Vinkristin-RONTS - instructions for use, doses, side effects, contraindications

Active substanceVincristineVincristine

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Dosage form: & nbspsolution for intravenous administration

Composition:

In 1 ml of solution contains:

active substance: vincristine sulfate 1.0 mg;

Excipients: mannitol 100.0 mg, methylparahydroxybenzoate 1.8 mg, propyl parahydroxybenzoate 0.2 mg, sodium hydroxide up to pH 4.5, sulfuric acid up to pH 4.5, water for injection up to 1 ml.

Description:Transparent from colorless to light yellow color solution.

Pharmacotherapeutic group:Antitumor agent - alkaloid

ATX: & nbsp

L.01.C.A.02 Vincristine

Pharmacodynamics:

Vincristine - alkaloid vinca pink (Catharanthus roseus), a cytotoxic chemotherapeutic agent.

Vincristine, binding to the molecules of the protein-tubulin, leads to a violation of the microtubular apparatus of cells and to the rupture of the mitotic spindle and stops mitosis at the stage of metaphase. Vincristine can also change the metabolism of amino acids, cAMP, glutathione, the activity of calmodulin-dependent Ca²⁺ transport ATPase, cellular respiration, biosynthesis of nucleic acids and lipids, has an immunosuppressive effect.

Pharmacokinetics:

After intravenous administration vincristine quickly distributed in the tissues of the body. Connection with plasma proteins - 75-90%, with shaped elements of blood - 15%. The drug penetrates poorly through the blood-brain barrier. The initial, middle and final half-lives are 5 minutes, 2.3 hours and 85 hours, respectively. The terminal half-life can range from 19 to 155 hours. Vincristine metabolized in the liver and excreted mainly with bile; 70-80% is excreted through the intestine in unchanged form and in the form of metabolites, from 10 to 20% is excreted by the kidneys. Pharmacokinetic parameters have significant individual variability.

Due to low plasma clearance to prevent cumulative toxicity, the interval between treatment cycles should be at least 1 week.

Patients with hepatic impairment

In patients with impaired hepatic function, a metabolic disorder may occur and, as a result, a decrease in vincristine excretion, which increases the risk of toxicity in these patients. If necessary, reduce the dose.

Children

Children have significant individual differences in pharmacokinetic parameters, such as clearance, volume of distribution and half-life; Besides,these parameters vary with age. Plasma clearance in children is usually higher than in adults and infants, but there is no clear data on the decrease in clearance in children with increasing age.

Indications:

Leukemia, Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, Ewing's sarcoma, rhabdomyosarcoma, Kaposi's sarcoma, Wilms tumor, neuroblastoma, uterine choriocarcinoma, small cell lung cancer.

Vincristine is also used in idiopathic thrombocytopenic purpura (resistant to corticosteroids and ineffectiveness of splenectomy).

Contraindications:

- Hypersensitivity to vincristine or any other component of the drug;

- neurodegenerative diseases (in particular demyelinating form of the Charcot-Marie-Toot syndrome);

severe hepatic impairment;

- threatening intestinal obstruction, especially in children;

- simultaneous radiation therapy involving the liver region;

- Pregnancy and the period of breastfeeding.

Carefully:Use with caution in the suppression of bone marrow hematopoiesis, a decrease in liver function, in the presence of a history of neuropathy, the presence of constipation,acute infectious diseases, with prior chemotherapy or radiotherapy, in elderly patients.

Pregnancy and lactation:

Vincristine is contraindicated in pregnancy.

If necessary, use during lactation should stop breastfeeding.

Women of childbearing age should use reliable contraceptive methods when applying vincristine.

Dosing and Administration:

Vincristine is administered strictly intravenously (avoid extravasation) at intervals of 1 week. The duration of the injection should be at least 1 minute.

Intrathecal use of the drug is prohibited!

The dose should be determined individually, depending on the treatment regimen used and the clinical condition of the patient.

Adults: usually 1.0-1.4 mg / m² body surface, a single dose should not exceed 2 mg. The maximum exchange rate is 10-12 mg / m².

For children: 1.5-2.0 mg / m² surface of the body. DFor children with a body weight ≤ 10 kg the initial dose should be 0.05 mg / kg per week.

The course of therapy is usually 4-6 weeks.

With a decrease in liver function (serum bilirubin concentration ≥3 mg / 100 ml (51 μmol / l) the dose of vincristine should be reduced by 50%.

When there are signs of severe damage to the nervous system, especially with the development of paresis, treatment with vincristine should not be done. After the disappearance of the neurological symptoms with the withdrawal of the drug, therapy can be resumed at a dose of 50% of the initial.

