Vincristine Sulphate Injection Solution 5mg / 5ml

1. Name Of The Medicinal Product

Vincristine Sulphate Injection Solution 5mg/5ml

2. Qualitative And Quantitative Composition

Vincristine Sulphate Injection Solution

		mg per unit dose	mg per mL
Vincristine Sulphate	BP	5mg	1mg/mL
Mannitol	BP	500mg	100mg/mL
Benzyl Alcohol	BP	45mg	9mg/mL
Water for Injection	BP	To	5mL

3. Pharmaceutical Form

Aqueous injection solution for IV use in a vial with anitmicrobial preservative.

4. Clinical Particulars

4.1 Therapeutic Indications

1.	The treatment of acute leukaemias.
2.	The treatment with other oncolytic drugs, of Hodgkins disease.
3.	The treatment of lymphomas, Wilms tumour, sarcomas.
4.	The treatment of tumours of the breast and lung.

4.2 Posology And Method Of Administration

Dosage and administration

This preparation is for intravenous use only. Intrathecal administration usually results in death (see 'Warnings' for treatment).

Vincristine sulphate is administered by intravenous injection at weekly intervals, the precise dose being determined by body weight.

Great care should be exercised in calculating the dose as overdosage may be extremely serious or even fatal. The dose should not be increased beyond the level which produces therapeutic benefit. In general, individual doses should not exceed 2mg; and white cell counts should be carried out before and after giving each dose.

Vincristine Sulphate Injection Solution may be injected into the tubing or side arm of a free-flowing IV infusion or directly into a vein over a one-minute period. For safety reasons when administering Vincristine Injection into a side arm of a fast running infusion, please ensure that pressure is maintained on the syringe plunger during administration, to avoid back pressure from the infusion forcing the plunger out of the syringe barrel. Care should be taken to avoid extravasation as this may cause local ulceration.

The following dosage regimens have been used:

Adults: The drug is usually administered intravenously at weekly intervals. The recommended dose is 1.4 to 1.5 mg/m² up to a maximum weekly dose of 2 mg.

Children: The usual dose is 2 mg/m². For children weighing 10 kg or less the starting dose should be 0.05 mg/kg administered as a weekly intravenous injection.

Elderly: The normal adult dose is still appropriate in the elderly.

Hepatic Impairment: 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. A 50 per cent reduction in the dose of vincristine sulphate is recommended for patients having a direct serum bilirubin value above 3 mg/100 ml (51 micromol/l).

4.3 Contraindications

Intrathecal administration of Vincristine Sulphate is usually fatal. Although there are no other known contraindications to the use of Vincristine Sulphate, careful notice should be given to those conditions listed under Warnings and Precautions.

Breast feeding during treatment (see use in Pregnancy and Lactation).

4.4 Special Warnings And Precautions For Use

Warnings

Syringes containing this product should be labelled 'VINCRISTINE FOR INTRAVENOUS USE ONLY'.

After intrathecal administration, removal of cerebrospinal fluid, and flushing with Lactated Ringer's and other solutions, has not prevented ascending paralysis leading to death. In one adult paralysis was arrested, with some recovery, by the following treatment initiated immediately:-

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

Vincristine Sulphate is a vesicant and may cause a severe local reaction or extravasation. If leakage into the surrounding tissue should occur during IV administration of Vincristine 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.

Precautions

Leucopenia is less likely following therapy with Vincristine Sulphate than is the case with other oncolytic agents. However, because of its possibility both physician and patient should remain alert for signs of any complicating infection. If leucopenia or a complicating infection is present, then administration of the next dose of Vincristine Sulphate warrants careful consideration.

Acute uric acid nephropathy, which may occur after administration of oncolytic agents, has also been reported with Vincristine Sulphate.

As Vincristine Sulphate penetrates the blood-brain barrier poorly, additional agents and routes of administration may be required for central nervous system leukaemias.

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

Care should be exercised to avoid accidental contamination of the eyes, as Vincristine sulphate is highly irritant and can cause corneal ulceration.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Allopurinol, yridoxine and isoniazid may increase the incidence of cytotoxic induced bone marrow depression. The mechanism for this potentiation has not been fully classified.

The neurotoxicity of Vincristine Sulphate may be additive with that of other drugs acting on the peripheral nervous system.

Vincristine Sulphate appears to increase the cellular uptake of methotrexate by malignant cells and this principle has been applied in high-dose methotrexate therapy.

The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily. This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes. Concurrent administration with itraconazole (a known inhibitor of the metabolic pathway) has been reported to cause an earlier onset and/or increased severity of neuromuscular side-effects. This interaction is presumed to be related to the inhibition of metabolism of vincristine sulphate.

4.6 Pregnancy And Lactation

Use in Pregnancy: Safe use of Vincristine Sulphate during pregnancy has not been established. The drug should not be used in women who are or who may become pregnant, unless the expected benefit outweighs the potential risk. Women being treated with Vincristine should take appropriate contraceptive measures during therapy. Vinca alkaloids may effect fertility and have been shown to be embryocidal.

