Vinorelbin, solution for infection, 10 mg/ml on 1 ml in фл. No. 1

General characteristics. Structure:

Main physical and chemical properties: transparent colourless solution; Structure: 1 ml Vinorelbin of the tartrate equivalent Vinorelbin of 10 mg; Excipients: tartaric acid, water for injections.

Pharmacological properties:

Vinorelbin differs structurally from vinblastine and other medicines of this group I katarantinnoit a part which is the place of structural modification Vinorelbin. It is given by Vinorelbin high-specific antimitotic properties and strengthens him lipophilicity. Generally the cytotoxic effect is shown in interaction with the device of microtubules of a cell of which the division spindle consists, and leads to a stop of a cellular cycle in metaphase. There are at least two types of points of binding from a tubulin. Linkng in points with high affinity, their smaller quantity, leads to interruption of process of synthesis of microtubules. Binding in points happens to low affinity at high concentration of drug and leads to splitting of microtubules on spiral pro-filaments and their final fracture. Researches prove high specificity Vinorelbin to microtubules of the cells which are in a mitosis phase. Vinorelbin almost does not show activity (except for high concentration) concerning the device of microtubules of axons and other classes of microtubules, and with it, perhaps, the smaller neurotoxicity by what other alkaloids of a periwinkle is connected.

Pharmacokinetics. Vinorelbin is applied intravenously. Within use of therapeutic doses of a dozozavisim the pharmacokinetics is not observed. After intravenous administration of drug in a dose of 30 mg/sq.m within 15-20 min. peak concentration in plasma makes 480 - 1230 ng/ml and gradually decreases during 2 h. There is a considerable distribution of drug in peripheral fabrics. Vinorelbin easily gets into fabrics and has the large volume of distribution (Vss = 27-76 l/kg). The highest concentration are observed in a liver, a spleen, kidneys, lungs, a thymus gland, heart and muscles. Minimum distribution in fatty tissue, marrow, brain tissues. It is observed considerable Vinorelbin's linkng with thrombocytes and lymphocytes. In blood of 78% of concentration of drug it is connected with thrombocytes. Linkng and with albumine and a-1-atsidglikoproteinom takes place, thus, the general binding of drug in blood serum makes 69 - 91%. Metabolism happens in a liver. One of active metabolites, diacetyl - винорельбин, has similar antineoplastic activity and toxicity. Vinorelbin is allocated with kidneys (16 - 21%) and on bile (34 - 58%. 2 / The 3rd renal elimination Vinorelbin from peripheral fabrics a terminal elimination half-life is observed in the first 24 h For slow a conclusion Vinorelbin, removed with urine varies from 27,7 to 43,6 h 95%, makes not changed drug.

Indications to use:

Not small-celled lung cancer. Vinorelbin is shown to patients for out-patient treatment of not small-celled lung cancer which does not plan surgical treatment and/or radiation therapy with a possibility of treatment or in case of spread of a disease as monodrug or in a combination with Cisplatinum. To patients with not small-celled lung cancer of the IV stage винорельбин it is shown as monodrug or in a combination with Cisplatinum. To patients with not small-celled lung cancer of the III stage винорельбин it is shown in a combination with Cisplatinum. Vinorelbin is also applied in cancer therapy of a mammary gland, a lymphogranulomatosis (Hodzhkin's disease), cancer of an ovary, cancer of the head and a neck.

Route of administration and doses:

Not small-celled lung cancer

• as monotherapy inoperable not small-celled IV stages:

adults: 30 mg/sq.m intravenously within 6 - 10 min. 1 times in week.

• in a combination with Cisplatinum for chemotherapy inoperable not small-celled the III stages:

adults: 30 mg/sq.m intravenously within 6 - 10 min. 1 times in week in a combination with Cisplatinum intravenously in the 1st and 29th day and then each 6 weeks.

Metastatic breast cancer

30 mg/sq.m intravenously within 6 - 10 min. 1 times in week quality of monotherapy or in a combination with other antineoplastic drugs.

Ovarian cancer or Hodzhkin's disease

30 mg/sq.m intravenously within 6 - 10 min. 1 times in week.

Cancer of the head and neck

20 - 25 mg/sq.m intravenously within 6 - 10 min. 1 times in week.

Dosing options

Hematologic toxicity

The quantity of neutrophils has to make not less than 0,5 x 109/l before introduction Vinorelbin. Correction of a dose has to be based on the data of neutrophils obtained in day of treatment.

If maintenance of neutrophils ³ 1,5 x 109/l: to enter 100% of a dose, i.e. 30 mg/sq.m.

If the maintenance of neutrophils 1,0 - 1,499 x 109/l to enter 50% of a dose, i.e. 15 mg/sq.m.

If the maintenance of neutrophils <1,0 x 109/l dose not to enter and check the maintenance of neutrophils in a week. If the maintenance of neutrophils remains <1,0 x 109/l during 3 weeks, it is necessary to stop introduction Vinorelbin.

