VINCRISTINE-NAPROD

Extreme caution is recommended in calculating and administering the dose to be injected, as an overdose can have serious or even fatal consequences.

As monotherapy, administration is weekly.

In combination with other antineoplastic drugs, the rate of injections depends on the protocol.

The usual dose is

For adults, the usual dose is 1.4 mg/m2 of body surface area (2 mg maximum) once a week.

Extreme caution is recommended in calculating and administering the dose of vincristine sulfate, as an overdose may have serious or even fatal consequences.

Do not increase the dose beyond the level producing therapeutic benefit.

Generally speaking, individual doses should not exceed 2 mg; perform a leukocyte count before each administration.

Children may tolerate a higher dose: for children weighing more than 10 kg, the usual dose is 1.5-2.0 mg/m2 of body surface area once a week.

In children weighing 10 kg or less, the usual starting dose is 0.05 mg/kg body weight once a week.

In infants, the dose is calculated based on individual body weight (not body surface area).

The ratio of body surface area to body weight is disproportionate in infants and, compared with larger children, pronounced neurological and hepatic adverse effects may appear after chemotherapy for acute leukemia.

The normal recommended dose for adults is suitable for the elderly.

In case of hepatic failure or elevation of direct bilirubinemia to more than 3 mg/100 mL (51 µmol/L), it is recommended to reduce the dose of vincristine sulfate by 50%.

Due to hepatic metabolism and biliary excretion of vincristine, reduced doses are recommended in patients with obstructive jaundice or other hepatic disorder.

If hepatic dysfunction is sufficient to reduce biliary excretion, an increase in the severity of adverse reactions is possible.

Vincristine sulfate should not be administered in cases of severe neurotoxicity, particularly in cases of paresis.

When symptoms subside after stopping the administration of vincristine sulfate, treatment can be resumed at 50% of the dose.

Vincristine sulfate should be administered under the strict supervision of physicians experienced in cytotoxic therapy.

Intrathecal administration of vincristine leads to fatal neurotoxicity.

Vincristine sulfate may be administered

Intravenous, by continuous infusion or bolus over at least 1 minute in a running infusion.

It is extremely important to ensure that the needle is correctly inserted into the vein before starting the injection.

Any infiltration into subcutaneous tissues should be avoided.

Extravasation during intravenous administration of vincristine sulfate may cause very significant irritation.

To prevent vascular irritation, the vein should be flushed well after administration of vincristine sulfate.

Syringes containing this product must be labeled. “VINCRISTINE RESERVED FOR INTRAVENOUS ADMINISTRATION; ADMINISTRATION BY OTHER ROUTES MAY BE FATAL.” In case of accidental intrathecal administration, immediate neurosurgical intervention is required to prevent ascending paralysis which can lead to death.

In a very small number of patients, life-threatening paralysis and subsequent death have been avoided, but the neurological sequelae have been devastating and recovery limited.

Based on published survival data, in the event of accidental intrathecal administration of vincristine, the following treatment should be implemented immediately after injection: Extraction, via lumbar access, of as large a volume of CSF as possible while guaranteeing patient safety.

Introduction of an epidural probe into the subarachnoid space via the intervertebral space above the initial lumbar access and irrigation of the CSF with lactated Ringer's solution.

Fresh frozen plasma should be ordered and, when available, add 25 mL per liter of lactated Ringer's solution.

Introduction of an intraventricular drain or catheter by a neurosurgeon and continued irrigation of the CSF with extraction of fluid through the lumbar access connected to a closed drainage system.

Ringer's solution should be administered by continuous infusion at a rate of 150 mL/h, or 75 mL/h when fresh frozen plasma has been added as indicated above.

The infusion rate should be adjusted to maintain a cerebrospinal fluid protein level of 150 mg/dL.

The following measures have also been implemented, but are probably not essential: Administration of folinic acid Intravenous in the form of a bolus of 100 mg, then a continuous infusion at a rate of 25 mg/h for 24 hours, then boluses of 25 mg every 6 hours for 1 week.

Intravenous administration of 10 g of glutamic acid over 24 hours, followed by 500 mg three times a day Oral for one month.

Administration of pyridoxine at a dose of 50 mg every 8 hours by intravenous infusion over 30 minutes.

Their role in reducing neurotoxicity is uncertain.

