Velbin - instructions for use, dose, side effects, contraindications

Vinorelbine is an antitumor agent of plant origin from the group of semisynthetic vincaalkaloids isolated from plants of the genus Vinca Periwinkle. Violates the polymerization of tubulin in the process of cellular mitosis. It blocks mitosis in phases G2 and M of the cell cycle and causes cell destruction in the interphase or subsequent mitosis. Acts mainly on mitotic microtubules, when high doses are applied it also affects axonal microtubules. The effect of spiral tubulin, caused by vinorelbine, is less pronounced than that of vincristine.

Pharmacokinetics:

Distribution

The volume of distribution of vinorelbine is high and averages 21.2 l / kg (range 7.5-39.7 l / kg), which indicates an extensive distribution of vinorelbine in tissues. Binding to plasma proteins is insignificant - 13.5%, vinorelbine in large quantities binds to blood cells, especially with platelets (about 78%).There is a significant seizure of vinorelbine with a pulmonary tissue, where a concentration of 300 times higher than in the blood plasma is achieved. Vinorelbine is not found in the brain tissues.

Metabolism

Vinorelbine is biotransformed in the liver under the action of an isoenzyme CYP3A4 cytochrome P450. All metabolites are identified and inactive, with the exception of 4-O-deacetyl-vinorelbine, which is the main active metabolite in the blood plasma. Sulfo- and glucuronic conjugates were not detected.

Excretion

The average half-life in the final phase is 40 hours (27.7-43.6). Systemic clearance of vinorelbine is high and approaches the rate of blood flow in the liver and averages 0.72 l / h / kg (0.32-1.26 l / h / kg).

Vinorelbine is mainly excreted in bile in unchanged form and in the form of metabolites. The kidneys produce less than 20% of the administered intravenous dose, mainly as a starting material.

Indications:

- non-small cell lung cancer;

- common breast cancer;

- prostate cancer, resistant to hormone therapy (in combination with small doses of oral glucocorticosteroids).

Contraindications:

- increased sensitivity to vinorelbine or other vinaalkaloids, as well as other components of the drug;

- initial number of neutrophils <1500 cells / μl of blood;

- the initial number of platelets <100 000 cells / μl of blood;

- severe infectious diseases at the beginning of therapy or transferred within the last 2 weeks;

- pregnancy;

- the period of breastfeeding;

- simultaneous application with the yellow fever vaccine;

- children under 18 years of age (efficacy and safety of use in children not established).

Carefully:

- Ischemic heart disease in history;

- hepatic failure of moderate to severe severity;

- simultaneous reception of strong inhibitors or inducers of isoenzyme CYP3A4.

Pregnancy and lactation:

During the treatment with Velbin, as well as at least 3 months after the end, women of childbearing age should use reliable methods of contraception.

In the case of pregnancy, you should immediately notify the attending physician of this.

During therapy with Velbin and for at least 3 months after the termination of treatment, men should use reliable contraceptive methods.It is necessary to pass the sperm for cryopreservation before the treatment, because it is possible to develop infertility after treatment.

Patients who plan to have children after treatment are recommended for genetic counseling.

Pregnancy

During admission during pregnancy vinorelbine can cause serious defects of the fetus, so taking VELBIN during pregnancy is contraindicated.

Breast-feeding

It is not known whether vinorelbine in human milk. The isolation of vinorelbine in the breast milk of animals has not been studied. It is impossible to exclude the risk of unwanted reactions when breastfeeding, so before breast-feeding, breastfeeding should be discontinued.

Dosing and Administration:

Strictly intravenously.

Intrathecal injection is strictly forbidden, it can lead to death!

Dosage regimen, frequency of administration and duration of treatment are determined by the attending physician.

The drug Velbin is administered as a 6-10 minute infusion.

The drug is previously diluted in 20-50 ml of 0.9% solution of sodium chloride for injection or in a 5% solution of dextrose for injection.Immediately 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.

Non-small cell lung cancer and advanced breast cancer

In the monotherapy regimen, the standard dose of the drug is 25-30 mg / m² body surface once a week.

