Navirel

The medical preparation of the pharmacological group of antineoplastic and immunomodulatory drugs Navirel is produced by the German pharmaceutical company Medak GmbH. Navirel is an organic compound of plant origin and a direct alkaloid of periwinkle. The international name is Vinorelbine.

Indications Navirel

The drug was developed by doctors and pharmacists for a strictly targeted purpose, therefore the indications for the use of Navirel are limited to:

• Use of the drug as a sole therapy for the last stage IV of malignant neoplasm of the mammary gland, complicated by metastasis.
• As a second stage of action on cancer cells, after unsuccessful chemotherapy based on drugs taxane or anthracycline. And also in case if such a method, for some reason, does not suit the patient.
• Non-small cell lung cancer, severe form (stage III, IV of the disease).

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Release form

The main and only form of release to date is a concentrated substance used as needed to prepare an infusion solution. The main active ingredient of the pharmacological drug is vinorelbine, which is included in its composition in the form of vinorelbine tartrate. The quantitative concentration of the active substance is 10 mg in one milliliter of concentrate. An auxiliary chemical compound can be called purified distilled water used for injections.

Pharmacodynamics

Vinorelbine is an immunomodulatory and antineoplastic pharmacological drug, hence the pharmacodynamics of Navirel. The drug is a substance with antitumor activity from the family of periwinkle alkaloids, but, unlike other drugs that are alkaloids of this plant, the residual catharanthine in vinorelbine undergoes structural modification. The active substance Navirel at the molecular-cellular level affects 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 addition of molecules of low-molecular chemical compounds (monomers), namely tubulin. The drug mainly binds selectively with mitotic microtubules, only with a large quantitative component does it begin to affect axonal microtubules. Tubulin spiralization occurs to a lesser extent than in the case of using vincristine in the treatment protocol. Navirel in the G2-M phase successfully blocks simple division of pathologically altered cells, which leads to their death. This occurs either during the period of "rest" of the cell (interphase), or during the next cycle of reproduction (mitosis).

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Pharmacokinetics

After intravenous bolus injection or infusion, plasma concentrations of vinorelbine are characterized by a three-exponential elimination curve. The terminal elimination phase results in a fairly long half-life of over forty hours. The pharmacokinetics of Navirel allow for high total clearance: from 0.97 to 1.26 l/h/kg. The active ingredient is widely distributed in the body with a distribution volume of 25.4 - 40.1 l/kg. Penetration of vinorelbine into lung tissue is significant, with the tissue-to-plasma concentration ratio in a surgical biopsy study being over 300. Plasma protein binding is fairly moderate, at only about 13.5%, while platelet binding is 78%. Linear pharmacological kinetics were observed with intravenous administration of Navirel at doses up to 45 mg/ ^m2.

Vinorelbine is metabolized primarily by cytochrome P450 CYP3A4. All metabolites have been identified and all are inactive, with the exception of 4-O-deacetylvinorelbine, which is the major metabolite in blood.

Renal excretion is very low, less than 20% of the administered amount. Low concentrations of deacetylvinorelbine have been detected in people with renal impairment, but Navirel is mainly found in the urine as unchanged compound. Excretion of the active substance occurs mainly through the bile duct and consists of metabolites, mainly unchanged vinorelbine.

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

Studies of the drug in elderly patients (over 70 years old) with non-small cell lung cancer were conducted by the manufacturer of the innovative drug. They showed that age does not affect the pharmacokinetics of Navirel. However, since the body of an "aged" patient is greatly weakened by concomitant pathology, increasing the dose of vinorelbine should be done with caution.

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Dosing and administration

The antitumor drug Navirel is used exclusively under the supervision of an oncologist who has experience in chemotherapeutic treatment. The method of administration and dosage stipulate the administration of vinorelbine intravenously and only in the form of infusions. Intrathecal use of the drug is strictly contraindicated.