Any contact of vincristine sulfate with the eyes should be avoided.

It is associated with a risk of severe irritation or ulceration of the cornea (particularly if the product is projected under pressure).

In case of contact with eyes, wash them immediately with plenty of water and seek medical or ophthalmological advice if eye irritation persists.

In case of accidental splash on the skin, wash with plenty of water then with mild soap and rinse thoroughly.

Any extravasation should be avoided.

If extravasation occurs, immediately interrupt the injection and inject any remaining dose into a different vein.

The local injection of hyaluronidase 250 IU/ml (1 mL Subcutaneous around the lesion) and the application of moderate heat to the site of extravasation facilitate the diffusion of the product and limit discomfort and the risk of cellulite to a minimum.

A device to manage cytostatic extravasation must be available in the department where vincristine sulfate is administered.

Due to the risk of leukopenia, the doctor and patient must be vigilant for the occurrence of an infection.

In the event of leukopenia, appropriate measures should be taken, including precise calculation of the time of administration of the next dose of vincristine sulfate.

Blood counts should be checked before each dose is administered.

Due to an increased risk of leukopenia and thrombocytopenia, closer monitoring is necessary in patients with bone marrow depression due to previous treatment or the disease itself.

Particular caution is required in case of history of neurological disorders, as well as in case of association of vincristine with potentially neurotoxic drugs.

The neurotoxic effect of vincristine sulfate may be additive to that of other neurotoxic agents or increased in cases of spinal cord irradiation and neurological disease.

Elderly patients may be more sensitive to the neurotoxic effects of vincristine sulfate.

Due to the increased thrombotic risk in tumor diseases, the use of anticoagulant treatment is frequent.

The great intra-individual variability of coagulability during these conditions, to which is added the possibility of an interaction between oral anticoagulants and anticancer chemotherapy, requires, if it is decided to treat the patient with oral vitamin K antagonists, to increase the frequency of INR controls.

Vinca alkaloids are metabolized by the cytochrome P450 isoenzyme 3A4 (CYP3A4) and constitute a substrate of P-glycoprotein.

An increase in the plasma concentration of vincristine is therefore possible in case of concomitant administration of inhibitors of CYP3A4 and P-glycoprotein, such as ritonavir, nelfinavir, ketoconazole, itraconazole, erythromycin, cyclosporin, nifedipine and nefazodone.

Concomitant administration of itraconazole and vincristine has been associated with earlier onset and/or premature neuromuscular adverse reactions and/or increased severity, probably related to inhibition of vincristine metabolism.

Concomitant administration of azole antifungals (e.g. itraconazole, voriconazole, posaconazole, isavuconazole and fluconazole) with vincristine may increase plasma concentrations of vincristine, which may lead to earlier onset and/or increased severity of neurotoxicity and other adverse effects.

Therefore, azole antifungals should be used with caution in patients treated with vincristine and should only be used when no other antifungal treatment options exist or when the potential benefits outweigh the risks of the combination.

Patients should be closely monitored for adverse effects associated with this concomitant use.

Caution should be exercised regarding the possible interaction between vincristine sulfate and calcium channel blockers, particularly nifedipine.

Concomitant administration of vincristine sulfate and nifedipine may result in decreased plasma clearance of vincristine sulfate with a risk of increased toxicity.

Concomitant administration of phenytoin and antineoplastic chemotherapy, including vincristine, has been associated with a reduction in phenytoin blood levels and an increase in the proconvulsant effect.

This combination is not recommended.

If it cannot be avoided, the dose should be adjusted based on blood tests.

Pharmacodynamic interactions are possible with other cytostatics: potentiation of therapeutic and toxic effects.

The combination of vincristine and other bone marrow depressant drugs, such as doxorubicin (particularly in combination with prednisone) may potentiate the depressant effects on the bone marrow.

When vincristine is used in combination with L-asparaginase, vincristine should be administered between and 24 hours before administration of L-asparaginase because decreased hepatic clearance of vincristine sulfate may result in cumulative hepatotoxicity.

Due to the neurotoxicity of vincristine sulfate, other potentially neurotoxic drugs, such as cyclosporin and isoniazid, should not be administered concomitantly.

Due to the immunosuppressive risk of vincristine, the formation of antibodies by the body in response to the vaccine may be reduced.

