VINCRISTINE SULFATE

VINCRISTINE SULFATE SHOULD ONLY BE ADMINISTRED INTRAVENOUSLY. FATAL IF GIVEN BY OTHER ROUTES See Section

In general the side effects are reversible and dose dependent. The most important toxic effects of vincristine have been associated with the central nervous system. The most often occurring side effects are neurotoxicity and alopecia; the most troublesome side effects are neuromuscular in origin.

Side effects may be pronounced in patients with hepatic impairment due to reduced metabolism and delayed biliary excretion. Side effects are listed by frequency, the most frequent first, using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Neoplasms, benign and malignant and unspecified (including cysts and polyps) Treatment related secondary malignancy Patients who have been treated with vincristine in combination with other cytotoxic products, of which it is known that they are carcinogenic, have developed secondary malignancies.

Blood and lymphatic system disorders Common Temporary thrombocytosis. Uncommon Severe bone marrow depression, anaemia, leukopenia and thrombocytopenia. Immune system disorders Common Acute occurrence of shortness of breath and bronchospasms, which can be severe and life threatening.

These symptoms were observed after the administration of vinca alkaloids (such as vincristine), particularly when administered concomitantly with mitomycin. The reaction can occur a few minutes to hours after the administration of a vinca alkaloid or to 2 weeks after a dose of mitomycin.

Rare Allergic reactions, such as anaphylaxis, rash and oedema, possibly related to vincristine therapy have been observed in patients who were treated with vincristine as part of multi-drug chemotherapy regimes. Nervous system disorders The neurological toxicity is the most important side effect of vincristine.

Neurological toxicity is dose and age related. As a result of neurotoxicity also constipation and ileus can occur (see “Gastrointestinal system disorders”). Common The most frequently occurring neurotoxic side effect is peripheral neuropathy (mixed sensorimotor), which occurs in almost all patients.

Often a specific order in the development of neuromuscular side effects occurs. In the beginning only sensory disturbances and paraesthesia occur. With continuation of the treatment nerve pain (amongst other in the jaw and testicles) and further motor difficulties can occur.

Loss of deep tendon reflexes, foot drop, muscle weakness, ataxia and paralysis have been reported with continuation of the treatment. Affection of the cranial nerve, amongst which isolated paresis and/or paralysis of muscles that are directed by the cranial nerves, can occur, without muscle weakness occurring anywhere else.

Paralysis of the cranial nerve and muscle weakness of the larynx can cause hoarseness and vocal cord paresis, amongst which potentially life threatening bilateral vocal cord paresis. Muscle weakness of the outer ocular muscles can cause ptosis, and optical and extra ocular neuropathy.

Transient cortical blindness has been reported. Vincristine also causes autonomic toxicity and toxicity of the central nervous system, although less frequent than peripheral neuropathy. Double vision and optic atrophy are observed. Uncommon Convulsions, frequently with hypertension, have been reported in a few patients receiving vincristine sulfate.

A few cases of convulsions followed by coma have been reported in children. Vincristine causes autonomic toxicity and toxicity of the CNS, although this occurs less frequently than peripheral neuropathy. g. altered state of awareness and mental changes like depression, agitation, sleeplessness, confusion, psychoses and hallucinations.

Not known Leukoencephalopathy. Ear and labyrinth disorders Uncommon Deafness. Cardiac disorders Uncommon Coronary artery disease, myocardial infarction. Coronary vascular disorders and myocardial infarction have occurred in patients who were treated with vincristine containing chemotherapy combinations and who were previously treated with radiotherapy of the mediastinum.

Rare Hypertension and hypotension. Respiratory, thoracic and mediastinal disorders Common Severe bronchospasm and dyspnea have been reported with vinca alkaloids, some of which were used in combination with mitomycin C. Gastrointestinal disorders Common Nausea, vomiting, constipation, abdominal pain.

Constipation can occur as a result of impaction of the upper part of the intestines while the rectum is empty. Colic-like abdominal pains can then occur. Uncommon Reduced appetite, weight loss, anorexia, diarrhoea, paralytic ileus. Especially in young children paralytic ileus is a possibility.

Rare Inflammation of the mucous membrane of the mouth, intestinal necrosis and/or perforation. Very rare Pancreatitis. Hepatobiliary disorders Rare Hepatic veno-occlusive disease, particularly in children. Skin and subcutaneous tissue disorders Very common Alopecia (is reversible when the administration of vincristine is discontinued).

Renal and urinary disorders In elderly patients the therapy with drug that causes urinary retention must be interrupted in the early days after the vincristine administration. Uncommon Polyuria, dysuria, urinary retention as a result of bladder atony, hyperuricaemia, uric acid nephropathy.

Rare SIADH syndrome (syndrome of inappropriate antidiuretic hormone secretion). The syndrome may be related to the neurotoxicity of the medicinal product possibly due to a direct effect on the hypothalamus. In these patients hyponatraemia occurs, in combination with urinary sodium excretion, without indication of renal or adrenal disorders, hypotension, dehydration, azotemia or oedema.

