patients with hereditary fructose intolerance.

Monitoring of laboratory parameters

Treatment with conduct under strict hematological control, determining the number of leukocytes, neutrophils, platelets and hemoglobin levels before each regular injection or ingestion. By reducing the number of neutrophils less 1500/mkl and / or platelets less than 75 000/mkl (for in / in the introduction) or less 100 000/mkl (Oral) application for another dose of the drug to postpone the normalization parameters simultaneously monitor the patient's condition.

Overdose

Symptoms: suppression of bone marrow function, neurotoxic reactions.

Treatment: In case of overdose the patient should be hospitalized; spend symptomatic therapy with careful monitoring of functions of vital organs. The specific antidote is known.

Drug Interactions

In a joint application with other cytostatic possible mutual exacerbation of side effects, in the first place - myelosuppression.

When combined with the use of mitomycin C may develop acute respiratory failure.

In the application in conjunction with paclitaxel increases the risk of neurotoxicity.

Application on the background radiation therapy leads to radiosensitization. Application Navelbina after radiotherapy can lead to the reinvention of the light reactions.

The simultaneous use of the drug with inducers and inhibitors of cytochrome P450 isoenzymes may lead to a change in the pharmacokinetics vinorelbina

Terms and Conditions of storage

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

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

From microbiological point of view of the drug after dilution should be used immediately. If the drug was not introduced immediately, the health worker assumes responsibility for the conditions and duration of storage before administration. Typically, the duration of such storage shall not exceed 24 hours at a temperature of 2 ° to 8 ° C, except when the dilution was carried out in controlled and validated aseptic conditions.

Expiration date concentrate - 3 years. After further dilution of the drug with saline or glucose solution shelf life of 24 h at room temperature.

Expiration capsules - 2.5 years.