The time interval between stopping the use of the immunosuppressive drug and recovering the body's ability to respond to the vaccine depends on the intensity and type of immunosuppressants, the underlying disease and other factors; estimates vary between 3 months and 1 year.

Due to the immunosuppressive risk of vincristine, the combination with a live virus vaccine may potentiate the replication and adverse effects of the viral vaccine and/or reduce the formation of antibodies by the body in response to the vaccine; these patients should only be vaccinated with the greatest caution, after careful assessment of their hematological status and only with the approval of the attending physician.

The time interval between stopping the use of an immunosuppressive drug and recovering the body's ability to respond to the vaccine depends on the intensity e Store and transport refrigerated (between 2°C and 8°C).

Store the bottle in the outer packaging, protected from light.

mg/ml, solution for injection is indicated alone or in combination with other oncolytic drugs, for the treatment: acute lymphoblastic leukemia malignant lymphomas, including Hodgkin's disease and non-Hodgkin's lymphomas, multiple myeloma solid tumors, including (metastatic) breast cancer and small cell lung cancer, Ewing sarcoma, embryonal rhabdomyosarcoma, primitive neuroectodermal tumors (such as medulloblastoma and neuroblastoma), Wilms tumor, and retinoblastoma idiopathic thrombocytopenic purpura (ITP).

Patients with true

ITP resistant to splenectomy and short-term adrenocorticoid therapy are likely to respond to vincristine, but it is not recommended as first-line treatment for ITP.

The recommended weekly dosage of vincristine administered for 3-4 weeks has led to permanent remissions in some patients.

If there is no response after 3-6 doses, additional doses are unlikely to provide any benefit.

The mechanisms of action of vincristine sulfate remain under investigation.

The mechanism of action of vincristine sulfate has been related to the inhibition of microtubule formation in mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage.

Central nervous system leukemia has been reported in patients undergoing otherwise successful therapy with vincristine sulfate.

This suggests that vincristine does not penetrate well into the cerebrospinal fluid.

Pharmacokinetic studies in patients with cancer have shown a triphasic serum decay pattern following rapid intravenous injection.

The initial, middle and terminal half–lives are 5 minutes, 2.3 hours, and 85 hours respectively; however, the range of the terminal half–life in humans is from to 155 hours.

The liver is the major excretory organ in humans and animals.

The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily.

This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes.

About 80% of an injected dose of vincristine sulfate appears in the feces and 10% to 20% can be found in the urine.

Within to 30 minutes after injection, over 90% of the drug is distributed from the blood into tissue, where it remains tightly, but not irreversibly, bound.

Current principles of cancer chemotherapy involve the simultaneous use of several agents.

Generally, each agent used has a unique toxicity and mechanism of action so that therapeutic enhancement occurs without additive toxicity.

It is rarely possible to achieve equally good results with single–agent methods of treatment.

Thus, vincristine sulfate is often chosen as part of polychemotherapy because of lack of significant bone–marrow suppression (at recommended doses) and of unique clinical toxicity (neuropathy).

ADMINISTRATION section for possible increased toxicity when used in combination therapy.

Pharmacotherapeutic group: antineoplastic vinca alkaloid, ATC code: L01CA02.

Vincristine sulfate is a salt of vincristine, an alkaloid extracted from the periwinkle Vinca rosea Linn.

Vinca alkaloids are classic “spindle poisons,” which bind to the microtubule protein tubulin and block cells during metaphase by preventing tubulin polymerization and thus microtubule formation and inducing depolymerization of existing microtubules.

Vinca alkaloids can exert their effect on the process in different ways: by binding to a specific site on tubulin and forming a tubulin-alkaloid aggregation complex by binding to a high affinity site on tubulin, incorporated into microtubules, and inhibiting the incorporation of additional tubulin into the existing microtubule by binding to a low affinity site on the microtubule wall, causing the protofilament to separate.

Vincristine may also act on other cellular systems, such as RNA and DNA synthesis, cyclic AMP, lipid biosynthesis, and calmodulin-dependent Ca2+ transport ATPase.

In general, adverse effects are reversible and dose-dependent.

The most significant toxic effects of vincristine are associated with the central nervous system.

The most common adverse effects are neurotoxicity and alopecia; the most bothersome side effects are of neuromuscular origin.