In non-small cell lung cancer. In case of application as a treatment course of therapy based on the sole 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. Mainly, Navirel is prescribed in the same dosages as in monotherapy (25-30 mg/m2 of body surface). The interval between drug administrations is adjusted and can be chosen as the first and fifth days of the treatment course, as well as the first and eighth. This criterion is determined by the attending physician. The duration of chemotherapy is usually three weeks.

In case of malignant neoplasms of the mammary gland, complicated by metastasis and widespread prevalence, vinorelbine is mainly administered in the amount of 25 to 30 mg/m2 of the patient's body surface once during the week.

The maximum permissible single dose of Navirel is 35.4 mg/m2.

The antitumor agent must be administered to the patient very carefully, by bolus infusion (over five to ten minutes), immediately after dilution in 50 mg/ml of 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 administering cytostatic agents, it is imperative to flush the vein with 0.9% sodium chloride solution.

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

In the presence of extensive metastasis in the patient's liver (i.e. more than 75% of the organ volume is replaced by a malignant tumor), the real impact of a reduced volume of drug elimination by the liver has not been studied. Therefore, in this situation, an empirical reduction in the amount of Navirel administered by one third was proposed. In this case, it is necessary to carefully monitor hematological toxicity.

If the patient's kidneys are pathologically affected, there is no pharmacokinetic justification for reducing the amount of vinorelbine taken.

Neutropenia may serve as a limitation or reduction of the administered dose of the drug, due to the toxicity of the antitumor agent. On the 8th - 12th day after the use of Navirel, a decrease in the level of neutrophils is observed, but it is determined for a short time and does not show a tendency to accumulate in the body.

If the neutrophil count is less than 2 thousand/mm3 ^and /or the platelet count is less than 75 thousand/mm3 ^, treatment should be delayed until their levels are restored. It is expected that the drug administration will be delayed in the first week in approximately 35% of treatment courses. The maximum single dose of the drug is 60 mg.

Clinical experience has not revealed significant differences in the results and features of complications for elderly patients, although it cannot be ruled out that some of them have greater sensitivity and the influence of concomitant age-related pathologies. Age does not affect the pharmacological kinetics of the active substance Navirel.

When using anticancer drugs, special safety precautions must be taken.

If Navirel is sprayed under pressure, there is a risk of severe irritation and even corneal ulceration. It is very important to avoid contact of the drug with the eyes. If the drug gets into the eyes, they must be immediately and thoroughly rinsed with isotonic sodium chloride solution or with plenty of water. After preparing the solution, any surface that has come into contact with the drug must be wiped, and hands and face must be washed.

Preparation and administration of vinorelbine is carried out only by experienced personnel who are able to work with such substances. Before the procedure, it is necessary to put on protective clothing: disposable gloves, protective glasses and clothing. If the solution is spilled, it must be carefully collected and the place thoroughly washed. 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 starting the infusion of vinorelbine, it is necessary to check that the cannula is accurately positioned in the cubital vein. Extravasation of the drug during intravenous administration can cause severe local irritation. In such a situation, the infusion is stopped immediately, 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 case of extravasation, glucocorticosteroids can be administered intravenously to reduce the risk of phlebitis.
2. Treatment should be initiated by determining hematological parameters (white blood cell count, hemoglobin level, granulocytes and platelets before each new injection). If the neutrophil count is less than 2000/mm3 ^and /or the platelet count is less than 75000/mm3 ^, treatment should be postponed until their levels are restored and the patient's condition should be constantly monitored.
3. If a patient exhibits signs or symptoms that suggest infection, a thorough evaluation should be performed immediately.
4. In the presence of significant liver damage, the dose should be reduced (but this should only be done by a doctor - oncologist): caution and mandatory careful monitoring of hematological parameters are recommended.
5. In case of renal impairment, no dosage adjustment is necessary due to the low renal excretion rate.
6. Navirel is not given in combination with radiation therapy if the treatment area includes the liver.
7. Strong CYP3A4 inhibitors or inducers should be used with caution due to the risk of changes in vinorelbine concentrations.
8. As a rule, this drug is not recommended for use in combination with live attenuated vaccines.
9. As a rule, this drug is not recommended for use in combination with itraconazole and phenytoin.
10. Vinorelbine may have genotoxic effects. Therefore, men who are treated are advised not to conceive a child during the entire treatment period, as well as for the next six months after the end of treatment.
11. In order to avoid bronchospasm, especially when used concomitantly with mitomycin C, appropriate precautions should be considered. Patients treated on an outpatient basis should be advised to contact their physician if dyspnea occurs.
12. It is recommended to measure the dosage of the administered drug especially carefully if the patient has a history of ischemic heart disease.
13. Since treatment with anticancer drugs can lead to irreversible infertility, men who want to experience the joy of fatherhood in the future are advised to play it safe and resort to sperm cryopreservation before starting the treatment course.
14. When using Navirel in medical therapy, there is a possibility of its influence on the quality of reaction and attention in the case of working with moving mechanisms and when driving vehicles.