With combined chemotherapy, the standard dose of the drug is 25-30 mg / m²body surface, but the frequency of administration decreases - on days 1 and 5 every 3 weeks or on days 1 and 8 every 3 weeks - depending on the protocol of antitumor therapy.

Prostate Cancer Resistant to Hormone Therapy

The standard dose of the drug is 30 mg / m² body surfaces on days 1 and 8 every 3 weeks in combination with a daily intake of oral glucocorticosteroids in low doses (for example, hydrocortisone in a dose of 40 mg / day).

Correction of the dosing regimen for hematological toxicity

With a decrease in the absolute number of neutrophils <1500 cells / μl and / or platelets < 100 000 cells / μL of blood, another injection of Velbin is delayed until

recovery of neutrophil count> 1500 cells / μL and / or platelets> 100,000 cells / μl.

Correction of the dosing regimen in specific patient groups

Impaired liver function

The pharmacokinetics of vinorelbine does not change in patients with hepatic insufficiency. Nevertheless, as a precautionary measure, it is recommended to reduce the dose to 20 mg / m² body surface and careful monitoring of hematological parameters in patients with moderate or severe hepatic impairment.

Impaired renal function

The effect of renal dysfunction on the pharmacokinetic properties of vinorelbine is not was investigated. However, due to the low level of renal elimination, a decrease in the dose of vinorelbine in the case of decreased renal function is not indicated.

Elderly patients

The pharmacokinetics of vinorelbine in elderly patients does not change. However, because older patients may be weakened, precautions should be taken when increasing the dose of Velbin.

Childhood

The drug is intended for patients with 18 years of age, since the safety and efficacy of vinorelbine in children have not been studied.

Side effects:

Adverse reactions are systematized according to the system-organ classes and are listed according to the following gradation:

very often (≥10%); often (≥ 1%, <10%); infrequently (≥ 0.1%, <1%); rarely (≥ 0.01%, <0.1%); very rarely (<0.01%), the frequency is unknown - single post-marketing messages, the frequency can not be estimated from available data.

Infectious and parasitic diseases

Often - bacterial, viral or fungal infections of various locations (respiratory, urinary and gastrointestinal tract) from mild to moderate severity, usually reversible with appropriate treatment.

Infrequently - Severe sepsis with multiple organ failure, septicemia.

Rarely - Complicated septicemia, sometimes fatal.

Frequency unknown - Neutropenic sepsis with a potentially fatal outcome.

On the part of the blood and lymphatic system

Often - Myelosuppression, leading to neutropenia (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 is not observed), anemia.

Often - Thrombocytopenia.

Frequency unknown - febrile neutropenia.

From the immune system

Frequency unknown - Systemic allergic reactions (anaphylaxis, anaphylactic shock or anaphylactoid type reactions).

From the endocrine system

Frequency unknown - Syndrome of inadequate secretion of antidiuretic hormone.

From the side of metabolism and nutrition

Rarely - severe hyponatraemia.

Frequency unknown anorexia.

From the nervous system

Often - neurological disorders, including reduction or loss of tendon reflexes.

Frequency unknown -weakness of the lower extremities with prolonged chemotherapy. Infrequent - severe paresthesia with sensory and motor symptoms.

The effect data, as a rule, are reversible.

From the heart

Rarely - ischemic heart disease (angina, myocardial infarction).

Rarely - tachycardia, fibrillation, heart rhythm disturbances, palpitation.

From the side of the vessels

Infrequently - arterial hypotension, arterial hypertension, sensation of "hot flashes", cooling of limbs.

Rarely - severe arterial hypotension, collapse.

On the part of the respiratory system, mediastinal organs, chest and mediastinal organs

Infrequently - shortness of breath, bronchospasm.

Rarely - Interstitial pneumonia.

From the gastrointestinal tract

Often - stomatitis, nausea, vomiting, constipation.

Often - diarrhea (usually moderate or moderate severity).

Rarely - paralytic intestinal obstruction, pancreatitis.

