Navigrel

The medical preparation of pharmacological group of antineoplastic and immunomodulating medications Navirel is manufactured by the German pharmacological company Medak GmbH. Navirel is an organic compound of plant origin and a direct vinca alkaloid. The international name is Vinorelbine.

Indications Navigrel

The drug was developed by physicians and pharmacists purely directional, therefore indications for use of Navirel are limited:

• Use of the drug as sole therapy in the last IV stage of malignant growth of the breast, weighed down by metastasis.
• As the second stage of exposure to cancer cells, after an unsuccessful chemotherapy on the basis of taxane drugs or anthracycline. And also if such a technique, for some reason does not suit the patient.
• Non-small cell cancer of lung, severe form (III, IV stage of the disease).

[1], [2], [3]

Release form

The main and the only form of release today is a concentrated substance, used as needed when preparing a solution for infusion. The main active substance of the pharmacological preparation is vinorelbine, which is part of its composition in the form of vinorelbine tartrate. The quantitative concentration of the active substance is 10 mg in one milliliter of concentrate. Auxiliary chemical compound can be called purified distilled water, used for injections.

Pharmacodynamics

Vinorelbine refers to immunomodulating and antineoplastic pharmacological drugs, hence the pharmacodynamics of Navirel. The drug is a substance with antitumor activity from the family of alkaloids of the periwinkle, but, unlike the other drugs that are the alkaloid of this plant, in vinorelbine the residual catarrhtin undergoes a structural modification. The active substance on the molecular level stimulates the fragile dynamic balance of tubulin in the system of cellular microtubules.

Navirel does not interfere with the process of formation of high-molecular substances (polymers) by multiple attachment of molecules of low-molecular chemical compounds (monomers), namely tubulin. Pharmacopreparation, preferentially, comes into contact selectively, with mitotic microtubules, only with a large quantitative component begins to affect the axonal microtubules. Spiralization of tubulin occurs to a lesser degree than when used in the protocol of treatment vincristine. Navirus in phase G2-M successfully blocks the simple division of pathologically altered cells, which leads to their death. This occurs either during the "rest" period of the cell (interphase), or during the next cycle of reproduction (mitosis).

[4], [5], [6], [7],

Pharmacokinetics

After intravenous bolus injection or infusion, vinorelbine concentration in the blood plasma is characterized by a triplex excision curve. The final phase of elimination causes a sufficiently long half-life, which is more than forty hours. The pharmacokinetics of Navirel allow maintaining a high level of total clearance: from 0.97 to 1.26 l / h / kg. The active ingredient is widely distributed in the body with a distribution volume in the range of 25.4 - 40.1 l / kg. The penetration of vinorelbine into the lung tissue is significant, the tissue-plasma concentration ratio in the surgical biopsy study was more than 300. Binding to plasma proteins shows a fairly moderate level, only about 13.5%, but the interaction with platelets is expressed by a figure of 78%. Linear pharmacological kinetics was observed with intravenous administration of Navirela in doses up to 45 mg / m ².

Vinorelbine is metabolized mainly by the action of CYP3A4 cytochrome P450. All metabolites were identified and all of them were inactive, with the exception of 4-O-deacetylvinorelbine, which is the main metabolite in the blood.

Kidney excretion shows a very low rate - less than 20% of the amount administered. Low concentrations of deacetylvinorelbine have been identified in people with kidney pathology, but mostly Navirel is found in the urine as an unchanged compound. The release of the active substance occurs mainly through the bile duct and consists of metabolites, mostly unchanged vinorelbine.

The effect of kidney dysfunction on the distribution of the active substance has not been investigated, but through a low degree of renal excretion there is no reason to reduce the amount of the drug administered. In patients with liver metastases, changes in mean vinorelbine clearance were observed only when more than 75% of the liver was affected.

The study of the drug in elderly patients (over 70 years) with non-small cell lung cancer was carried out by the manufacturer of the innovative drug. They showed that the age does not affect the pharmacokinetics of Navirela. However, since the organism of the patient "at the age of" is greatly weakened by the concomitant pathology, an increase in the dose of vinorelbine must be exercised with caution.

[8], [9], [10], [11]

Dosing and administration

The anti-neoplastic drug Navirel is used exclusively under the supervision of a doctor - an oncologist who has experience in chemotherapeutic treatment. The method of administration and dose determine the administration of vinorelbine intravenously and only in the form of infusions. Intrathecal use of the drug is strictly contraindicated.

With non-small cell lung cancer. In the case of treatment as a treatment course based on the single use of Navirel, the dosage for adult patients is prescribed from 25 to 20 mg per square meter. The drug is administered to the patient once a week.

