Vin克里斯тин-mili

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VINKRISTIN-MILI (VINCRISTIN-MILI)

Composition:

Active substance: vincristine sulfate;

1 ml of solution contains 1 mg of vincristine sulfate;

Excipients: mannite (E 421), methylparaben (E 218), propylparaben (E 216), water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear solution.

Pharmacotherapeutic group. Antineoplastic agents. Plant alkaloids and other natural agents. ATC code L01C A02.

Pharmacological properties.

Pharmacodynamics.

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

The antineoplastic and cytotoxic activity of vincristine is associated with disruption of microtubule and mitotic spindle formation, as well as interference with DNA and RNA synthesis in cells.

Pharmacokinetics.

Following intravenous injection, vincristine is rapidly cleared from blood plasma. Within 15–30 minutes, over 90% of the drug is distributed from plasma into tissues and other blood components. The volume of distribution at plateau phase is 8.4 ± 3.2 L/kg.

Within 20 minutes after intravenous administration, more than 50% of vincristine binds to blood components, particularly to platelets, which contain high concentrations of tubulin.

The drug poorly penetrates the blood-brain barrier.

Metabolism.

Vincristine is extensively metabolized in the liver, likely by the cytochrome P450 microsomal enzyme system, including CYP3A enzymes.

Excretion.

The pharmacokinetic profile after intravenous bolus administration is triphasic. The half-life during the first and second phases is 5 minutes and 2.3 hours, respectively; the terminal phase half-life shows considerable variability (ranging from 15 to 155 hours), with an average of 85 hours. Plasma clearance is slow; therefore, an interval of at least 1 week between treatment cycles is required to avoid cumulative toxicity.

The liver is the primary organ of excretion. The drug is predominantly eliminated via feces (approximately 80%), with a smaller portion excreted in urine (10–20%).

Patients with hepatic impairment.

In patients with impaired liver function, metabolism is altered such that excretion of vincristine is likely reduced, increasing the risk of toxicity.

Children.

In children, there is greater inter- and intra-subject variability in pharmacokinetic parameters such as clearance, volume of distribution, and elimination half-life. Plasma clearance in children is generally higher than in adults or infants, although it has not been precisely established whether vincristine clearance decreases with age.

Clinical characteristics.

Indications.

Acute leukemias, Hodgkin’s lymphoma, non-Hodgkin’s lymphomas (all histological subtypes and clinical stages), reticulum cell sarcoma, lymphosarcoma, embryonal rhabdomyosarcoma, neuroectodermal tumors (such as medulloblastoma and neuroblastoma), Wilms’ tumor, Ewing’s sarcoma, bone sarcomas, breast cancer, small cell lung cancer, multiple myeloma, retinoblastoma, idiopathic thrombocytopenic purpura resistant to splenectomy and short-term adrenocorticosteroid therapy.

Contraindications.

Intrathecal administration of the drug is strictly prohibited! Intrathecal administration of vincristine may result in fatal outcomes.

Hypersensitivity to vincristine sulfate or to any of the excipients, demyelinating form of Charcot–Marie syndrome, acute hepatic dysfunction, myelosuppression (bone marrow suppression), neurological disorders, constipation and intestinal obstruction (especially in children), radiation therapy to the liver area, neuromuscular disorders, bacterial and viral infections. Vincristine must not be administered during or immediately after administration of vaccines containing live viruses.

Special safety precautions.

Healthcare personnel handling the drug must wear protective clothing (gloves, goggles, gown, mask). Pregnant women must not be involved in handling the drug.

Interactions with other medicinal products and other forms of interactions.

Interactions common to all cytotoxic agents.

Due to increased risk of thrombotic events in cancer patients, anticoagulant therapy is often used. When anticoagulants and antineoplastic chemotherapy are used concomitantly, INR (International Normalized Ratio) levels should be monitored.

Cytochrome P450 isoenzyme and P-glycoprotein inhibitors.