From the liver and biliary tract

Often - transient increase in the activity of "liver" transaminases without clinical symptoms.

From the skin and subcutaneous tissues

Often - alopecia (usually moderate degree).

Rarely generalized skin reactions.

Frequency unknown - erythema on the palms and feet.

From the osteomuscular system and connective tissue.

Often - Arthralgia, pain in the temporomandibular joint, myalgia.

General disorders and disorders at the site of administration

Often - reactions at the site of administration may include erythema, burning pain, vein discoloration, and phlebitis at the site of administration.

Often - asthenia, weakness, fever, pain of different localization, including pain in the chest and in the area of the tumor.

Rarely - necrosis of tissues at the injection site.

Overdose:

The main expected overdose manifestations include suppression of bone marrow function, sometimes in combination with infection, fever,dynamic intestinal obstruction and impaired liver function.

The specific antidote is not known.

In case of an overdose, the patient should be hospitalized and the functions of vital organs should be carefully monitored. Appropriate measures should be taken: blood transfusion, administration of antibiotics, growth factors. It is recommended to monitor liver function.

Interaction:

Pharmaceutical interaction

Do not use alkaline solutions to dilute the concentrate (sedimentation is possible).

Do not mix ready-made solution for Velbin infusions with other medications for intravenous administration.

Pharmacodynamic interaction

Vaccines: in connection with the immunosuppressive effect of the drug and the possibility of developing severe infections, it is not recommended during the period of chemotherapy to carry out vaccination with live (weakened) vaccines.

Itraconazole: an increase in the neurotoxicity of vinorelbine due to an increase in vinorelbine concentration in the blood plasma as a result of a decrease in its metabolism in the liver.

Phenytoin: it is possible to reduce the anticonvulsant effect of phenytoin, decrease the efficacy and increase the toxicity of vinorelbine.

Cisplatinum: There is no mutual influence in the combined use of vinorelbine and cisplatin for several treatment cycles. However, the frequency of cases of granulocytopenia with the use of a combination of vinorelbine with cisplatin is higher than in the case of monotherapy with vinorelbine.

Cytotoxic: when combined with other cytostatics, the mutual aggravation of side effects is possible, first of all - myelosuppression.

Oral anticoagulants: the mutual aggravation of side effects is possible, the INR (international normalized relationship) should be systematically monitored, as well as careful monitoring of the patient's general condition.

Cyclosporin, tacrolimus: marked immunosuppression with risk of lymphoproliferation.

Inhibitors of the isoenzyme CYP3A4 (eg, ketoconazole): an increase in the neurotoxicity of vinorelbine due to an increase in vinorelbine concentration in the blood plasma as a result of a decrease in its metabolism in the liver.

Inductors of the isoenzyme CYP3A4 (for example, rifampicin): decreased efficacy and increased toxicity of vinorelbine due to increased metabolism in the liver.

Inductors and inhibitors of cytochrome P450: a change in the pharmacokinetics of vinorelbine is possible.

Mitomycin C: increased pulmonological toxicity of mitomycin (risk of bronchospasm, acute respiratory failure, there were rare cases of interstitial pneumonia).

Inductors and inhibitors of P-glycoprotein: since it is known that vinca alkaloids are a substrate for P-glycoprotein, caution should be exercised when the preparation of Velbin is combined with preparations that alter the function of this transport protein.

Special instructions:

- The drug is intended exclusively for intravenous administration. Intrathecal injection is strictly prohibited, as this leads to death!

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

- Since hematopoietic suppression is the main risk, during careful treatment with Velbin, thorough hematologic monitoring should be carried out - determining the number of leukocytes, neutrophils, platelets and hemoglobin on the day of each injection.

- An undesirable reaction restricting the dose of the drug is predominantly non-cumulative (not increasing with repeated injections) neutropenia. The smallest number of cells is observed on the 7-14 day after drug administration, this phenomenon is rapidly reversible within 5-7 days. With a decrease in the absolute number of neutrophils <1500 cells / μl and / or platelets <100,000 cells / μl of blood, the next administration of the drug is postponed until the number of neutrophils is restored ≥ 1500 cells / μl and / or platelets ≥ 100,000 cells / μl.