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Use Navirel during pregnancy

To date, there is no information about the use of Navirel during pregnancy and the results of this effect. In the process of studies conducted on animals, it was found that vinorelbine has a teratogenic effect on the biological organism, as well as an embryo-lethal and feto-lethal effect. Women are strongly advised to avoid conception during the period of vinorelbine therapy. During this time, it is worth protecting yourself by using effective contraceptives. You should not refuse them for another three months from the date of stopping taking the drug in question. This drug should not be prescribed to women during pregnancy. The only exceptions may be cases due to medical indications associated with the vital necessity for the patient. If a woman becomes pregnant during therapy, it is imperative to inform her doctor and undergo genetic testing for the risk of pathological changes in the fetus.

The drug Navirel can have a genotoxic effect on the patient's body. Therefore, men who are treated with vinorelbine are not recommended to conceive a child during the entire course of treatment, as well as for another six months after its completion.

There is no information on the penetration of the active substance into breast milk. Therefore, breastfeeding of the newborn must be stopped before the drug is administered to the body. This drug is not prescribed to children.

Contraindications

Any pharmacological drug is a complex of chemical compounds capable of affecting the human body, both in a positive and negative field. Therefore, before introducing it into the treatment protocol, it is necessary to know well not only the reasons for use, but also the contraindications for the use of Navirel. In our case, these are:

• Individual intolerance of the patient's body to vinorelbine, as well as to other periwinkle alkaloids.
• Low level of neutrophils in the patient's blood (less than 2 thousand per cubic millimeter).
• A severe current or recent, within the last two weeks, infectious disease.
• The level of platelets in plasma is below 75 thousand per cubic millimeter.
• It should not be administered in combination with other live attenuated vaccines.
• A severe form of pathological changes in the liver, not associated with the development of oncological neoplasms.
• Navirel is contraindicated for use in combination with the yellow fever vaccine.
• The drug is not recommended to be included in the treatment protocol for patients of reproductive age if they do not use effective contraceptive protection.
• Concomitant use with itraconazole and phenytoin is not allowed.

It is strictly forbidden to administer the drug intrathecally (administration of the drug into the subarachnoid space of the spinal cord and brain or into the ventricles of the brain).

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Side effects Navirel

The pharmacological agent is classified as a toxic chemical. Therefore, the side effects of Navirel are quite extensive in 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 combination chemotherapy together with other antitumor drugs more often causes the side effects listed below than in the case of monotherapy. At the same time, the intensity of their manifestation is much brighter. Specific side effects and tandem drugs of the treatment course should not be discounted.