Vinca alkaloids are metabolized by cytochrome P450 3A4 (CYP3A4) isoenzyme and are substrates for P-glycoproteins. Thus, plasma concentrations of vincristine may increase when co-administered with CYP3A4 and P-glycoprotein inhibitors such as ritonavir, nelfinavir, ketoconazole, itraconazole, erythromycin, cyclosporine, nifedipine, and nefazodone.

Concomitant administration of vincristine and itraconazole may be accompanied by premature and/or pronounced neuromuscular adverse reactions, likely related to inhibition of vincristine metabolism.

Ketoconazole

Concomitant use of azole antifungal agents (e.g., itraconazole, voriconazole, posaconazole, isavuconazole, and fluconazole) with vincristine may lead to increased plasma concentrations of vincristine, potentially resulting in earlier onset and/or increased severity of neurotoxicity and other adverse reactions (see section "Special precautions for use"). Therefore, azole antifungal agents should be used with caution in patients receiving vincristine and only when no alternative antifungal therapy is available or when potential benefit outweighs the risks of such combination. Patients should be closely monitored for adverse reactions when these agents are used concomitantly.

Phenytoin and fosphenytoin.

Concomitant administration of phenytoin and antineoplastic chemotherapy regimens containing vincristine may reduce blood levels of phenytoin and increase the risk of seizures. Use of this combination is not recommended. Although the role of vincristine has not been fully established, phenytoin dosage adjustments should be based on subsequent monitoring of its blood levels.

Other cytostatic agents.

Pharmacodynamic interactions may occur with other cytostatic agents: potentiation of both therapeutic and toxic effects. Concurrent use of vincristine with other myelosuppressive agents, such as doxorubicin (especially in combination with prednisolone), may potentiate bone marrow suppression.

Asparaginase/isoniazid and other neurotoxic medicinal products.

Severe and prolonged peripheral neuropathy may occur when neurotoxic agents (such as isoniazid, L-asparaginase, and cyclosporin A) are administered to patients receiving vincristine. When vincristine sulfate is used in combination with
L-asparaginase, administration of vincristine should precede the enzyme by 12–24 hours to reduce toxicity, as prior administration of L-asparaginase may decrease hepatic clearance of vincristine. These patients should receive other known neurotoxic drugs with caution and under continuous neurological monitoring.

Vaccines/inactivated virus

Since the immune system may be suppressed by vincristine therapy, the body's ability to produce antibodies in response to vaccination may be reduced. The time interval between discontinuation of immunosuppressive drugs and restoration of the body’s ability to produce antibodies in response to vaccination ranges from 3 months to 1 year and depends on the underlying disease, intensity and type of immunosuppressive therapy, and other factors.

Vaccines/live virus

Since the immune system may be suppressed by vincristine therapy, concomitant administration of a vaccine containing live virus may enhance viral replication and vaccine-related adverse effects and/or reduce the body's ability to produce antibodies in response to vaccination.

The decision to vaccinate such patients should be made by a physician based on careful assessment of their hematological status. The time interval between discontinuation of immunosuppressive drugs and restoration of the body’s ability to produce antibodies in response to vaccination ranges from 3 months to 1 year and depends on the underlying disease, intensity and type of immunosuppressive therapy, and other factors. Patients with leukemia in remission should not receive live virus vaccines at least 3 months after chemotherapy.

Digoxin.

Absorption of digoxin, and thus its therapeutic effect, may be reduced in patients receiving chemotherapy, including vincristine. Caution should be exercised when digoxin and vincristine are used concomitantly, and digoxin dosage adjustments may be necessary.

Mitomycin C.

Cases of acute respiratory failure and severe bronchospasm have been reported after administration of vinca alkaloids. These reactions most commonly occurred when a vinca alkaloid was used concomitantly with mitomycin C and were particularly serious in patients with a history of pulmonary dysfunction. These reactions may begin minutes after injection of the vinca alkaloid or several hours later, and may also occur within 2 weeks after mitomycin C administration. Progressive dyspnea may develop, requiring ongoing treatment. In such cases, vincristine should not be administered further.

