Vinblastine Sulphate 1mg/Ml Injection
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Vinblastine Sulphate 1mg/ml Injection.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 1 ml contains 1.0 mg of vinblastine sulphate.
Each 10 ml presentation contains 10 mg of vinblastine sulphate.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection.
A clear, colourless sterile injection.
4. CLINICAL PARTICULARS
4.1. Therapeutic Indications
Vinblastine sulphate is a cytotoxic drug that arrests cell growth at the metaphase. Its actions are more pronounced on the rapidly dividing cell than on the normal cell. It appears to act, like vincristine, by binding to the microtubular proteins of the mitotic spindle, preventing polymerisation.
Vinblastine sulphate is effective as a single agent, but its therapeutic effect is enhanced when used in combination with other antineoplastic drugs. Vinblastine sulphate has been used in the treatment of Hodgkin's disease (Stages III and IV); lymphocytic lymphoma (nodular and diffuse, poorly and well differentiated); histiocytic lymphoma; advanced stages of mycosis fungoides; advanced carcinoma of the testis; Kaposi's sarcoma and Letterer-Siwe disease (histocytosis X). Vinblastine sulphate may be used in the treatment of choriocarcinoma resistant to other chemotherapeutic agents; carcinoma of the breast, unresponsive to appropriate endocrine surgery and hormonal therapy.
4.2 Posology and method of administration
Method of administration
The solution may be injected either directly into the vein or into the injection site of a running intravenous infusion. Injection of vinblastine sulphate may be completed in about one minute.
For intravenous use only.
Fatal IF GIVEN BY OTHER ROUTES (see Warnings)
Syringes containing this product should be overlabelled with the intrathecal warning label provided - 'FOR INTRAVENOUS USE ONLY. FATAL IF GIVEN BY OTHER ROUTES'.
Posology
Vinblastine sulphate is given intravenously at weekly intervals according to the needs of the patient. Therapy is initiated by a single intravenous dose in accordance with the following dosage table, and white blood cell counts should be made to determine the sensitivity of the patient to vinblastine. Dosage should not be increased after that dose which reduces the white cell count to approximately 3000 cells/mm3.
|
Adults |
Children | |
|
mg/m2 bsa |
mg/m2 bsa | |
|
First Dose |
3.7 |
2.5 |
|
Second Dose |
5.5 |
3.75 |
|
Third Dose |
7.4 |
5.0 |
|
Fourth Dose |
9.25 |
6.25 |
|
Fifth Dose |
11.1 |
7.5 |
Dosage increase may be continued but must not exceed 18.5 mg/m2 for adults or 12.5 mg/m2 for children.
Patients should be maintained on the maximum weekly dose that does not cause the above degree of leucopenia.
For most adult patients this dosage will be 5.5 mg/m2 - 7.4 mg/m2, however, leucopenia can be produced at 3.7 mg/m2, other patients may require 11.1 mg/m2 and, very rarely, 18.5 mg/m2.
A FURTHER DOSE OF VINBLASTINE SHOULD NOT BE GIVEN UNTIL THE WHITE CELL COUNT HAS RETURNED TO AT LEAST 4000/mm3, EVEN THOUGH 7 DAYS MAY HAVE ELAPSED.
In some cases, oncolytic activity may be encountered before the leucopenic effect and, when this occurs, there is no necessity to increase subsequent doses.
Duration of maintenance therapy is dependent upon the disease state and the antineoplastic agent combination.
Differing clinical opinions are held for the appropriate duration of maintenance therapy in Hodgkin's disease. Prolonged chemotherapy for maintaining remissions involves several risks such as life-threatening infections, sterility and possibly the appearance of other cancers through suppression of immune response.
Patients with hepatic impairment
As vinblastine is excreted principally by the liver, toxicity may be increased when there is hepatic insufficiency and it may be necessary to reduce initial doses in the presence of significantly impaired hepatic or biliary function. A reduction of 50% in the dose is recommended for patients having a direct serum bilirubin value above 3 mg/100ml.
Patients with renal impairment
Since metabolism and excretion are primarily hepatic, no modification is recommended for patients with impaired renal function.
Vinblastine should not be given intramuscularly, subcutaneously or intrathecally.
4.3 Contraindications
For intravenous use only. Fatal if given by other routes (see Warnings).
Vinblastine sulphate is contraindicated in patients who are leucopenic. It should not be used in the presence of bacterial infection. Such infections should be brought under control with antiseptics or antibiotics before the initiation of therapy with vinblastine sulphate.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Warnings: Vinblastine sulphate 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 sulphate, 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 sulphate during pregnancy. There is insufficient information to assess vinblastine sulphate’s 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 sulphate, 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.
Precautions: Patients should be carefully monitored for infection until the white cell count has returned to normal levels, if leucopenia with less than 2000 white blood cells per mm3 occurs following a dose of vinblastine sulphate.
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 sulphate 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 sulphate injection. If accidental contamination occurs, severe irritation or corneal ulceration may result. The affected eye should be thoroughly irrigated with water immediately.
4.5 Interaction with other medicinal products and other forms of interaction
i) 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.
ii) 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.
(iii) Co-administration of cisplatin has been reported to cause higher plasma concentrations of vinblastine.
(iv) 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.