In case of suspected co-infection on the day of initiation of therapy, the patient should be examined and the benefit-risk ratio should be evaluated when deciding whether to administer the drug.

Special care should be taken in patients with ischemic heart disease in the history of the disease (see section Side effect).

If dyspnoea, cough or hypoxia of unexplained etiology appears, the patient should be examined to exclude pulmonary toxicity. Patients in outpatient care should inform the attending physician of the development of these symptoms. In order to avoid the development of bronchospasm, especially when combined therapy with mitomycin C, it is recommended to take preventive measures.

In the case of paralytic intestinal obstruction, the drug should be discontinued. Treatment can be continued after restoration of normal intestinal motility.

The contact of the concentrate with the eye can lead to severe irritation and even ulceration of the cornea if the drug has entered the eyes under pressure. If the product gets into the eyes, immediately and thoroughly wash them with 0.9% solution of sodium chloride and consult an ophthalmologist.

Velbin should not be used concomitantly with radiotherapy if the area of irradiation covers the liver.

The drug Velbin is strictly contraindicated with simultaneous administration with a vaccine against yellow fever.

VELBIN should be used with caution with strong inhibitors or isoenzyme inducers CYP3A4, since they affect the concentration of vinorelbine in the blood plasma. Simultaneous administration with phenytoin, itraconazole and live attenuated vaccines is not recommended.

In view of the low excretion of vinorelbine by the kidneys, there is no prerequisite for reducing the dose of the drug in patients with impaired renal function.

For information on use during pregnancy, breast feeding and on the impact on fertility, see section Application in pregnancy and during breastfeeding.

Instructions for the introduction of ready-made mortar and waste disposal

Preparation for the introduction and administration of Velbin should be carried out by medical personnel who are trained in the safe handling of antitumor drugs.

Personnel should use eye protection, disposable gloves, a mask and apron.

The drug should be administered strictly intravenously: it is very important to make sure that the needle or catheter is precisely set in the vein prior to the start of the drug administration.

With extravasation, the infusion of the drug should be stopped immediately, the vein washed with 0.9% sodium chloride solution, the remainder of the dose should be injected into another vein. In the case of extravasation, to reduce the risk of phlebitis, glucocorticosteroids should be injected intravenously.

Storage of a ready-made solution for infusions

FROM microbiological point of view, the ready-made solution for infusions should be used immediately. If the drug has not been injected immediately, the health care provider assumes responsibility for the conditions and duration of storage prior to administration.The duration of such storage should not exceed 24 hours at a temperature of 2 to 8 ° C in a place protected from light.

Unused solution or waste must be disposed of in accordance with current legislation.

Effect on the ability to drive transp. cf. and fur:

The ability of vinorelbine to influence the management of vehicles and mechanisms has not been studied. Care should be taken when driving vehicles and engaging in other potentially hazardous activities in the event of the development of adverse reactions that affect the concentration of attention and the speed of psychomotor reactions.

Form release / dosage:Concentrate for the preparation of a solution for infusions of 10 mg / ml.

Packaging:1 ml or 5 ml in a glass bottle sealed with a bromobutyl rubber stopper with a silicate filler and rolled in an aluminum cap with a polypropylene disc. Vials can be covered with a transparent protective layer of shrink film. 1 bottle with instructions for use in a cardboard pack.

Storage conditions:At a temperature of 2 to 8 ° C. Keep out of the reach of children!

Shelf life:

3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LS-002697

Date of registration:29.12.2011 / 23.10.2013

Expiration Date:Unlimited

The owner of the registration certificate:AKTAVIS GROUP, AO AKTAVIS GROUP, AO Iceland

Manufacturer: & nbsp

ACTAVIS ITALY, S.p.A. Italy

Representation: & nbspAktavis, Open Company Aktavis, Open Company

Information update date: & nbsp24.01.2017

Illustrated instructions

Instructions

Velbin (Velbin)