Radiation therapy.

Radiation therapy may enhance the peripheral neurotoxicity of vincristine. When chemotherapy is administered concurrently with radiation therapy to areas involving the liver, administration of vincristine should be postponed until completion of the radiation therapy course.

Cyclosporine, tacrolimus.

Excessive immunosuppression with risk of lymphoproliferative disorders may occur.

Allopurinol, pyridoxine, isoniazid.

Concomitant use of vincristine with certain drugs (allopurinol, pyridoxine, isoniazid) may increase the frequency of bone marrow suppression.

Methotrexate.

Vincristine sulfate enhances uptake of methotrexate by tumor cells. This principle has been applied in high-dose methotrexate therapy regimens.

Other agents.

During concomitant administration of vincristine and colony-stimulating factors (G-CSF, GM-CSF), atypical neuropathies with sensations of tingling or burning in the distal extremities have been more frequently reported. In patients with Wilms’ tumor, severe hepatotoxicity, including veno-occlusive disease, has been observed with the combination of vincristine and dactinomycin. In combination with bleomycin, vincristine may cause Raynaud’s syndrome in a dose-dependent manner. Concomitant use of vincristine with nifedipine may enhance vincristine toxicity. Combination of vincristine and actinomycin may lead to hepatotoxicity.

Special precautions for use.

Treatment with the drug should be administered only by an experienced specialist in chemotherapy under conditions of a specialized inpatient facility.

Vincristine-Mili must be administered intravenously only.

Intrathecal administration of the drug is strictly contraindicated!

Intramuscular and subcutaneous administration of vincristine is also contraindicated.

Accidental intrathecal administration.

Intrathecal administration of vincristine may result in fatal outcomes. Following accidental intrathecal injection, immediate neurosurgical intervention is required to prevent ascending paralysis leading to death. In case of accidental intrathecal administration of vincristine, the following treatment must be initiated immediately after the injection:

1. Removal via lumbar puncture of as much cerebrospinal fluid as safety considerations allow.
2. Placement of an epidural catheter into the subarachnoid space through an intervertebral space above the site of the initial lumbar puncture, followed by irrigation of cerebrospinal fluid with Ringer's lactate solution. If possible, 25 mL of fresh frozen plasma should be added to each 1 L of Ringer's lactate solution.
3. Placement of an intraventricular drain or catheter by a neurosurgeon, with continued irrigation of cerebrospinal fluid and simultaneous removal via lumbar access connected to a closed drainage system. Ringer's lactate solution should be infused continuously at a rate of 150 mL/hour, or at 75 mL/hour if fresh frozen plasma has been added as described above.

The infusion rate should be adjusted to maintain cerebrospinal fluid protein levels at 150 mg/dL.

The following additional measures may also be applied, although their significance may be limited:

Folic acid should be administered intravenously as a bolus injection of 100 mg, followed by infusion at 25 mg/hour for 24 hours, then bolus injections of 25 mg every 6 hours for 1 week. Glutamic acid should be administered intravenously at 10 g over 24 hours, followed by oral administration of 500 mg three times daily for 1 month. Pyridoxine should be administered intravenously at 50 mg every 8 hours, with each infusion lasting 30 minutes. The role of these agents in reducing neurotoxicity is unclear.

Extravasation.

Extravasation may lead to soft tissue necrosis; to prevent this, infiltration sites should be infiltrated with hyaluronidase or hydrocortisone at a dose of 20–25 mg, and warm compresses should be applied to the affected area.

Use in the early postoperative period.

Vincristine-Mili should be administered with caution in the early postoperative period, as a significant portion of the intravenously administered drug may accumulate in the postoperative wound, causing edema, inflammation, and local tissue necrosis.

Accidental exposure to eyes.

Accidental exposure of the drug to the eyes should be avoided, as vincristine may cause corneal ulcers. In case of contact with eyes, they should be thoroughly rinsed with large amounts of water or isotonic saline solution.

