22-Oxovincaleukoblastine Other names: Leurocristine Vincristine Vincrystine

Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vincristine sulfate with itraconazole (a known inhibitor of the metabolic pathway) has been reported to cause an earlier onset and/or an increased severity of neuromuscular side-effects. This interaction is presumed to be related to inhibition of the metabolism of vincristine.

When vincristine sulfate is used in combination with L-asparaginase, it should be given 12 to 24 hours before administration of the enzyme in order to minimise toxicity, since administering L-asparaginase first may reduce hepatic clearance of vincristine.

Severe hepatotoxicity, including veno-occlusive disease has been reported in patients treated with a combination of vincristine and dactinomycin for renal carcinoma.

The neurotoxicity of vincristine sulfate may be additive with that of isoniazid and other drugs acting on the nervous system.

Vincristine sulfate appears to increase the cellular uptake of methotrexate by malignant cells and this principle has been applied in high-dose methotrexate therapy.

Acute shortness of breath and severe bronchospasm have been reported following the administration of vinca alkaloids. These reactions have been encountered most frequently when the vinca alkaloid was used in combination with mitomycin-C and may be serious when there is pre-existing pulmonary dysfunction. The onset may be within minutes or several hours after the vinca is injected and may occur up to 2 weeks following the dose of mitomycin. Progressive dyspnoea, requiring chronic therapy, may occur. Vincristine should not be re-administered.

The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations, that included vincristine sulfate, have been reported to reduce blood levels of the anticonvulsant and to increase seizure activity. Although the contribution of the vinca alkaloids has not been established, dosage adjustment of phenytoin, based on serial blood level monitoring, may need to be made when it is used in combination with vincristine.

Acute uric acid nephropathy, which may occur after administration of oncolytic agents, has also been reported with vincristine sulfate.

Leucopenia is less likely following therapy with vincristine sulfate than is the case with other oncolytic agents. It is usually neuromuscular rather than bone marrow toxicity that limits dosage. However, because of the possibility of leucopenia, both physician and patient should remain alert for signs of any complicating infection. If leucopenia or a complicating infection is present, then administration of the next dose of vincristine sulfate warrants careful consideration. On occasions, these infections may prove fatal.

Caution is necessary with the use of all oncolytic drugs during pregnancy. Both men and women receiving vincristine should be informed of the potential risk of adverse effects. Reliable methods of contraception or abstinence are recommended.

Vincristine can cause foetal harm following maternal or paternal exposure, although there are no adequate and well-controlled studies. Women of childbearing potential should be advised to avoid becoming pregnant while receiving vincristine and use effective contraception during treatment.

If vincristine is used during pregnancy or if the patient becomes pregnant while receiving this medicinal product she should be informed of the potential hazard to the foetus.

There are no or limited amount of data from the use of vincristine sulfate in pregnant women. Studies in animals have shown reproductive toxicity.

There is insufficient information on the excretion of vincristine sulfate in human milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from vincristine sulfate therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

No studies on the effects on the ability to drive and use machines have been performed.

In general, adverse reactions are reversible and are related to dosage size and cumulative dosage. The use of small amounts of vincristine daily for long periods is not advised. The most common adverse reaction is alopecia; the most troublesome adverse reactions are neuromuscular in origin.

When single weekly doses of vincristine are employed, the adverse reactions of leukopenia, neuritic pain, and constipation are usually of short duration (i.e. less than 7 days). When the dosage is reduced, these reactions may lessen or disappear. They seem to be increased when the calculated amount of medicinal product is given in divided doses. Other adverse reactions, such as alopecia, sensory loss, paraesthesia, difficulty in walking, slapping gait, loss of deep-tendon reflexes and muscle wasting may persist for at least as long as therapy is continued. Generalised sensorimotor dysfunction may become progressively more severe with continued treatment, but the neuromuscular difficulties may persist for prolonged periods in some patients. Re-growth of hair may occur while maintenance therapy continues.

The following adverse reactions have been reported:

Infections and infestations: Infection, sepsis, neutropenic sepsis.

Neoplasms benign, malignant and unspecified (incl cysts and polyps): The occurrence of secondary malignancies has been reported rarely in patients treated with vincristine in association with other anticancer drugs known to be carcinogenic.

