Special Warning : אזהרת שימוש

4.4   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 under pressure). When contact with the eyes occurs, the eyes must be flushed immediately with large quantities of water.
Patients should consult a physician or ophthalmologist if the irritation of the eyes persists.
In the event of accidental projection on the skin, wash abundantly with water then with a mild soap and rinse thoroughly.

Extravasation
Extravasation should be avoided. Should extravasation occur, the injection should be stopped immediately and the possible remaining dose should be injected in a different vein. Local injection of hyaluronidase 250 IU/mL (1 mL subcutaneous around the lesion and moderate heat application at the site where extravasation occurred can help disperse the drug and limit the discomfort and possible cellulitis to a minimum). In the unit where vincristine sulfate is administered, the hospital’s cytostatics extravasation set should be available.


Myelotoxicity

Since leukopenia can occur, both the physician and the patient should be alert to the occurrence of an infection. When leukopenia occurs, suitable measures should be taken, amongst which a careful consideration about the time at which the next dose of vincristine sulfate should be administered. A complete blood count should be done before administration of each dose.
Due to an increased risk of leukopenia and thrombocytopenia, closer monitoring is necessary in patients in whom previous therapy or the disease itself has suppressed bone marrow function.

Neurotoxicity
Special attention should be paid to patients with existing neurological disorders Careful observation of the patient is required with the combined use of vincristine and pharmaceuticals with a potential neurotoxicity.


The neurotoxic effect of vincristine sulfate may be additive with other neurotoxic agents or increased by spinal cord irradiation and neurological disease. Elderly patients may be more susceptible to the neurotoxic effects of vincristine sulfate.

Interaction with azole antifungals
Concomitant administration of azole antifungals 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.
Reserve azole antifungals for patients receiving vincristine who have no alternative antifungal treatment options (see section 4.5).

Hepatic impairment
Hepatic dysfunction may increase the circulating concentrations and the plasma half-life of vincristine with an increase in its adverse effects because vincristine is predominantly metabolised in the liver.
Vincristine should not be given to patients receiving radiotherapy if the radiation field includes the liver.
Hepatic and renal functions, blood cell count and neurological functions should be assessed before starting therapy and during treatment, and before each course of treatment. If there are signs of bone marrow depression, the next dose should only be given after careful assessment of the clinical picture. The same applies to the occurrence of neurological symptoms, as severe neuropathies may develop if treatment is continued.

Patients who received vincristine chemotherapy in combination with anticancer drugs known to be carcinogenic have developed secondary malignancies. The contributing role of vincristine in this development has not been determined.

Prophylactic measures for the prevention of constipation, such as an adjusted diet and the use of laxatives, in particular lactulose, are recommended.

Vincristine should be administered with caution to patients with ischaemic heart disorders.

Acute elevation with the serum uric acid level can occur during the remission-induction with acute leukaemia; therefore the serum uric acid levels should be frequently determined during the first 3-4 weeks of the treatment or suitable measures should be taken to prevent uric acid neuropathy.

Contraceptive measures should be taken by both the male and the female patients during the treatment and for 6 months after discontinuation of the treatment (also see section 4.6).
Excipient(s):

Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium-free'.

Effects on Driving

4.7   Effects on ability to drive and use machines

Due to the (neurological and gastrointestinal) side effects this medicinal product may affect the ability to drive and use machines..