Accidental skin contact.

In case of accidental skin contact, wash thoroughly with large amounts of water and mild soap, then rinse well.

Hepatic impairment.

Particular attention should be paid to patients with hepatic dysfunction. In liver impairment, plasma concentration and elimination half-life of vincristine may increase, leading to enhanced adverse effects; dosage regimen adjustment of vincristine is required.

Neurological disorders.

Particular attention should be paid to patients with pre-existing neurological disorders. The neurotoxic effect of vincristine sulfate may be additive with other neurotoxic agents or may be exacerbated by spinal irradiation or pre-existing neurological disease. Close monitoring of patients is necessary when vincristine is used in combination with other neurotoxic drugs. Elderly patients may be more sensitive to the neurotoxic effects of vincristine sulfate. Therapy should be interrupted if signs of neurotoxicity appear.

The drug poorly penetrates the blood-brain barrier; therefore, alternative antineoplastic therapy regimens may be required in the treatment of leukemia with neuroleukemia.

Secondary malignancies.

Secondary malignancies may develop in patients who have received chemotherapy with vincristine in combination with other antineoplastic agents known to be carcinogenic. The potential role of vincristine in this phenomenon has not been established.

Constipation.

Vincristine sulfate is not recommended for patients with constipation. Prophylactic measures to prevent constipation, such as dietary adjustments and use of laxatives (particularly lactulose) or enemas, are recommended.

Cardiovascular system.

Vincristine should be administered with caution in patients with ischemic heart disease.

Regular ECG monitoring is required during vincristine treatment.

Hematological system.

Blood counts must be monitored during treatment. Leukopenia may occur; therefore, both physician and patient should remain vigilant for signs of infection. If leukopenia develops, appropriate measures should be taken, including careful consideration of the timing of the next dose of vincristine sulfate. A complete blood count must be performed before each administration of Vincristine-Mili. If the leukocyte count falls below 3000/mm³, therapy should be discontinued and prophylactic antibiotics should be prescribed.

Due to the increased risk of leukopenia and thrombocytopenia, more careful monitoring is required in patients whose prior therapy or underlying disease has caused bone marrow suppression.

Eyes.

Patients should undergo regular ophthalmoscopic examinations and visual field testing during treatment. Therapy should be discontinued at the first suspicion of optic nerve damage. If a patient reports eye pain or decreased visual acuity, a thorough ophthalmological examination is required.

Alopecia.

The degree of alopecia during chemotherapy may be reduced by applying local scalp hypothermia or using a tourniquet (tight-fitting cap). A tight bandage should not be applied to the scalp in patients with leukemia or lymphoma, or in the presence of scalp metastases or infiltrates.

Mitomycin-C.

Dyspnea and bronchospasm most commonly occur when the drug is combined with mitomycin-C and may require intensive treatment, especially in patients with respiratory insufficiency. These reactions may occur within minutes or hours after vincristine administration and up to two weeks after mitomycin-C administration. Progressive dyspnea requires discontinuation of Vincristine-Mili therapy (see section "Interaction with other medicinal products and other forms of interaction").

Uric acid.

Serum uric acid levels may increase during vincristine therapy. This parameter should be monitored during the first 3–4 weeks of treatment, and appropriate measures should be taken to prevent neuropathy associated with uric acid diathesis. Laboratory tests should be repeated until values normalize. Allopurinol should be used if necessary.

Hyponatremia.

Serum sodium concentration should be periodically monitored during vincristine therapy. Hyponatremia may develop due to impaired antidiuretic hormone secretion and should be corrected with 0.9% sodium chloride solution.

Children.

During treatment of children with malignant tumors, monitoring of intellectual, emotional, language, and central nervous system functions is required.

Fertility.