Adverse effects may be more pronounced in patients with hepatic impairment due to reduced metabolism and delayed bile excretion.

Adverse reactions are listed according to their frequency, with the most common appearing first, using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated based on available data).

Within each frequency group, adverse reactions are presented in descending order of seriousness.

Benign, malignant and unspecified tumors (including cysts and polyps) Patients treated with vincristine in combination with other cytotoxic drugs, known to be carcinogenic, have developed secondary cancers.

Temporary thrombocytosis.

Severe bone marrow depression, anemia, leukopenia and thrombocytopenia.

Acute shortness of breath and bronchospasm, potentially severe and potentially life-threatening.

These symptoms have been observed following administration of vinca alkaloids (such as vincristine), particularly in combination with mitomycin.

The reaction can occur within minutes to several hours after administration of a vinca alkaloid or up to 2 weeks after a dose of mitomycin.

Allergic reactions, such as anaphylaxis, rash and edema, potentially related to treatment with vincristine, have been observed in patients treated with vincristine as part of a chemotherapy protocol combining several agents.

Neurological toxicity is the most important adverse effect of vincristine.

Neurological toxicity is dose and age related.

Neurotoxicity can also cause constipation and ileus.

The most common neurotoxic adverse reaction is peripheral neuropathy (both sensory and motor), which occurs in virtually all patients.

Neuromuscular adverse reactions often develop in a specific order.

They generally begin with only sensory disturbances and paresthesia.

With continued treatment, nerve pain (among others in the jaw and testicles) and other motor difficulties may occur.

Tendon areflexia, equinus foot, muscle weakness, ataxia, and paralysis have been reported with continued treatment.

Cranial nerve damage, including isolated paresis and/or paralysis of the muscles directed by the cranial nerves, is possible, without other muscle weakness.

Cranial nerve palsy and laryngeal muscle weakness can cause hoarseness of the voice and vocal cord paresis, including bilateral vocal cord paresis that can be life-threatening.

Weakness of the external eye muscles can cause ptosis and optic and extraocular neuropathy.

Transient cortical blindness has been described.

Vincristine also causes autonomic and central nervous system toxicity, although less common than peripheral neuropathy.

Cases of double vision and optic atrophy are observed.

Seizures, often associated with high blood pressure, have been reported in a small number of patients receiving vincristine sulfate.

A few cases of convulsions followed by coma have been described in children.

Vincristine causes autonomic nervous system and

CNS toxicity, although less common than peripheral neuropathy.

Effects on the

CNS, such as altered consciousness and mental changes such as depression, agitation, insomnia, confusion, psychoses and hallucinations.

Arterial coronary artery disease, myocardial infarction.

Cases of vascular coronary artery disease and myocardial infarction have occurred in patients treated with combination chemotherapy containing.

Vincristine sulfate is contraindicated in the following cases: hypersensitivity to the active substance or to any of the excipients mentioned in section 6.1 neuromuscular disorders (for example, the demyelinating form of Charcot-Mary Tooth disease) severe impairment of liver function; constipation and risk of ileus, particularly in children treatment with radiotherapy of the liver.

Particular attention will be given to the pathological conditions indicated in section 4.4 Special warnings and precautions for use.

This preparation is for intravenous use only.

It should be administered by individuals experienced in the administration of Vincristine Sulfate Injection.

The intrathecal administration of Vincristine Sulfate

Injection usually results in death.

To reduce the potential for fatal medication errors due to incorrect route of administration, Vincristine Sulfate Injection should be diluted in a flexible plastic container and prominently labeled as indicated "FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES." See OVERDOSAGE section for the treatment of patients given intrathecal Vincristine Sulfate Injection.

Vincristine sulfate can cause fetal harm when administered to a pregnant woman.

When pregnant mice and hamsters were given doses of vincristine sulfate that caused resorption of 23% to 85% of fetuses, fetal malformations were produced in those that survived.

Five monkeys were given single doses of vincristine sulfate between days and 34 of their pregnancies; 3 of the fetuses were normal at term, and 2 viable fetuses had grossly evident malformations at term.

In several animal species, vincristine sulfate can induce teratogenesis as well as embryo death at doses that are nontoxic to the pregnant animal.