Blood and lymphatic system disorders: Leukopenia and neutropenia; vincristine does not appear to have any constant or significant effect upon the platelets or the red blood cells, however, anaemia, haemolytic anaemia and thrombocytopenia have been reported. If thrombocytopenia is present when treatment with vincristine sulfate is begun, it may actually improve before the appearance of marrow remission. Clinical consequences of leukopenia may be fever, infections and sepsis. There have been occasional reports of fatal infections during vincristine therapy.

Immune system disorders: Rare cases of allergic-type reactions, such as anaphylaxis, rash and oedema, temporally related to vincristine therapy have been reported in patients receiving vincristine as a part of multi-drug chemotherapy regimens.

Endocrine disorders: Rare occurrences of a syndrome attributable to inappropriate anti-diuretic hormone secretion have been observed in patients treated with vincristine. There is a high urinary sodium excretion in the presence of hyponatraemia; renal or adrenal disease, hypotension, dehydration, azotaemia and clinical oedema are absent. With fluid deprivation, improvement occurs in the hyponatraemia and in the renal loss of sodium.

Metabolism and nutrition disorders: Anorexia.

Nervous system disorders (often dose limiting): Neuritic pain, sensory loss, paraesthesia, difficulty in walking, loss of deep tendon reflexes, ataxia, paresis, foot drop and cranial nerve palsies, especially ocular palsies and laryngeal nerve paralysis. Frequently, there appears to be a sequence in the development of neuromuscular side effects. Initially, one may encounter only sensory impairment and paraesthesia. With continued treatment, neuritic pain may appear and later, motor difficulties. No reports have yet been made of any agent that can reverse the neuromuscular manifestations of vincristine sulfate. Convulsions, frequently with hypertension, have been reported in a few patients receiving vincristine. Several instances of convulsions followed by coma have been reported in children.

Eye disorders: Transient cortical blindness and optic atrophy with blindness have been reported.

Ear and labyrinth disorders: Treatment with vinca alkaloids has resulted rarely in both vestibular and auditory damage to the eighth cranial nerve. Manifestations include partial or total deafness, which may be temporary or permanent, and difficulties with balance, including dizziness, nystagmus and vertigo. Particular caution is warranted when vincristine sulfate is used in combination with other agents known to be ototoxic, such as the platinum-containing oncolytics.

Cardiac disorders: Chemotherapy combinations which have included vincristine, when given to patients previously treated with mediastinal radiation, have been associated with coronary artery disease and myocardial infarction. Causality has not been established.

Vascular disorders: Hypertension and hypotension have occurred.

Respiratory, thoracic and mediastinal disorders: Acute shortness of breath and severe bronchospasm have been reported following the administration of vinca alkaloids. Pharyngeal pain has also been reported.

Gastro-intestinal disorders: Constipation, abdominal cramps, paralytic ileus, diarrhoea, nausea, vomiting, oral ulceration, intestinal necrosis and/or perforation have occurred. The constipation which may be encountered responds well to such usual measures as enemas and laxatives. Constipation may take the form of upper colon impaction and the rectum may be found to be empty on physical examination. Colicky abdominal pain, coupled with an empty rectum, may mislead the clinician. A flat film of the abdomen is useful in demonstrating this condition. A routine prophylactic regimen against constipation is recommended for all patients receiving vincristine sulfate. Paralytic ileus may occur, particularly in young children. The ileus will reverse itself upon temporary discontinuance of vincristine and with symptomatic care. Parotid gland pain has also been reported.

Skin and subcutaneous tissue disorders: Alopecia, rash.

Musculoskeletal and connective tissue disorders: Muscle wasting, jaw pain, bone pain, back paid, limb pain and myalgias have been reported; pain in these areas may be severe.

Renal and urinary disorders: Polyuria, dysuria and urinary retention due to bladder atony have occurred. Other drugs known to cause urinary retention (particularly in the elderly) should, if possible, be discontinued for the first few days following administration of vincristine.

General disorders and administration site conditions: Fever, headache, injection site reaction.

Investigations: Weight loss.