There are no convincing in vivo or in vitro data demonstrating the mutagenicity of vincristine. Data on the effect of vincristine monotherapy on human fertility are lacking. Clinical data on the use of vincristine as part of polychemotherapy show the possibility of azoospermia in men and amenorrhea in post-pubertal women. Recovery of reproductive function occurs within several months after completion of therapy, although not in all patients.

The use of vincristine as part of polychemotherapy in pre-pubertal patients may less frequently lead to irreversible azoospermia and amenorrhea.

Patients should be counseled regarding the possibility of future fertility. Male patients should be informed about sperm preservation.

Pregnancy prevention.

Vincristine is known to have harmful effects on the fetus; therefore, the use of Vincristine-Mili is contraindicated during pregnancy. Women of reproductive age should be advised to avoid pregnancy while receiving vincristine. Contraceptive measures should be used by both male and female patients during treatment and for 6 months after discontinuation of therapy.

Interaction with azole antifungal agents.

Concomitant use of azole antifungal agents with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and paralytic ileus. Use of alternative (reserve) azole antifungal agents may be considered in patients receiving vincristine when no other antifungal treatment options are available (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding.

The drug should not be used during pregnancy or breastfeeding. Contraceptive measures should be used by both male and female patients during treatment and for 6 months after discontinuation of therapy.

If pregnancy occurs during treatment, the patient should be informed of the risks to the unborn child and should remain under medical supervision.

Ability to affect reaction speed when driving or operating machinery.

There are no data on the effect of vincristine on the ability to drive or operate machinery. However, the possibility of developing adverse (neurological) reactions during Vincristine-Mili therapy that may impair psychomotor performance should be considered.

Dosage and Administration

Vincristine-Mili may be administered only intravenously. Administration by any other route may result in fatal outcomes.

Vincristine sulfate dosage must be calculated and administered with extreme caution, as overdosage may lead to severe or even fatal consequences.

When used as monotherapy, the drug is administered once weekly. When used in combination with other antineoplastic agents, the frequency of administration depends on the treatment protocol.

Adults.

The usual dose is 1.4–1.5 mg/m² of body surface area administered once weekly; the maximum dose is 2 mg/m². The duration of treatment course is 4–6 weeks. The cumulative course dose should not exceed 10–12 mg/m².

Children.

Vincristine-Mili is administered at a dose of 1.4–2 mg/m² of body surface area once weekly; the maximum dose is 2 mg/m². The dose for children should be calculated based on body weight: for children weighing 10 kg or less, the initial dose should be 0.05 mg/kg once weekly.

Elderly patients.

No dose adjustment is required.

Patients with impaired hepatic function.

Since vincristine is metabolized in the liver and excreted via bile, dose reduction is recommended for patients with obstructive jaundice or other hepatic impairment.

For patients with hepatic dysfunction or serum direct bilirubin levels exceeding 3 mg/100 ml, a 50% reduction in vincristine sulfate dose is recommended.

Vincristine should not be administered in the presence of severe neurotoxicity (particularly paralysis). If symptoms improve after discontinuation of the drug, treatment may be resumed at 50% of the original dose.

Administration method

Vincristine sulfate must be administered only under strict supervision of a physician experienced in the use of cytotoxic agents.

Intrathecal administration of vincristine results in fatal neurotoxicity.

The lyophilized powder in the vial should be reconstituted by adding a suitable diluent (the resulting solution contains 0.1 mg of vincristine per 1 mL). This solution may then be further diluted with 0.9% sodium chloride solution and administered as an intravenous injection or concomitantly with an intravenous infusion of 0.9% sodium chloride via an infusion set, administered no faster than over 1 minute.

Care must be taken to avoid subcutaneous infiltration. Extravasation during intravenous administration of vincristine sulfate may cause significant irritation. To prevent vascular irritation, the vein should be thoroughly flushed after administration of vincristine sulfate.

The recommended therapeutic dose should not be exceeded. Individual doses generally should not exceed 2 mg. Complete blood count (leukocyte count) must be performed before and after each dose administration.

Children.

The drug is prescribed to children according to clinical indications.