There are no adequate and well–controlled studies in pregnant women.

If this drug is used during pregnancy or if the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard to the fetus.

Women of child–bearing potential should be advised to avoid becoming pregnant.

Patients with the demyelinating form of

Charcot–Marie–Tooth syndrome should not be given Vincristine Sulfate Injection.

Careful attention should be given to those conditions listed under WARNINGS and PRECAUTIONS.

This preparation is for intravenous use only See WARNINGS.

Neurotoxicity appears to be dose related.

Extreme care must be used in calculating and administering the dose of Vincristine Sulfate Injection since overdosage may have a very serious or fatal outcome.

The usual dose of Vincristine Sulfate

Injection for pediatric patients is 1.5–2 mg/m 2.

For pediatric patients weighing 10 kg or less, the starting dose should be 0.05 mg/kg, administered once a week.

Injection for adults is 1.4 mg/m 2.

A 50% reduction in the dose of Vincristine Sulfate Injection is recommended for patients having a direct serum bilirubin value above 3 mg/100 mL.

The drug is administered intravenously at weekly intervals.

TO REDUCE THE POTENTIAL FOR FATAL MEDICATION ERRORS DUE TO INCORRECT ROUTE OF ADMINISTRATION, VINCRISTINE SULFATE INJECTION SHOULD BE DILUTED IN A FLEXIBLE PLASTIC CONTAINER AND PROMINENTLY LABELED AS INDICATED FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES See WARNINGS.

The concentration of Vincristine Sulfate

Injection is 1 mg/mL.

Do not add extra fluid to the vial prior to removal of the dose.

Withdraw the solution of Vincristine Sulfate

Injection into an accurate dry syringe, measuring the dose carefully.

Do not add extra fluid to the vial in an attempt to empty it completely.

Preparation for flexible plastic container Vincristine Sulfate Injection when diluted with 0.9% Sodium Chloride Injection in concentrations from 0.0015 mg/mL to 0.08 mg/mL is stable for up to 24 hours when protected from light or 8 hours under normal light at 25°C. Caution: It is extremely important that the intravenous needle or catheter be properly positioned before any vincristine is injected.

Leakage into surrounding tissue during intravenous administration of Vincristine Sulfate Injection may cause considerable irritation.

If extravasation occurs, the injection should be discontinued immediately and any remaining portion of the dose should then be introduced into another vein.

Local injection of hyaluronidase and the application of moderate heat to the area of leakage will help disperse the drug and may minimize discomfort and the possibility of cellulitis.

Injection must be administered via an intact, free–flowing intravenous needle or catheter.

Care should be taken that there is no leakage or swelling occurring during administration.

The diluted Vincristine Sulfate

Injection may be infused via a flexible plastic container directly into an intravenous catheter/needle or into a running intravenous infusion.

Patients Receiving Radiation Therapy Vincristine Sulfate

Injection should not be given to patients while they are receiving radiation therapy through ports that include the liver.

When Vincristine Sulfate Injection is used in combination with L–asparaginase, Vincristine Sulfate Injection should be given to 24 hours before administration of the enzyme in order to minimize toxicity; administering L–asparaginase before Vincristine Sulfate Injection may reduce hepatic clearance of vincristine.

Injection should not be diluted in solutions that raise or lower the pH outside the range of 3.5 to 5.5.

It should not be mixed with anything other than 0.9% Sodium Chloride Injection USP.

Whenever solution and container permit, parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Procedures for proper handling and disposal of anticancer drugs should be considered.

Several guidelines on this subject have been published.

There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Injection, USP, is available as follows: Unit of Sale Total Strength/Total Volume (Concentration) NDC 61703–309–06 Carton of 1 single-dose flip-top vial (blue cap) 1 mg/mL NDC 61703–309–16 Carton of 1 single-dose flip-top vial (blue cap) 2 mg/2 mL (1 mg/mL) This product should be refrigerated between 2°C–8°C (36°F–46°F).

Discard unused solution.

Protect from light.

This product should be refrigerated between 2°C–8°C (36°F–46°F).

Discard unused solution.

Protect from light.

It is not known whether this drug is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions due to vincristine sulfate in nursing infants, a decision should be made either to discontinue nursing or the drug, taking into account the importance of the drug to the mother.

ADMINISTRATION section.