If complex therapy is used, together with other cytostatic agents, the exact amount of vinorelbine administered is determined in accordance with the treatment protocol. Primarily, Navirel is prescribed in the same dosages as with monotherapy (25-30 mg / sq. M body surface area). The gap between the drug inputs is adjusted and can be chosen as the first and fifth days of the treatment course, and the first and the eighth. This criterion is determined by the attending physician. Duration of chemotherapy is usually three weeks.

In the case of malignant tumors of the breast, laden with metastasis and widespread, vinorelbine is preferably administered in an amount of 25 to 30 mg / sq. M. Of the body surface of the patient once a week.

The maximum permissible single dose administered was 35.4 mg / m 2.

The antitumor agent should be administered to the patient very carefully, by bolus infusion (within five to ten minutes), immediately after dilution in 50 mg / ml 5% glucose solution or 0.9% sodium chloride solution in an amount of 20-50 ml. And also by short intravenous penetration (twenty to thirty minutes) after dilution in 125 ml of 0.9% sodium chloride solution or 5% glucose solution 50 mg / ml. After completion of the procedure for the administration of cytotoxic agents, it is necessary to rinse the vein with 0.9% sodium chloride solution.

If there is a history of a patient with breast cancer of moderate pathological damage of the liver (metastases occupy less than 75% of the liver volume), the clearance of vinorelbine does not change. That is, for such patients there is no pharmacokinetic justification for decreasing the dosage of Navirela.

If there is extensive metastasis in the patient's liver (that is, more than 75% of the body volume is replaced by a malignant tumor), the real effect of the reduced amount of drug elimination by the liver has not been investigated. Therefore, in this situation, it was suggested empirically to reduce the number of injected Navirela by a third. It is necessary to carefully monitor hematologic toxicity.

If the patient's kidneys have undergone pathological damage, then there is no pharmacokinetic justification for reducing the amount of vinorelbine taken.

Restriction or reduction of the injected dose of the drug may be neutropenia, due to the toxicity of the antitumor agent. On the 8th-12th day after the application of Navirel, a decrease in the level of neutrophils is observed, but it is determined shortly and does not show a tendency to accumulation in the body.

If the neutrophil count is less than 2,000 / mm ³ and / or the platelet count is less than 75,000 / mm ³, then treatment should be deferred until their level is restored. It is expected that the introduction of the drug is delayed in the first week in approximately 35% of treatment courses. The maximum, single-entry, the amount of the drug is 60 mg.

Clinical experience did not reveal significant differences in the results and features of complications for elderly patients, although it is impossible to exclude in some of them a greater sensitivity and the effect of concomitant age pathologies. Age does not affect the pharmacological kinetics of the active substance Navirela.

When using anticancer drugs, special precautions must be taken.

If Navirel is sprayed under pressure, there is a risk of severe irritation and even the formation of a corneal ulcer. It is very important to avoid contact of the drug with the eyes. If the product gets into the eyes, they must be rinsed immediately with an isotonic solution of sodium chloride or under a lot of water. After the preparation of the solution, any surface that is in contact with the pharmacological preparation must be wiped, and hands and face washed.

Preparation and administration of vinorelbine is carried out only by experienced personnel, who can work with similar substances. Before the procedure, you need to wear protective clothing: wear disposable gloves, goggles and clothing. If the solution spills, it must be carefully collected and the place well washed. The unused medicinal product must be destroyed in accordance with the standards for the disposal of toxic chemical compounds.

1. The antitumor drug should be administered intravenously very carefully. Before the infusion of vinorelbine, it is necessary to check that the cannula is precisely located in the ulnar vein. Extravasation of a pharmacological preparation in the course of intravenous administration can cause severe local irritation. In this situation, the infusion is immediately stopped, the affected vein is washed with 0.9% sodium chloride solution, and the remaining drug is injected into the vein of the other arm. In the case of extravasation, glucocorticosteroids can be given intravenously to reduce the risk of phlebitis.
2. Treatment therapy should begin with the definition of hematological indicators (setting the number of leukocytes, hemoglobin, granulocytes and platelets before each new injection). If the number of neutrophils is less than 2000 / mm ³ and / or the platelet count is less than 75,000 / mm ³, treatment should be postponed until their level is restored and the patient needs constant monitoring.
3. If the patient shows signs or symptoms suggestive of an infection, a thorough examination should be carried out immediately.
4. If there is a significant lesion of the liver, the dose should be reduced (but do it only by a doctor - oncologist): caution and mandatory careful monitoring of hematological parameters is recommended.
5. In the case of kidney damage, there is no need to adjust the dose through a low level of renal excretion.
6. No one is prescribed for radiation therapy in parallel with radiotherapy if the treatment site includes a liver.
7. Powerful inhibitors or inducers of CYP3A4 should be used with caution because of the risk of changes in vinorelbine concentration.
8. As a rule, this drug is not recommended for use in combination with live atenuovaniemi vaccines.
9. As a rule, this drug is not recommended to be used in combination with itraconazole and phenytoin.
10. Vinorelbine may have a genotoxic effect. Therefore, men who are being treated are not recommended to conceive a child during the entire treatment period, and also during the next six months after the end of treatment.
11. In order to avoid bronchospasm, especially with concomitant use with mitomycin C, it is necessary to consider appropriate precautions. Patients who are treated as outpatients need to be informed that they need to see a doctor in case of dyspnea.
12. It is recommended to carefully measure the dosage of the drug administered if a history of the patient is diagnosed with ischemic heart disease.
13. Since treatment with antitumor drugs can lead to irreversible infertility, men who wish to experience the joy of paternity in the future, it is advisable to be safe and apply to the cryopreservation of sperm even before the beginning of the treatment course.
14. When using Navirela in medical therapy, the possibility of its influence on the quality of reaction and attention in the case of working with driving mechanisms and when driving vehicles.

