ELDISINE Powder for solution for injection Ref.[9071] Active ingredients: Vindesine

This preparation is for intravenous use only. It should be administered by individuals experienced in the administration of vindesine sulphate. The intrathecal administration of vindesine sulphate usually results in death. Syringes containing this product should be labelled “FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.” An auxiliary sticker is provided in the pack with this warning.

Extemporaneously prepared syringes containing this product must be packaged in an overwrap which is labelled "DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES."

After inadvertent intrathecal administration of vinca alkaloids, 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 survival cases involving the related vinca alkaloid vincristine sulphate, if vindesine 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, 25ml 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 150ml/h, or at a rate of 75ml/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 150mg/dl.

The following measures have also been used in addition but may not be essential:

Glutamic acid has been given IV 10gm over 24 hours, followed by 500mg tds by mouth for 1 months. Folic acid has been administered intravenously as a 100mg bolus and then infused at a rate of 25mg/h for 24 hours, then bolus doses of25mg 6-hourly for 1 week. Pyridoxine has been given at a dose of 50mg 8-hourly by intravenous infusion over 30 minutes. Their roles in the reduction of neurotoxicity are unclear.

.Clinically, the dose-limiting toxicity of vindesine is granulocytopenia, although in general oncolytic activity is obtained at doses causing little or no effect on the granulocytes. Individual patient variation has been observed with respect to the severity of side-effects, including neurotoxicity, granulocytopenia, alopecia and decrease in bowel motility.

When granulocytopenia occurs, the nadir in the granulocyte count may be expected to occur 3-5 days after the last day of drug administration. Recovery of the granulocyte count is rapid thereafter and is usually complete within 7-10 days after the last dose.

The thrombocyte count is usually either unaffected or increased by weekly therapy with vindesine. However, significant thrombocytopenia has occurred occasionally, particularly when doses are given more frequently than once a week. It is probably more likely to occur when patients are thrombocytopenic (less than 100,000 cells/mm³) prior to therapy with vindesine.

The effect of vindesine upon the red blood cell count and haemoglobin concentration is usually insignificant when other treatment does not complicate the picture. It should be remembered, however, that patients with malignant disease may exhibit anaemia even in the absence of any treatment.

If granulocytopenia with less than 1,000 granulocytes/mm³ occurs following a dose of vindesine, the patient should be watched carefully for evidence of infection until the granulocyte count has returned to a safe level.

While neurotoxicity is not usually dose-limiting, there have been instances in which neurotoxicity has made it necessary to reduce the dosage or temporarily discontinue use of vindesine. Neurotoxicity induced by vindesine is believed to be generally less severe and less progressive in nature than the effects observed with vincristine.

Particular attention should be given to dosage and neurological side-effects if vindesine is administered to patients with pre-existing neuromuscular disease, and also when other drugs with neurotoxic potential are being used. The neurotoxicity associated with vindesine therapy may be additive.

Care should be exercised when vindesine has been the cause of acute abdominal pain, as paralytic ileus may be a significant risk if further doses of vindesine are given, particularly if the dose is increased. Prophylactic measures should be taken to prevent obstipation that may result from a decrease in bowel motility.

Extreme care should be exercised to prevent injection outside the vein. Extravasation during intravenous injection will cause cellulitis and phlebitis. If the amount of extravasation is great, sloughing will occur. Healing of such wounds may require several weeks and be attended by severe pain. The discomfort may persist after healing of the ulcer. Cytotoxic drugs should only be administered by appropriately trained staff.

Care must be taken to avoid contamination of the eye with concentrations of vindesine used clinically. If accidental contamination occurs, severe irritation and/or corneal ulceration may result. The eye should be washed immediately and thoroughly with water or saline.

When chemotherapy is being given in conjunction with radiation therapy through portals, which include the liver, the use of vindesine should be delayed until radiation therapy has been completed.

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

The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations have been reported to have reduced blood levels of the anticonvulsant and to have increased seizure activity. Although the contribution of the vinca alkaloids has not been established, dosage adjustment of phenytoin may need to be made when used in combination with vindesine.

Caution should be exercised in patients concurrently taking drugs shown to inhibit drug metabolism by hepatic cytochrome P450 isoenzyme in the CYP3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vindesine sulphate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side effects.

Usage in pregnancy or lactation

The safety of this product for use during pregnancy has not been established. Animal studies with vindesine suggest that teratogenic effects may occur. The benefit-to-risk ratio must be carefully considered before use in pregnant patients.

Eldisine should not normally be given to mothers who are breast-feeding.

Men and women should be advised regarding contraception during treatment with vindesine due to the potential risks involved.

Not applicable.

Prior to the use of the drug, patients and/or their parents/guardians should be advised of the possibility of untoward symptoms. Acute toxicity appears to be dose related and is more likely to occur if doses above 4mg/m² are employed. Granulocytopenia is usually the dose limiting factor. Neurotoxicity is common and appears to be related to the cumulative total dose given.

The following side effects have been reported:

Gastro-intestinal: Nausea, vomiting, constipation, stomatitis, vesiculation of the mouth, ileus, diarrhoea, anorexia, abdominal pain, dysphagia, dyspepsia, perforated duodenal ulcer (nausea and vomiting usually may be controlled by anti-emetic agents).

Neurological: Numbness and tingling of hands/feet (paraesthesia), peripheral neuritis, jaw pain, mental depression, loss of deep tendon reflexes, foot drop, headache, convulsions. Cortical blindness has been reported in patients treated with multiple agent chemotherapy that has included vindesine. The contribution of vindesine to this reaction is unknown. 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 vindesine sulphate is used in combination with other agents known to be ototoxic, such as the platinum-containing oncolytics.

Haematological: Granulocytopenia, thrombocytopenia, thrombocytosis, mild anaemia.

Pulmonary: see section 4.5.

Cutaneous: Alopecia from mild to total is the commonest side effect. Regrowth of hair may occur while still on therapy. Maculopapular rashes, cellulitis with extravasation. Injection site reaction (see section 4.2).

Miscellaneous: Generalised musculoskeletal pain, malaise, chills and fevers, asthenia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Eldisine should never be mixed with any other drug.