Use in Lactation: Vincristine Sulphate should not be used in women who are breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

Not known.

4.8 Undesirable Effects

Vincristine is a vesicant and may cause a severe local reaction on extravasation. It should only be administered by physicians experienced in cytotoxic chemotherapy.

Vincristine may cause granulocytopenia and users should be alert to signs of infection. Pre-existing granulocytopenia does not preclude treatment, but care should be taken in such patients.

Daily administration of small doses of Vincristine Sulphate may result in the prolongation of side-effects which would otherwise be of short duration.

Side-effects of Vincristine Sulphate appear to be dose-related and, particularly in the case of neurotoxicity, relating to the total accumulated dose given.

Neuropathies are the most common side effect in all age groups and are often dose-limiting. The neuropathy may occur as neuritic pain, paraesthsia, sensory loss and peroneal weakness resulting in foot drop and impaired gait. Headache and jaw pain are associated with cranial nerve involvement. No reversal agent for the neuromuscular effects has been reported as yet.

Gastrointestinal side-effects such as constipation, abdominal cramps, paralytic ileus, vomiting and diarrhoea may be encountered. The prophylactic use of stool softeners and mild cathartics is recommended to avoid impaction as a result of the constipation.

Bladder neuropathies are uncommon but have been reported.

Reversible alopecia occurs in approximately 20% of all cases treated with Vincristine Sulphate and patients should be warned of this possibility.

Other side-effects reported in a small number of patients are weight loss, polyuria, dysuria and fever.

4.9 Overdose

Symptoms are those associated with acute neurotoxicity, seizures, fluid retention, paralytic ileus.

Side effects to Vincristine Sulphate are dose related and are exaggerated by overdosage. There is, as yet, no antidote for Vincristine Sulphate.

Supportive therapy should be directed to the prevention of the side effects resulting from hypersecretion of antidiuretic hormone by restriction of fluid intake and possibly the use of an appropriate diuretic. Anticonvulsants, e.g. Phenobarbitone may be necessary for control of seizures and cathartics administered to prevent ileus.

Routine cardiovascular monitoring is recommended together with daily haematology as an indicator for transfusion requirements.

Folinic acid has been used for treatment of overdosage. An intravenous injection of 15mg Folinic Acid may be given every 3 hours for 24 hours, then every 6 hours for at least 48 hours.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Although the mechanism of action has not been definitely established, Vincristine appears to bind to or crystallize critical microtubular proteins of the mitotic spindle, thus preventing their proper polymerization and causing metaphase arrest. In high concentrations, the drug also exerts complex effects on nucleic acid and protein synthesis. Vincristine exerts some immunosuppressive activity.

5.2 Pharmacokinetic Properties

Vincristine is not reliably absorbed form the gastro-intestinal tract. After intravenous injection it disappears rapidly from the blood. It is extensively protein bound and it is reported to be concentrated in blood platelets. It is metabolised in the liver and excreted primarily in the bile – about 70% of a dose is found in faeces, as unchanged drug and metabolites, over 72 hours. Some also appears in the urine. Vincristine does not appear to cross the blood-brain barrier in significant amounts.

Following rapid IV injection of Vincristine, serum concentrations of the drug appear to decline in a triphasic manner. The terminal elimination half-life of Vincristine has ranged from 10.5 – 15.5 hours.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Mannitol	BP	500.0mg
Benzyl Alcohol	BP	45.0mg
Water for Injections	BP	to	5.0mL

6.2 Incompatibilities

It is not recommended that Vincristine Sulphate should be mixed with any other drug and should not be diluted in solutions that raise or lower the pH outside the range 3.5 to 5.5. Frusemide both in syringe and injected sequentially into Y-site with no flush between, results in immediate precipitation.

6.3 Shelf Life

18 months.

6.4 Special Precautions For Storage

Store between 2°C and 8°C. Protect from light.

6.5 Nature And Contents Of Container

Vials of 5mL containing Vincristine Sulphate 5mg/5mL solution in printed cartons of five conventional glass vials or five Onco-Tain^® vials.

6.6 Special Precautions For Disposal And Other Handling

Cytotoxic Handling Guidelines

4.2 Posology And Method Of 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)

1.	Chemotherapeutic agents should be prepared for administration only by professionals who have been trained in the safe use of preparation.
2.	Operations such as reconstitution of powder and transfer to syringes should be carried out only in the designated area.
3.	The personnel carrying out these procedures should be adequately protected with clothing, gloves and eye shield.
4.	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 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 then 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

Faulding Pharmaceuticals Plc,

Queensway

Royal Leamington Spa

Warwickshire

CV31 3RW

8. Marketing Authorisation Number(S)

UK PL 4515/0043.

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 28 June 1990, Renewed October 1995

10. Date Of Revision Of The Text

April 1999