• Secondary infection with progressive superinfection - fungal, viral or bacterial infection of various localizations.
• Anemia.
• Less commonly, severe sepsis with failure of internal organs can be observed.
• In isolated cases, complicated septicemia is diagnosed.
• Paralytic ileus. Suppression of bone marrow function, which in most cases results in neutropenia (third or fourth degree – with monotherapy).
• Acute manifestations of thrombocytopenia.
• An allergy that manifests itself as a reaction of the skin - redness, itching and rashes, as well as problems with the respiratory system.
• There are isolated cases of Quincke's edema and anaphylactic shock.
• Hyponatremia is a low level of sodium ions in the blood.
• Constipation.
• Decreased response of deep tendon reflexes.
• Neurological disorders.
• Paresthesia of the gastrointestinal tract with sensory and motor symptoms.
• Weakening of muscle activity in the lower limbs.
• In rare cases, negative symptoms from the cardiovascular system can be observed: ischemic heart disease, tachycardia, myocardial infarction, heart rhythm disturbances.
• Arterial hypotension.
• Impaired sensitivity in the limbs.
• Failure in thermoregulation of the extremities.
• Dyspnea.
• Spasms of bronchial tissues. Such a reaction can manifest itself both immediately after the drug enters the body and after several hours.
• Interstitial lung disease.
• There are isolated cases of respiratory failure.
• Liver dysfunction (increased levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase and total bilirubin).
• Hives.
• Erythematous lesion of the skin localized on the palms and soles.
• Myalgia is a painful symptom in muscle tissue.
• Arthralgia is the appearance of pain in the joints.
• Less common is pain in the jaw area.
• Increased creatinine levels.
• Decreased overall tone of the body, rapid fatigue.
• Fever.
• Redness, pain and phlebitis at the injection site. Less common - cellulitis and tissue necrosis around the injection site.

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Overdose

With all antitumor drugs, it is necessary to be extremely careful. This also applies to Navirel. When an increased dose of the drug is administered, an overdose occurs and the patient's body is able to react with pathological symptoms. This may be:

• Bone marrow hypoplasia is tissue underdevelopment.
• May be accompanied by a secondary infection – superinfection.
• Fever.
• Paralytic intestinal obstruction.

Such overdose symptoms are treated with supportive symptomatic therapy, such as blood transfusions or broad-spectrum antibiotics. No single antidote is currently known.

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Interactions with other drugs

The drug in question behaves in many ways similar to all cytotoxic drugs. Since it is used in chemotherapy of oncological diseases, it is necessary to study the interactions of Navirel with other drugs with special attention.

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

L-asparaginase may reduce the clearance of vinorelbine in the liver, increasing its toxicity. To reduce the manifestations of this interaction, Navirel should be administered 12-24 hours before the use of L-asparaginase.

When prescribing tacrolimus or cyclosporine, the risk of developing excessive immunosuppression with lymphoproliferation must be taken into account.
Concomitant use with vinca alkaloids and mitomycin C increases the risk of developing bronchospasm and dyspnea. In isolated cases, especially when used in combination with mitomycin, cases of interstitial pneumonia have been observed.

Since CYP3A4 is primarily involved in the metabolism of vinorelbine, combination with inducers (eg, rifampicin, phenytoin, carbamazepine, phenobarbital) or inhibitors of this enzyme (eg, ketoconazole, ritonavir, itraconazole, erythromycin, and clarithromycin) may result in changes in the pharmacological kinetics of vinorelbine.

Itraconazole should not be administered concomitantly with Navirel due to the possibility of progressive neurotoxicity.

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

If the patient is receiving anticoagulant treatment, it is necessary to increase the frequency of monitoring of the coagulation index (INR), due to the high individual variability of the coagulation level throughout the course of the disease and the possibility of interactions between oral anticoagulants and anticancer chemotherapy.

Navirel is believed to increase the binding of methotrexate to cells when the drugs are used simultaneously. In this situation, to achieve a therapeutic effect, it is necessary to reduce the amount of methotrexate administered. During treatment with Navirel, yellow fever vaccines should not be used due to a fairly high probability of developing a pathology that can lead to the death of the patient. Other live attenuated vaccines should not be used in parallel (especially in patients with low immune protection due to an existing disease) due to the potential risk of developing a systemic, possibly fatal disease. Inactivated vaccines should be used if they exist (for example, against poliomyelitis).

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Storage conditions

Storage conditions for the anticancer drug Navirel require a room that meets certain requirements.

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

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Shelf life

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

After the solution has been prepared, the physical and chemical stability of Navirel is observed for another day (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. The responsibility for the relevant indicators lies with a special medical worker.

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