VINBLASTINE SULFATE Solution for injection Ref.[8715] Active ingredients: Vinblastine

Warnings

Vinblastine sulfate must be used only by physicians experienced in cytotoxic chemotherapy.

The following treatment successfully arrested progressive paralysis in a single patient mistakenly given the related vincristine sulfate, intrathecally. This treatment should be initiated immediately:

1. Removal of as much CSF as is safely possible.
2. Flushing with Lactated Ringer’s solution by continuous infusion at 150 ml/h, through a catheter in a cerebral lateral ventricle and removed through lumbar access, until fresh plasma became available.
3. Fresh frozen plasma, 25 ml, diluted with 1litre of Lactated Ringer’s was then infused similarly at 75 ml/h. The rate of infusion should be adjusted to maintain a spinal fluid protein level of 150 mg/dl.
4. Glutamic acid, 10 g, was given iv over 24 hours, followed by 500 mg tds by mouth for 1 month. Glutamic acid may not be essential.

Vinblastine SHOULD NOT BE GIVEN intramuscularly, subcutaneously or intrathecally.

Syringes containing this product should be overlabelled with the intrathecal warning label provided - ‘FOR INTRAVENOUS USE ONLY. FATAL IF GIVEN BY OTHER ROUTES’.

Caution is necessary with the use of vinblastine sulfate during pregnancy. There is insufficient information to assess vinblastine sulfates effect on fertility in men and women. However, aspermia has been reported in man.

Animal studies suggest that teratogenic effects may occur. The drug should not be used in pregnant women unless the expected benefit outweighs the potential risk.

As with other antineoplastic agents, vinblastine may cause a severe local reaction on extravasation. If leakage into the surrounding tissue should occur during intravenous administration of vinblastine sulfate, the injection should be discontinued immediately and any remaining portion of the dose should be introduced into another vein. Local injection of hyaluronidase with the application of heat has been used to disperse the drug in order to minimise discomfort and the possibility of tissue damage.

Liver disease may alter the elimination of vinblastine in the bile, markedly increasing toxicity to peripheral nerves and necessitating a dosage modification in affected patients.

The vial stopper contains dry natural rubber (a derivative of latex), which may cause allergic reactions.

Precautions

Patients should be carefully monitored for infection until the white cell count has returned to normal levels, if leucopoenia with less than 2000 white blood cells per mm³ occurs following a dose of vinblastine sulfate.

When cachexia or ulcerated areas of the skin are present, a more profound leucopenic response may be produced by vinblastine. Therefore, its use should be avoided in older persons suffering from either of these conditions.

Leucocyte and platelet counts have sometimes fallen precipitously after moderate doses of vinblastine sulfate in patients with malignant cell infiltration of the bone marrow.

Further use of the drug in such patients is inadvisable. Avoid contamination of the eye with vinblastine sulfate solution for injection. If accidental contamination occurs, severe irritation or corneal ulceration may result. The affected eye should be thoroughly irrigated with water immediately.

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

Vinblastine used as part of a combination regimen with mitomycin may result in acute respiratory distress and pulmonary infiltration. Cases of respiratory distress with interstitial pulmonary infiltrates have been reported in patients given a regimen comprising vinblastine, mitomycin, and progesterone (MVP). Acute shortness of breath and severe bronchospasm have been reported following the administration of the 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 a dose of mitomycin. Progressive dyspnoea, requiring chronic therapy, may occur. Vinblastine should not be re-administered.

Co-administration of cisplatin has been reported to cause higher plasma concentrations of vinblastine.

There have been reports of Raynaud’s phenomenon and gangrene following co-administration of vinblastine and bleomycin, and of other vascular events (such as myocardial infarction and cerebrovascular accident) following combined treatment with vinblastine, bleomycin and cisplatin.

Erythromycin may increase the toxicity of vinblastine.

Serum levels of anticonvulsants may be reduced by cytotoxic drug regimes, which include vinblastine.

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 vinblastine sulfate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side-effects.

Pregnancy

Although information on the use of vinblastine during pregnancy is limited, the drug may cause foetal toxicity when administered to pregnant women. The drug causes resorption of foetuses in animals and produces gross foetal abnormalities in surviving offspring. There are no adequate and controlled studies to date using vinblastine in pregnant women, and the drug should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective. Women of childbearing potential should be advised to avoid becoming pregnant while receiving the drug. When vinblastine is administered during pregnancy or the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the foetus.

Breast-feeding

It is not known whether vinblastine is excreted in human milk. Because of the potential for serious adverse reactions due to vinblastine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.

Fertility

The effect of vinblastine on fertility in humans is not fully known. Aspermia has occurred in some individuals during vinblastine therapy.

Not relevant.

The use of small amounts of vinblastine daily for long periods is not advisable, even though the resulting total dosage may be similar to the recommended dosage. Little or no therapeutic advantage has been demonstrated when such regimens have been used and side-effects are increased.

The incidence of side effects with vinblastine sulfate appears to be dose related and most do not persist longer than 24 hours. Neurological effects are uncommon but can occur and may last longer than 24 hours.

Leucopoenia is the most common side effect and dose limiting factor.

The following side effects have been reported:

Blood and lymphatic system disorders

Leucopoenia, thrombocytopenia, anaemia.

Nervous system disorders

Numbness, paraesthesia’s, peripheral neuritis, mental depression, loss of deep tendon reflexes, headache, convulsions, 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 vinblastine sulfate is used in combination with other agents known to be ototoxic, such as the platinum-containing oncolytics.

Cardiac disorders

Myocardial infarction, cerebrovascular accident (cases of unexpected myocardial infarction and cerebrovascular accidents have occurred in patients undergoing combination chemotherapy with vinblastine, bleomycin and cisplatin).

Vascular disorders

Hypertension.

Respiratory, thoracic and mediastinal disorders

Acute respiratory distress (including shortness of breath) has been reported when vinblastine is given in combinations with mitomycin (see section 4.5).

Gastrointestinal disorders

Nausea, vomiting, constipation, oral mucosal blistering, diarrhoea, anorexia, abdominal pain, rectal bleeding, pharyngitis, haemorrhagic enterocolitis, bleeding from an old peptic ulcer, ileus, stomatitis. Antiemetics may be used to control nausea and vomiting.

Skin and subcutaneous tissue disorders

Blister (skin), alopecia (usually not total and in some cases the hair regrows during maintenance therapy).

Musculoskeletal and connective tissue disorders

Myalgia, bone pain, jaw pain, tumour pain (pain in tumour-containing tissue).

General disorders and administration site conditions

Malaise, asthenia, dizziness.

Injection site reaction (see section 4.2)

Extravasation during intravenous injection may result in cellulitis and phlebitis. In extreme instances sloughing may occur. Syndrome of inappropriate ADH secretion has been reported with higher than recommended doses. Raynaud’s phenomenon has occurred when patients are being treated with vinblastine in combination with bleomycin and cisplatin for testicular cancer.

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: United Kingdom, Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Vinblastine sulfate is incompatible with furosemide, when injected sequentially into Y-site with no flush between or when mixed in syringe. Immediate precipitation results.