[19], [20], [21], [22]

Use Navigrel during pregnancy

To date, there is no information about the use of Navirel during pregnancy and the results of this exposure. In the same studies conducted on animals, it was found that vinorelbine has a teratogenic effect on the biological organism, as well as embryo-lethal and fetoletal effect. Women are strongly advised to avoid conception during treatment with vinorelbine. At this time, it is worth to protect yourself by using effective contraceptives. Do not abandon them for another three months from the date of discontinuation of the drug in question. This medication should not be given to women during the period of gestation. An exception can only be cases caused by medical indications related to the vital need for the patient. If during the period of therapy a woman becomes pregnant, it is necessary to inform your doctor in person and to undergo genetic tests for the risk of pathological changes in the fetus.

The drug Navirel can genotoxically affect the patient's body. Therefore, men who are treated with vinorelbine, are not recommended to conceive a child throughout the course of treatment, as well as for another six months after its termination.

There is no information on the penetration of the active substance into the mother's milk. Therefore, feeding a newborn baby should be stopped before the introduction of the drug into the body. This medication is not prescribed for children.

Contraindications

Any pharmacological preparation is a complex of chemical compounds capable of affecting the human body, both in a positive and negative field. Therefore, before you enter it into the protocol of treatment, you need to know well not only the causes of use, but also contraindications to the use of Navirel. In our case this is:

• Individual intolerance of the patient's body to vinorelbine, as well as to other vinca alkaloids.
• Low level of neutrophils in the patient's blood (less than 2 thousand per cubic millimeter).
• Severe current or, recently, during the last two weeks, the transferred infectious disease.
• The platelet count in the plasma is below 75,000 per cubic millimeter.
• Do not enter into a comprehensive treatment together with other live atenuovannymi vaccines.
• Severe form of pathological changes in the liver, not associated with the development of cancer.
• Contraindicated in the use of Navirel together with the yellow fever vaccine.
• The drug is not recommended to enter into the protocol of therapy for patients of the reproductive period, if they do not use effective contraceptive protection.
• Do not use together with itraconazole and phenytoin.

Categorically, it is not possible to administer the drug intrathecally (administration of the drug into the subshell space of the spinal cord and brain or into the ventricles of the brain).

[12], [13], [14], [15],

Side effects Navigrel

The drug is classified as a group of toxic chemicals. Therefore, side effects of Navirel are quite extensive with monotherapy and most often affect the gastrointestinal tract and bone marrow. It is also necessary to understand that the use of the active substance in combined chemotherapy together with other antitumoral drugs more often causes the following side effects than in the case of monotherapy. At the same time, the intensity of their manifestation is much brighter. It is not necessary to discount the specific side reactions and tandem preparations of the treatment course.

• Secondary infection with progressive superinfection is a fungal, viral or bacterial lesion of different localization.
• Anemia.
• Less often you can observe severe sepsis with insufficient functioning of the internal organs.
• In isolated cases, a complicated septicemia is noted.
• Paralytic ileus. Oppression of the bone marrow, resulting in, in most cases, become neutropenia (third or fourth degree - with monotherapy).
• Acute manifestations of thrombocytopenia.
• Allergy, manifested by the reaction of the skin - redness, the appearance of itching and rashes, as well as problems on the part of the respiratory system.
• Quincke edema and anaphylactic shock are rare.
• Hyponatremia is a low level of sodium in the blood.
• Constipation.
• Decreased reaction of deep tendon reflexes.
• Violations of a neurological nature.
• Paresthesia of the gastrointestinal tract with sensory and motor symptoms.
• Weakening the muscular activity of the lower limbs.
• In rare cases, it is possible to observe negative symptoms from the cardiovascular system: ischemic heart disease, tachycardia, myocardial infarction, cardiac rhythm malfunction.
• Arterial hypotension.
• Impaired sensation in the extremities.
• Failure in thermoregulation of the extremities.
• Dyspnea.
• Spasms of bronchial tissues. Such a reaction can manifest itself immediately immediately after the drug is taken into the body, and after a few hours.
• Interstitial lung disease.
• Cases of respiratory insufficiency are rare.
• Failures in the work of the liver (an increase in the parameters of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase and total bilirubin).
• Hives.
• Erythmic lesion of the skin with localization on the palms and soles.
• Myalgia is a pain symptomatology in the muscular tissues.
• Arthralgia - the appearance of pain in the joints.
• Less common pain in the jaw area.
• Increase in the level of creatinine.
• Decrease in the general tone of the body, rapid fatigue.
• Fever.
• Redness, pain and phlebitis at the injection site. Less commonly - cellulite and necrosis of tissues located around the site of the injection.