Overdose

Symptoms.

Overdose of vincristine leads to intensification of adverse reactions. In children under 13 years of age, a tenfold overdose may result in fatal outcome. Severe clinical manifestations of overdose may occur in children under 13 years of age when administered at doses of 3–4 mg/m², and in adults when administered as a single dose of 3 mg/m² or higher. Symptoms of overdose may include seizures; paralytic ileus; complications related to inadequate antidiuretic hormone secretion; or other manifestations of adverse reactions.

Treatment.

There is no specific antidote. Symptomatic and supportive treatment should be administered, with monitoring of fluid and electrolyte balance, ECG, and peripheral blood parameters. In case of generalized seizures, anticonvulsant medications should be used. Enemas may be administered to prevent ileus. If necessary, blood transfusions, red blood cell concentrate, and platelet transfusions should be administered. Intravenous calcium folinate should be administered at a dose of 100 mg every 3 hours for 24 hours, then every 6 hours for at least 48 hours. Hemodialysis is ineffective.

Adverse Reactions.

The most common toxic effects of vincristine are related to the central nervous system. In general, adverse reactions are reversible and dose-dependent. Children usually tolerate vincristine better than adults. The most frequent adverse reactions are neurotoxicity and alopecia; the most serious adverse reactions are associated with neuromuscular apparatus impairment. Elderly patients have an increased susceptibility to neurotoxicity.

After administration of weekly single doses of vincristine, transient adverse reactions such as leukopenia, neuritic pain, and constipation may occur (although these usually last no longer than 7 days). The severity of these reactions may decrease or the reactions may disappear completely after dose reduction. The severity of such reactions increases if the required total dose of the drug is administered in divided portions. Therefore, it is not recommended to use vincristine in small amounts over a prolonged period. Other adverse reactions, such as alopecia, loss of sensation, paresthesia, difficulty walking, shuffling gait, loss of deep tendon reflexes, and muscular dystrophy, manifest throughout the entire course of treatment. As treatment continues, general sensorimotor dysfunction may progress to a more severe condition, and in some patients, individual neuromuscular disorders may persist for a prolonged period. Hair regrowth may begin before completion of maintenance therapy.

Infections and infestations: infection, sepsis, neutropenic sepsis.

Neoplasms benign, malignant and of unspecified nature (including cysts and polyps): secondary malignant neoplasms in patients who received vincristine in combination with other cytotoxic agents with proven carcinogenicity.

Blood and lymphatic system disorders: reversible thrombocytosis, severe bone marrow suppression, anemia, hemolytic anemia, neutropenia, leukopenia, and thrombocytopenia. If thrombocytopenia is present at the beginning of treatment, it may actually improve prior to achieving bone marrow remission. Clinical consequences of leukopenia may include fever, infections, and sepsis.

Immune system disorders: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioneurotic edema, allergic reactions, rash, and swelling.

Respiratory, thoracic and mediastinal disorders: dyspnea, bronchospasm, acute respiratory failure.

Nervous system and psychiatric disorders: neurological toxicity is the most serious adverse reaction to vincristine administration. Neurological toxicity is dose- and age-dependent. As a result of neurotoxicity, constipation and intestinal obstruction may also occur (see "Gastrointestinal disorders"). Other possible adverse reactions include neuralgia and myalgia (including trigeminal neuralgia and testicular pain syndrome, laryngeal pain, salivary gland pain, bone pain, back pain, limb pain), coma, foot drop, dysuria, peripheral neuropathy (mixed sensory-motor), sensory disturbances, paresthesia, loss of deep tendon reflexes, gait disturbances, shuffling gait, muscle weakness, ataxia, paralysis, cranial nerve impairment (paresis/paralysis), laryngeal muscle weakness, hoarseness and vocal cord paresis (including potentially life-threatening bilateral vocal cord paralysis), ptosis, optic neuropathy, extraocular neuropathy, transient blindness, diplopia and optic atrophy, seizures with hypertension, leukoencephalopathy, toxic effects on the central nervous system, which may manifest as depression, excitement, sleep disturbances, insomnia, confusion, psychosis, and hallucinations. Exacerbation of concomitant neurological disorders is possible.