At patients with fever and/or a septic state against the background of a neutropenia.

If maintenance of neutrophils ³ 1,5 x 109/l: to enter 75%.

If the maintenance of neutrophils 1,0 - 1,499 x 109/l to enter 37,5%.

If content of neutrophils less than 1,0 x 109/l: if therapy Vinorelbin was not carried out for more than 3 weeks for the fact that the maintenance of neutrophils remained <1,0 x 109/l, therapy Vinorelbin needs to be stopped.

Insufficiency of function of a liver

In cases when at treatment Vinorelbin develops a hyperbilirubinemia, a dose Vinorelbin is adjusted according to an indicator of the general bilirubin.

The general bilirubin of £20 mg/l to enter 100% of a dose, i.e. 30 mg/sq.m. The general bilirubin of 21-30 mg/l to enter 50% of a dose, i.e. 15 mg/sq.m.

The general bilirubin> 30 mg/l to enter 25% of a dose, that is 7,5 mg/sq.m.

Insufficiency of function of kidneys

If the general clearance of creatinine (CrCl) more than 60 ml/min., dose adjustment is not carried out. Therapy Vinorelbin is not recommended to patients with a renal failure (CrCl of £60 mg/min.).

Neurotoxicity

In case of development of symptoms of a neyroksichnost Vinorelbin is recommended to stop introduction.

Features of use:

• Precautionary measures during the work with drug.
•  Vinorelbin it is necessary to apply under the leadership of the doctor having experience of use of antineoplastic chemotherapeutic drugs.
• At preparation and administration of solutions of drug, as well as during the work with other antineoplastic means, it is necessary to be careful and use gloves. In case of drug solution hit on skin or mucous membranes it is necessary to wash away immediately carefully solution from skin water with soap, and mucous to wash out water.
• Suppression of function of marrow is the toxic effect limiting a dose Vinorelbin. During treatment it is regularly necessary to determine by drug the maintenance of neutrophils before therapy and before each subsequent course of treatment Vinorelbin. Low level of neutrophils is observed on 7 - the 10th day after administration of drug, and recovery of level happens in the next 7-14 days. Therapy needs to be stopped in case of decrease in number of neutrophils to 1,0 x 109/l.
• As винорельбин shows the toxic action of rather quickly growing cells, use to a sargramostim (GM-KSF), a filgrastim (G-KSF) it is contraindicated during 24 h after introduction Vinorelbin.
• It is necessary to monitor carefully emergence of signs, new symptoms of neuropathy also deterioration in an initial state at patients with neuropathy history irrespective of its etiology.
• It is necessary to avoid vaccination at chemotherapy and a course of radiation therapy.
• Patients with chicken pox and a herpes infection (herpes zoster, varicella-zoster) in the anamnesis treat risk group of development of a generalized infection.
• Dental procedures have to be finished prior to therapy or the blood delayed until recovery of a normal picture.
• The risk of bleeding increases at the patients who are at the same time accepting anticoagulants, NPVP, inhibitors of thrombocytes including aspirin, strontium-89 chloride, and thrombolytic means.
• The drugs interacting with R-450 cytochrome such as macroleads, antifungal means azolny groups, inhibitors of anti-retrovirus protease, nifedipine, нефазодон, carbamazepine, phenobarbital, rifampicin and рифабутин, can also break metabolism Vinorelbin; but, clinical value was not established.
• To watch symptoms of pulmonary toxicity, especially at patients with initial dysfunction of breath.
• It was reported about cases of development of locks, paralytic impassability, the obstructive phenomena in intestines, a necrosis and/or perforation.
• It is necessary to be careful at purpose of drug to patients with insufficiency of function of a liver or kidneys.

 

Side effects:

Hematologic toxicity. Dozolimitiruyushchim toxicity at use Vinorelbin consists of a neutropenia, anemia and thrombocytopenia. The neutropenia is observed at 2/3 patients. Decrease in level of neutrophils is observed on 7 - the 14th day, normalization of number of neutrophils happens for the 24th day.

Despite rather big frequency of a neutropenia (9,1% of cycles of treatment), only 7% of patients demand hospitalization through neytropenichesky a fever or a documentary infectious complication. Frequency of development of episodes of a neutropenia and leukopenia decreases in the course of performing further treatment Vinorelbin. Heavy oppression of marrow is not typical. Anemia is noted often, but moderate expressiveness. Such trombotichesky episodes as thrombosis of a pulmonary artery and a deep vein thrombosis were noted at the patients receiving therapy Vinorelbin. These complications arose at seriously ill patients with the existing risk factors of development of thrombosis.

Gastrointestinal toxicity. Nausea of moderate or moderately severe arises at 34% of patients. Through the low frequency of development heavy nausea and vomiting therapy by antagonists of serotonin usually is not required. Locks are noted in 29%, isolated cases of development of paralytic impassability are described. Also the obstructive phenomena in intestines, a necrosis and/or perforation were noted.