[16], [17], [18],

Overdose

With all antitumor drugs, you must be extremely cautious. This applies to Navirela. When you receive an increased dose of medication, you get an overdose of it and the patient's body is able to react with pathological symptoms. It can be:

• Bone marrow hypoplasia - tissue underdevelopment.
• May be accompanied by a secondary infection - superinfection.
• A fever.
• Paralytic obstruction of the intestine.

Such symptoms of overdose are prevented by maintenance symptomatic therapy, such as blood transfusions or broad-spectrum antibiotics. Sole antidote for today is not known.

[23], [24], [25]

Interactions with other drugs

This drug, in many respects behaves similarly to all cytotoxic drugs. Since it is used in cancer chemotherapy, it is necessary to study with particular attention the interactions of Navirel with other drugs.

The use of vinorelbine in combination with cisplatin (quite often used combination) does not affect the pharmacokinetic properties of both drugs. However, the likelihood of developing granulocytopenia with the combination of Navirel and cisplatin is higher than with monotherapy of the drug in question.

L-asparaginase can reduce the clearance of vinorelbine in the liver, increasing its toxicity. To reduce the manifestations of this interaction, Navirel should be prescribed 12 to 24 hours before the application of L-asparaginase.

When appointing tacrolimus or cyclosporine, the risk of developing excessive immunosuppression with lymphoproliferation should be considered.
Concomitant use with vinca alkaloids and mitomycin C increases the risk of bronchospasm and dyspnea. In some cases, especially when used in conjunction with mitomycin, there have been cases of interstitial pneumonia.

Since vinorelbine metabolism mainly involves CYP3A4, combining with inducers (eg, rifampicin, phenytoin, carbamazepine, phenobarbital) or inhibitors of this enzyme (eg, ketoconazole, ritonavir, itraconazole, erythromycin and clarithromycin) can alter the pharmacological kinetics of vinorelbine.

Itraconazole should not be administered in parallel with Navirel because of the possibility of progressing neurotoxicity.

Vinorelbine is a substrate of the P-glycoprotein, so its simultaneous administration with inhibitors (eg, quinidine, cyclosporin, verapamil) or inducers of this transport protein may affect the concentration of the active substance in question.

If the patient is treated with anticoagulants, it is necessary to increase the frequency of blood clotting (INR) monitoring, through high individual variability of the blood coagulation level throughout the course of the disease and the possibility of interaction between oral anticoagulants and anticancer chemotherapy.

Navirel, presumably, increases the connection with methotrexate cells in case the drugs are used simultaneously. In this situation, in order to achieve a therapeutic effect, it is necessary to reduce the amount of methotrexate administered. During the treatment with Navirel, yellow fever vaccines should not be used because of the high probability of developing a pathology capable of leading to death of the patient. Other live atenuated vaccines can not be used in parallel (especially for patients with low immune defenses due to an existing disease) through the potential risk of developing a systemic, possibly lethal disease. Inactivated vaccines should be used if they exist (for example, from polio).

[26], [27], [28], [29], [30], [31],

Storage conditions

The storage conditions of the anti-cancer drug Navirel require a room meeting certain requirements.

• The room temperature is within two to eight degrees above zero (the refrigerator).
• The drug should not be frozen.
• Protection from light and direct sunlight.
• The place should not be accessible to children.

[32], [33]

Shelf life

Three years is the shelf life of the drug in question. The date of production and the end date of use must be indicated on the packaging, and it is necessary to closely monitor the end date of use. If the drug has not been used in the recommended period, its subsequent use is strictly prohibited.

After the preparation of the solution, the physico-chemical stability of Navirela is observed for another 24 hours, if the storage temperature varied within two to eight degrees above zero. From a microbiological point of view, the product must be used immediately after dilution. Responsibility for the relevant indicators is borne by a special medical officer.

[34], [35],