A sequential pattern often occurs in the development of neuromuscular adverse effects. Initially, there may be only sensory disturbances and paresthesia. With continued treatment, neuralgia may appear, followed later by impairment of musculoskeletal function.

Auditory disorders: vestibular and auditory complications involving the 8th cranial nerve. Manifestations include partial or total deafness—either permanent or intermittent; balance problems, including dizziness, nystagmus, and vertigo. Caution should be exercised when administering vincristine sulfate in combination with other ototoxic agents, such as platinum-containing oncology drugs.

Eye disorders: transient cortical blindness, optic atrophy with blindness.

Cardiac and vascular disorders: angina pectoris and myocardial infarction (in patients who received combination chemotherapy including vincristine and who had previously undergone mediastinal irradiation), arterial hypertension and hypotension, arrhythmia.

Respiratory, thoracic and mediastinal disorders: severe bronchospasm and dyspnea have been reported following administration of vinca alkaloids, sometimes in combination with mitomycin C.

Gastrointestinal disorders: nausea, vomiting, aphthous stomatitis, oral ulcers, abdominal cramps and pain, decreased appetite, weight loss, anorexia, diarrhea, paralytic ileus (especially in children), mucosal inflammation of the mouth, intestinal necrosis and/or perforations, pancreatitis. Constipation, which may occur, responds well to routine measures such as enemas and laxatives. Constipation with an empty rectum upon examination may be misleading. Upper colonic constipation with an empty rectum may mislead the physician. Functional intestinal obstruction (intestinal paresis) may occur, particularly in young children. Symptoms of intestinal obstruction resolve spontaneously after temporary discontinuation of vincristine and symptomatic treatment.

Hepatobiliary disorders: veno-occlusive liver disease (particularly in children), elevated liver enzymes.

Skin and subcutaneous tissue disorders: alopecia (reversible after discontinuation of vincristine), rash.

Renal and urinary disorders: elderly patients should discontinue medications causing urinary retention in the first days after vincristine administration. Polyuria, dysuria, and urinary retention due to bladder atony, hyperuricemia, uric acid nephropathy, SIADH (syndrome of inappropriate antidiuretic hormone secretion). The syndrome may be related to the neurotoxicity of the drug, possibly due to a direct effect on the hypothalamus. In such patients, hyponatremia occurs, combined with urinary sodium excretion, without signs of renal or adrenal dysfunction, hypotension, dehydration, azotemia, or edema. Hyponatremia and renal sodium loss may be reduced by fluid restriction.

Reproductive system and breast disorders: irreversible infertility after chemotherapy with vincristine is more common in men than in women. Azoospermia has been observed in men receiving combination chemotherapy regimens containing vincristine with prednisone and cyclophosphamide or mechlorethamine and procarbazine, amenorrhea.

General disorders and administration site conditions: irritation at injection site, burning sensation, erythema, fever, phlebitis, pain, cellulitis, necrosis, headache, weakness. These symptoms may occur following irritation of the vessel wall or in case of extravasation during administration.

Shelf life.

2 years.

Storage conditions. Store at 2–8 °C in the original packaging, in a place inaccessible to children.

Incompatibilities. Due to the lack of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Packaging. 1 ml in a vial, 1 or 10 vials in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Venus Remedies Limited.

Manufacturer’s address and location of operations.

Hill Top Industrial Estate, Jarmajri, ERIP Phase-I (Ext.), Battali Kalan, Baddi, District Solan, Himachal Pradesh 173205, India.

Marketing Authorization Holder. Milpharm Limited.

Address of the Marketing Authorization Holder. 2nd Floor, Office Premises, 4 Charterfield House, Castle Street, Taunton, Somerset, England, TA1 4AS, United Kingdom.