With liquid restriction the hyponatraemia and the loss of sodium through the kidneys can be improved. Very rare […]

4 Special warning and precautions for use. Posology Extreme care must be used in calculating and administering the dose to be injected, because overdose can have severe and even fatal results. When used as monotherapy, the dose should be administered at 1 week intervals.

In combination with other antineoplastic agents, the dosing frequency depends on the protocol. 4 mg/m² (maximum of 2 mg) once a week. The dose of vincristine sulfate should be calculated and administered with extreme care, because overdose can have severe and even fatal results.

The dose should not be increased beyond the level which produces therapeutic benefit. In general, individual doses should not exceed 2 mg; and white cell counts should be carried out before giving each dose. 0 mg/m² once a week. 05 mg/kg once a week.

Note:

In infants the dose is calculated according to individual body weight (not according to body surface area). The ratio between body surface area and body weight is unfavorable in infants and pronounced neurological and hepatic side effects can occur after chemotherapy for acute leukemia, compared to older children.

Elderly The normal adult dose is still appropriate in the elderly. Hepatic impairment In patients with hepatic impairment or with a direct serum bilirubin value above 3 mg/100 ml (51 μmol/l) a reduction of 50% of the dose of vincristine sulfate is recommended.

Because of the hepatic metabolism and biliary excretion of vincristine, reduced doses are recommended in patients with obstructive jaundice or other hepatic impairment. Patients with liver disease sufficient to decrease biliary excretion may experience an increase in the severity of side effects.

In case of severe neurotoxicity, vincristine sulfate should not be administered, particularly in case of paresis. When the complaints decrease after discontinuation of the administration of vincristine sulfate, the treatment may be resumed with 50% of the dose.

Method of administration Vincristine sulfate should only be used under strict supervision of physicians experienced in the treatment with cytotoxic products. Intrathecal administration of vincristine results in fatal neurotoxicity. Vincristine sulfate can be administered intravenously via an infusion or as a bolus injection of at least 1 minute via a running infusion.

Caution: it is extremely important that the needle be properly positioned in the vein before any drug is injected. Care should be taken to avoid infiltration of subcutaneous tissues. 4). In order to prevent vascular irritation, the vein should be flushed well after the administration of vincristine sulfate.

1; - neuromuscular disorders (such as the demyelinating form of Charcot-Marie-Tooth syndrome); - a severe liver function disorder; - constipation and impending ileus, especially in children; - radiotherapy in which the liver is involved.

4 Special warnings and precautions for use. 4 Special warnings and precautions for use Vincristine sulfate should only be used under the strict supervision of physicians experienced in the treatment with cytotoxic products. Syringes containing this product should be labelled: ‘VINCRISTINE FOR INTRAVENOUS USE ONLY, FATAL IF GIVEN BY OTHER ROUTES’ Accidental intrathecal administration After inadvertent intrathecal administration, immediate neurosurgical intervention is required in order to prevent ascending paralysis leading to death.

In a very small number of patients, life-threatening paralysis and subsequent death was averted but resulted in devastating neurological sequelae, with limited recovery afterwards. Based on the published management of these survival cases, if vincristine is mistakenly given by the intrathecal route, the following treatment should be initiated immediately after the injection: 1.

Removal of as much CSF as is safely possible through the lumbar access. 2. Insertion of an epidural catheter into the subarachnoid space via the intervertebral space above initial lumbar access and CSF irrigation with lactated Ringer's solution.

Fresh frozen plasma should be requested and, when available, 25 ml should be added to every 1 litre of lactated Ringer's solution. 3. Insertion of an intraventricular drain or catheter by a neurosurgeon and continuation of CSF irrigation with fluid removal through the lumbar access connected to a closed drainage system.

Lactated Ringer's solution should be given by continuous infusion at 150 ml/h, or at a rate of 75 ml/h when fresh frozen plasma has been added as above. The rate of infusion should be adjusted to maintain a spinal fluid protein level of 150 mg/dl.

The following measures have also been used in addition but may not be essential: • Folinic acid has been administered intravenously as a 100 mg bolus and then infused at a rate of 25 mg/h for 24 hours, then bolus doses of 25 mg 6- hourly for 1 week.

• Intravenous administration of glutamic acid 10 g over 24 hours, followed by 500 mg three times daily by mouth for one month. • Pyridoxine has been given at a dose of 50 mg 8 hourly by intravenous infusion over 30 minutes. Their roles in the reduction of neurotoxicity are unclear.

Contact with the skin and the mucous membranes Care should be taken to avoid contact of vincristine sulfate with the eyes. This can result in severe irritation or ulcer formation of the cornea (especially if the medicinal product is administered […]

1; - neuromuscular disorders (such as the demyelinating form of Charcot-Marie-Tooth syndrome); - a severe liver function disorder; - constipation and impending ileus, especially in children; - radiotherapy in which the liver is involved.

Careful notice should also be given to those conditions listed in section