When used in elderly patients correction of the dose is not required.

Side effects:

From the nervous system: Peripheral sensory neuropathy (paresthesia, numbness, loss of deep tendon reflexes, sagging feet, muscle weakness, ataxia, paralysis), neuralgia (including pain in the jaw, throat, parotid glands, back, bones, muscles and male sexual glands) dysfunction of the cranial nerves (hoarseness, vocal fold paresis, ptosis, optic neuropathy and other neuropathies), transient cortical blindness, nystagmus, diplopia, optic nerve atrophy, spasms with increased blood PRESSURE tions, headache, dizziness, depression, agitation, increased drowsiness, confusion, psychosis, hallucinations, sleep disturbances, hearing loss, impaired motor function.

Neurotoxicity is a dose limiting factor.

From the digestive system: constipation, abdominal pain, anorexia, weight loss, nausea, vomiting, diarrhea, paralytic intestinal obstruction (especially in children), stomatitis, necrosis of the small intestine wall and / or perforation.

From the hepatobiliary system: primary thrombosis of hepatic veins (especially in children).

From the urinary system: polyuria, dysuria, delay urination due to atony of the bladder, hyperuricemia, urate nephropathy.

From the endocrine system: syndrome of inadequate secretion of antidiuretic hormone (hyponatremia in combination with a high level of sodium excretion in the urine without signs of impaired renal and adrenal function, hypotension, dehydration, azotemia or edema).

From the cardiovascular system: coronary heart disease, myocardial infarction (in patients who previously received radiotherapy in the mediastinum, when combined chemotherapy with the inclusion of vincristine), increasing or lowering blood pressure.

From the respiratory system: acute respiratory failure and bronchospasm, sometimes expressed and life-threatening (observed with vincristine in combination with mitomycin).

From the hemopoietic system and hemostasis system: anemia, leukopenia, thrombocytopenia, transient thrombocytosis. Usually vincristine does not have a significant effect on hematopoiesis.

From the skin and skin appendages: alopecia.

On the part of the reproductive system: azoospermia, amenorrhea.

Allergic reactions: anaphylactic shock, skin rash, angioedema.

Local reactions: irritation at the injection site; when the product gets under the skin, inflammation of the subcutaneous fat, phlebitis, pain, necrosis of surrounding tissues may develop.

Other: fever, arthralgia, myalgia.

Overdose:

In case of an accidental overdose, vincristine should be expected to increase in side effects.

Treatment should be symptomatic and should include restriction of fluid intake, the appointment of diuretics (to prevent the syndrome of ADH secretion), the use of phenobarbital (to prevent seizures), the use of enemas and laxatives (prevention of intestinal obstruction).It is also necessary to monitor the activity of the cardiovascular system and carry out hematological control. In addition to the above, calcium folinate in a dose of 100 mg intravenously every 3 hours for 24 hours and then every 6 hours for at least 48 hours.

The specific antidote is not known. Hemodialysis is ineffective.

Interaction:

Vinkaalkaloids are metabolized by cytochrome P-450 isoenzyme - CYP3A4 and are substrates for P-glycoprotein. In this regard, with the simultaneous use of inhibitors CYP3A4 and P-glycoprotein, such as, for example, ritonavir, nelfinavir, ketoconazole, itraconazole, erythromycin, fluoxetine, nefazodone, ciclosporin and nifedipine there may be an increase in the plasma concentration of vincristine in the blood. Simultaneous administration of itraconazole and vincristine was associated with faster and / or more pronounced neuromuscular side effects, which is probably due to inhibition of vincristine metabolism.

Simultaneous administration of phenytoin in combination with antitumor treatment, including vincristine, led to a decrease in the content of phenytoin in the blood and, accordingly, to a decrease in the anticonvulsant effect.

Myelo-depressants and prednisolone reinforce oppression of bone marrow hematopoiesis.

With the simultaneous use of neurotoxic drugs (for example, isoniazid, asparaginase and ciclosporin) simultaneously with vincristine, the development of severe and prolonged peripheral neuropathy is possible. Therefore, drugs with known neurotoxic effects should be administered with caution under continuous neurological monitoring.

Vincristine decreases the effectiveness of digoxin and ciprofloxacin.

Verapamil increases the toxicity of vincristine.

With simultaneous application vincristine weakens the effect of anti-gouty drugs.

With simultaneous use with uricosuric drugs, the risk of nephropathy increases.

When vincristine is used in combination with mitomycin, the likelihood of developing respiratory depression and bronchospasm increases.