Neurotoxicity. The neurotoxicity is observed at 20% of patients and the hypesthesia, muscular weakness and loss of deep tendon jerks (5%) is characterized by moderate peripheral neyropatiya in the form of paresthesia. Weakness in the lower extremities can be observed after prolonged treatment. The neurotoxicity is reversible after the therapy termination.

Lungs. Cough, short wind, a bronchospasm in combination with intersticial infiltrates develop the first minutes after an injection or in several hours later more often. It was reported about cases of a fluid lungs, acute respiratory insufficiency, acute respiratory distresssindromy adults.

The alopecia of moderate character is observed at 35% of patients.

Reactions in the place of an injection in the form of feeling of pain in the place of an injection, venous pain and thrombophlebitis arose in 16% of patients at long infusion. Similar symptoms were observed at 5 - 10% during short infusion (20 min.). It was reported about development of a pain syndrome in hands and legs.

Mialgiya, weakness in muscles, a gnathalgia were marked out at 5% of patients. These symptoms connect with neurotoxic shows of drug.

Ekstravazation can lead to emergence of feeling of pain, ulcer of skin and a necrosis of soft tissues in the place of an injection. About development of chemical phlebitis, throughout a vein proksimalno from the place of an injection it was reported at 10% of patients. Skin ulcers after an ekstravazation Vinorelbin can develop in the remote period. For the prevention of development of an ulcer effective warm compresses and hyaluronidase. In case of an ekstravazation it is necessary to stop infusion and to complete input through other vein, it is desirable on the second extremity. About a skin depigmentation along a vein it was reported in one third of patients.

Others. It was reported about electrolytic disturbances, including hyponatremias with, or without syndrome of insufficient secretion of antidiuretic hormone. About development of a syndrome of insufficient secretion of antidiuretic hormone it was reported in seriously sick patients (<1%).

Hemorrhagic cystitis, raising of indicators alanine of transaminase (ALT) and an alkaline phosphatase were noted very seldom. Also it was reported about allergic reactions (<2%).

Interaction with other medicines:

It was reported about development of heavy complications from respiratory tracts at use Vinorelbin in a combination with mitomitsiny. Therapy of complications can demand use of oxygen, bronchodilators, corticosteroids: especially it concerns patients with initial dysfunctions of breath.

Frequency of emergence of a neutropenia, vestibular complications and ototoxicity considerably increases when using Vinorelbin in a combination with Cisplatinum in comparison with use Vinorelbin quality of monotherapy.

Simultaneous use of means, oppressing function of marrow and immune system (other antineoplastic and immunosuppressive drugs) can strengthen undesirable side effects.

It is necessary to pay attention to possible development of symptoms of neuropathy in the patients receiving treatment Vinorelbin in a combination with paklitaksely.

Vinorelbin's use for the patients who were earlier receiving or receiving radiation therapy can cause the back beam reaction.

Vinorelbin, perhaps, increases capture by methotrexate cells in case drugs are used at the same time. Thus, for achievement of therapeutic effect it is necessary smaller quantity of a methotrexate.

Vinorelbin increases quantity of the cells sensitive to Bleomycinum for stops of cells in metaphase.

Simultaneous use of live virus vaccines for patients with the compromised immune status was followed by development of serious and fatal infections.

Contraindications:

Vinorelbin is contraindicated to patients with the initial content of neutrophils less than 1,0 x 109/l.

For expressed irritant action contraindicated Intrathecal introduction Vinorelbin. For risk of development of a heavy necrosis of skin and soft tissues contraindicated intramuscular and hypodermic introduction Vinorelbin.

Vinorelbin is contraindicated to patients at whom reactions of hypersensitivity on винорельбин were noted.

Pregnancy and lactation. Researches on animals showed what винорельбин possesses embriotoksichesky and fetotoksichesky action. The drug uses given on safety Vinorelbin by pregnant women were not investigated. At use of drug during pregnancy or at approach of pregnancy it is necessary to warn the patient of rather potential risk for a fruit. Drug is contraindicated at pregnancy.

Women of childbearing age need to recommend to avoid pregnancy approach. It is unknown whether drug in breast milk is emitted. For the purpose of prevention of harmful effects on the child during treatment by drug it is necessary to stop feeding by a breast.

Overdose:

Antidotes for use in case of drug overdose Vinorelbin are unknown. It was reported about overdose cases in the doses, by 10 times exceeding (30 mg/sq.m). The main complication of overdose are a heavy neutropenia with risk of development of an infection, paralytic impassability, stomatitis and an esophagitis. Also it was reported about a marrow aplasia, sepsis and paresis. In case of overdose holding the general supporting actions using, if necessary, hemotransfusion, growth factors and antibiotics is shown.

Storage conditions:

To store in the place, unavailable to children. To store at a temperature of 2 - 8 °C in the place protected from light. Not to freeze.

Period of validity - 2 years.

Issue conditions:

According to the recipe

Packaging:

1 or 10 bottles on 1 ml or 5 ml in a cardboard box.