(v) Erythromycin may increase the toxicity of vinblastine.
(vi) Serum levels of anticonvulsants may be reduced by cytotoxic drug regimes, which include vinblastine.
(vii) 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 sulphate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side-effects.
4.6 Fertility, pregnancy and lactation
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.
The effect of vinblastine on fertility in humans is not fully known. Aspermia has occurred in some individuals during vinblastine therapy.
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.
4.7 Effects on ability to drive and use machines
Not applicable
4.8 Undesirable effects
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 sulphate 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.
Leucopenia is the most common side effect and dose limiting factor.
The following side effects have been reported:
Blood and lymphatic system disorders: Leucopenia, thrombocytopaenia, anaemia.
Nervous system disorders: numbness, paraesthesias, 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 sulphate 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).
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, Interactions with other Medicinal Products and other Forms of Interaction).
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 infections and infestations: blister (skin), alopecia (usually not total and in some cases the hair regrows during maintenance therapy).
Musculoskeletal and connective tissue disorders: 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, Posology and Method of Administration).
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.
4.9. Overdose
Side effects following the use of vinblastine are dose related. Therefore, following administration of more than the recommended dose, patients can be expected to experience these effects in an exaggerated fashion.
In addition, neurotoxicity similar to that seen with vincristine sulphate may be observed.
Treatment: Supportive care should include: (1) prevention of the side effects that result from the syndrome of inappropriate secretion of antidiuretic hormone. This includes restriction of fluid intake and perhaps the use of a diuretic acting on the loop of Henle and distal tubule function; (2) administration of an anticonvulsant; (3) prevention and treatment of ileus; (4) monitoring the patient's cardiovascular system; and (5) daily blood counts for guidance in transfusion requirement.
The major effect of excessive doses of vinblastine will be on granulocytopoiesis, and this may be life-threatening.
PHARMACOLOGICAL PROPERTIES
5.
5.1. Pharmacodynamic Properties
Although the mechanism of action has not been definitely established, vinblastine appears to bind to or crystallise critical microtubular proteins of the mitotic spindle, thus preventing their proper polymerisation and causing metaphase arrest. In high concentrations, vinblastine also exerts complex effects on nucleic acid and protein synthesis. Vinblastine reportedly also interferes with amino acid metabolism by blocking cellular utilisation of glutamic acid and thus inhibits purine synthesis, the citric acid cycle, and the formation of urea. Vinblastine exerts some immunosuppressive activity.
5.2. Pharmacokinetic Properties
Vinblastine sulphate is unpredictably absorbed from the GI tract. Following intravenous administration, the drug is rapidly cleared from the blood and distributed into body tissues.
Vinblastine crosses the blood-brain barrier poorly and does not appear in the CSF in therapeutic concentrations. Vinblastine is reported to be extensively metabolised, primarily in the liver, to desacetylvinblastine, which is more active than the parent compound on a weight basis. The drug is excreted slowly in urine and in faeces via the bile.
5.3. Pre-clinical Safety Data
None stated.
6. PHARMACEUTICAL PARTICULARS
6.1. List of Excipients
Sodium Chloride BP 9.0 mg Water for Injection BP to 10.0 ml
6.2.
Incompatibilities
Vinblastine sulphate is incompatible with furosemide, when injected sequentially into Y-site with no flush between or when mixed in syringe. Immediate precipitation results.
6.3. Shelf-Life
24 months.
6.4. Special Precautions for Storage
The product must be stored between 2°C and 8°C and protected from light.
6.5. Nature and Content of Container
10 ml, Type I clear conventional glass vial, West Type 1888 rubber closure, aluminium spun cap ring, in packs of 5 vials.
Also supplied as 10 ml, Type I clear Onco-Tain vials, West Type 1888 rubber closure, aluminium spun cap ring, in packs of 5 vials.
6.6 Special precautions for disposal and other handling Cytotoxic Handling Guidelines Administration
Should be administered only by or under the direct supervision of a qualified physician who is experienced in the use of cancer chemotherapeutic agents.
Preparation (Guidelines)
a) Chemotherapeutic agents should be prepared for administration only by professionals who have been trained in the safe use of the preparation.
b) Operations such as reconstitution of powder and transfer to syringes should be carried out only in the designated area.
c) The personnel carrying out these procedures should be adequately protected with clothing, gloves and eye shield.
d) Pregnant personnel are advised not to handle chemotherapeutic agents.
Contamination
a) In the event of contact with the skin or eyes, the affected area should be washed with copious amounts of water or normal saline. A bland cream may be used to treat the transient stinging of skin. Medical advice should be sought if the eyes are affected.
b) In the event of spillage, operators should put on gloves and mop up the spilled material with a sponge kept in the area for that purpose. Rinse the area twice with water. Put all solutions and sponges into a plastic bag and seal it.
Disposal
Syringes, containers, absorbent materials, solution and any other contaminated material should be placed in a thick plastic bag or other impervious container and incinerated.
7 MARKETING AUTHORISATION HOLDER
Hospira UK Limited
Queensway
Royal Leamington Spa
Warwickshire
CV31 3RW
UK
8. MARKETING AUTHORISATION NUMBERS
PL 4515/0051.
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION 16th March 1990/26th September 2003
10 DATE OF REVISION OF THE TEXT
17/12/2013