If it is necessary to use the drug in combination with asparaginase vincristine can be administered only 12-24 hours before the injection of asparaginase. Assigning asparaginase before the administration of vincristine can disrupt its excretion from the liver.

In connection with the possible suppression of the immune system function, caused by the treatment with vincristine, the formation of antibodies in response to the vaccine can be reduced. With simultaneous administration with live viral vaccines, it is possible to intensify the process of replication of the vaccine virus, increase its side / adverse effects and / or reduce the production of antibodies in the patient's body in response to the introduction of the vaccine.

Patients with leukemia in remission should not receive a live viral vaccine for at least 3 months after the last treatment with chemotherapy.

The pharmacodynamic interaction of vincristine with other cytostatics can enhance therapeutic and toxic effects.

Simultaneous application of vincristine and other suppressing function of bone marrow medicines, such as doxorubicin (especially in combination with prednisolone) can enhance the depressive effect on the bone marrow.

Radiation therapy can lead to increased peripheral neurotoxicity vincristine.

Against the background of the use of cyclosporine, tacrolimus may develop excessive immunosuppression with a risk of lymphoproliferation

In combination with bleomycin, depending on the dose vincristine can cause Reynaud's syndrome.

In the course of concomitant administration, vincristine and colony-stimulating factors (G-CSF, GM-CSF) were more often reported atypical neuropathies with a sensation of tingling or burning in the distal parts of the extremities.

Do not mix vincristine with other drugs in one syringe.

Glucorticosteroids, androgens, estrogens and progestins intensify the action of vincristine.

Pharmaceutically incompatible with a solution of furosemide (precipitation).

Special instructions:

Treatment with vincristine should be carried out under the strict supervision of a physician with experience in cytotoxic therapy.

The drug should be administered strictly intravenously. Intrathecal injection can lead to the development of lethal neurotoxicity!

During treatment should be carried out regular hematological control. In case of detection of leukopenia with the introduction of repeated doses, special care should be taken.

When the activity of "liver" transaminases increases, the dose of vincristine should be reduced.

Periodically, the concentration of sodium in serum should be determined.For the correction of hyponatremia, the administration of appropriate solutions is recommended.

Special control is given to patients who have a history of neuropathy.

When symptoms of neurotoxicity appear, treatment with vincristine should be discontinued.

To support regular work of the intestine, it is recommended that an appropriate diet, taking laxatives or using enemas.

In the case of extravasation, vincristine should be discontinued immediately, and the remainder administered to another vein. The feeling of local discomfort can be minimized by local administration of hyaluronidase and the use of moderate heat or cold compresses.

Caution should be given vincristine elderly people, as neurotoxicity in them can be more pronounced.

Any complaint of pain in the eyes or a decrease in vision requires a careful ophthalmological examination.

To prevent the development of urate nephropathy, regular monitoring of serum uric acid levels is required. With an increase in the level of uric acid, alkalinization of urine and the administration of uricosynthesis inhibitorsallopurinol).

Carefully vincristine prescribe to patients with coronary heart disease. Women and men during treatment with vincristine and at least 3 months afterwards should use reliable methods of contraception.

Side effects are dose-dependent and can be completely eliminated upon cancellation.

Impossible intramuscular introduction because of the possibility of developing tissue necrosis.

When working with vincristine solution, you should follow the rules for handling cytotoxic drugs. Avoid contact with solution! If the solution comes into contact with skin, mucous membranes or eyes, rinse thoroughly with plenty of water. Contact vincristine in the eyes can lead to severe irritation and ulcerative lesions of the cornea.

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

Considering that during the application of vincristine neurotoxicity and other symptoms affecting the general condition may develop, during treatment it is necessary to refrain from driving motor vehicles and practicing potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Solution for intravenous administration, 1 mg / ml.

Packaging:

1 ml, 2 ml or 5 ml into the bottle of hydrophilic class I light-shielded glass, sealed with a stopper and bromobutyl rubber under running in with an aluminum cap or an aluminum cap with a plastic insert.

1 Vial with instructions for use in a cardboard pack.

Storage conditions:

In the dark place at a temperature of 2 to 8 ° C.

Keep out of the reach of children.

Shelf life:

2 of the year.

Do not use the drug after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003309

Date of registration:13.11.2015 / 11.07.2016

Expiration Date:13.11.2020

The owner of the registration certificate:RNTS named after N.N. Blokhin RAMS RNTS named after N.N. Blokhin RAMS Russia

Manufacturer: & nbsp

RNTS named after N.N. Blokhin RAMS Russia

Information update date: & nbsp16.02.2017

Illustrated instructions

Instructions

VINCRYSTIN-RONTS® (VINCRISTINE-RONC®)