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Hospira UK Ltd

Horizon, Honey Lane, Hurley, Maidenhead, SL6 6RJ, UK
Fax: +44 (0)800 098 8653
Medical Information Direct Line: 1 800 633 363


Summary of Product Characteristics last updated on medicines.ie: 11/09/2017
SPC Vincristine Sulphate 1 mg/ml Solution for Injection or Infusion


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1. NAME OF THE MEDICINAL PRODUCT

Vincristine Sulphate 1 mg/ml Solution for Injection or Infusion


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml contains 1 mg of vincristine sulphate.

Each 2 ml presentation contains 2 mg of vincristine sulphate.

For a full list of excipients, see section 6.1.


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3. PHARMACEUTICAL FORM

Solution for injection/infusion

A sterile colourless solution.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

Vincristine Sulphate is used primarily as a component of various chemotherapeutic regimens for the treatment of acute leukaemias. It has also been used in conjunction with other oncolytic drugs in the treatment of Hodgkin's Disease, all forms of lymphoma, Wilm's tumour, sarcomas and tumours of the breast, brain and lung.


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4.2 Posology and method of administration

This preparation is for intravenous use only. It should only be administered by individuals experienced in vincristine administration.

FOR INTRAVENOUS USE ONLY.

FATAL IF GIVEN BY OTHER ROUTES (see Warnings)

In case of mistaken administration by the intrathecal route, see section 4.4.

Vincristine Sulphate is administered by intravenous infusion 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.

It is recommended to infuse Vincristine Sulphate over 5 to 10 minutes after dilution in a 50 ml infusion bag with Sodium Chloride 9 mg/ml (0.9%) solution for injection. After administration the vein must be flushed through thoroughly. Care should be taken to avoid extravasation as this may cause local ulceration.

Syringes containing this product should be overlabelled with the warning label provided: 'FOR INTRAVENOUS USE ONLY. FATAL IF GIVEN BY OTHER ROUTES'.

Because of the narrow range between therapeutic and toxic levels and variations in response, the dosage must always be adjusted to the individual.

The following dosage regimens have been used:

Acute Leukaemia

Adults: The suggested dose is 1.4 - 1.5 mg/m2 given on a weekly basis to a maximum weekly total dose of 2mg.

Children: The suggested dose is 1.4 – 2.0 mg/m2 given on a weekly basis beginning with the lowest dose in the range with a maximum weekly dose of 2 mg.

Once the remission has occurred, dosage may often be reduced for maintenance therapy.

Other Tumours

25 micrograms/kg body weight weekly until a response is observed and 5-10 micrograms/kg body weight thereafter for maintenance.


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4.3 Contraindications

FOR INTRAVENOUS USE ONLY.

FATAL IF GIVEN BY OTHER ROUTES (see Warnings)

- Use in the management of non-malignant disease, except for immunosuppression.

- Use in the presence of untreated infection.

- Patients with the demyelinating form of Charcot-Marie-Tooth syndrome must not be given vincristine.

- Patients who have shown signs of hypersensitivity to vincristine or to any of the excipients listed in section 6.1


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4.4 Special warnings and precautions for use

Warnings

Vincristine Sulphate should only be administered under the direction of a specialist oncology service having the facilities for regular monitoring of clinical biochemical and haematological effects during and after administration.

Vincristine Sulphate is for intravenous use only.

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 administration:

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.

Syringes containing this product should be overlabelled with the warning label provided: 'FOR INTRAVENOUS USE ONLY. FATAL IF GIVEN BY OTHER ROUTES'

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

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

Precautions

Leucopenia is less likely following therapy with Vincristine Sulphate than is the case with other oncolytic agents. It is usually neuromuscular rather than bone marrow toxicity that limits dosage. 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. On occasions, these infections may prove fatal. Vincristine should only be used with caution in patients with bone marrow depression or in those having infiltration of marrow by malignant cells.

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 neurological disease. Elderly patients may be more susceptible to the neurotoxic effects of Vincristine Sulphate.

A routine prophylactic regimen against constipation is recommended for all patients receiving vincristine sulphate. Paralytic ileus may occur, particularly in young children. The ileus will reverse itself upon temporary discontinuance of vincristine and with symptomatic care.

The elimination of Vincristine Sulphate may be reduced in the presence of impaired hepatic or biliary function and the dose must be decreased accordingly.

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

There is a possibility that this product may exert a carcinogenic effect with long term therapy, although to date no positive evidence is available.

Both in vivo and in vitro laboratory tests have failed to demonstrate conclusively that the product is mutagenic. Fertility following treatment with vincristine alone for malignant disease has not been studied in humans. Clinical reports of both male and female patients who received multiple-agent chemotherapy that included vincristine indicate that azoospermia and amenorrhoea can occur in postpubertal patients. Recovery occurred many months after completion of chemotherapy in some but not all patients. When the same treatment is administered to prepubertal patients, it is much less likely to cause permanent azoospermia and amenorrhoea.

Patients who received vincristine chemotherapy in combination with anticancer drugs known to be carcinogenic have developed second malignancies. The contributing role of vincristine in this development has not been determined. No evidence of carcinogenicity was found following intraperitoneal administration in rats and mice, although this study was limited.

Care should be exercised to avoid accidental contamination of the eyes as vincristine sulphate is highly irritant and can cause corneal ulceration. The eye should be washed immediately and thoroughly.


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4.5 Interaction with other medicinal products and other forms of interaction

Allopurinol, pyridoxine 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.

Treatment with vinca alkaloids has resulted rarely in both vestibular and auditory damage to the eighth cranial nerve. Particular caution is warranted when vincristine sulfate is used in combination with other agents known to be ototoxic, such as the platinum-containing oncolytics.

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

Acute shortness of breath and severe bronchospasm have been reported following administration of 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 isadministered and may occur up to two weeks following the dose of mitomycin. Progressive dyspnoea, requiring chronic therapy, may occur. Vincristine should not be re-administered.

The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations, that included vincristine sulphate, have been reported to reduce blood levels of the anticonvulsant and to increase seizure activity. Although the contribution of the vinca alkaloids has not been established, dosage adjustment of phenytoin, based on serial blood level monitoring, may need to be made when it is used in combination with vincristine.

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 vincristine sulphate with itraconazole (a known inhibitor of the metabolic pathway) has been reported to cause an earlier onset and/or an increased severity of neuromuscular side-effects (see Section 4.8 Undesirable effects). This interaction is presumed to be related to inhibition of the metabolism of vincristine.

When vincristine is used in combination with L-asparaginase, it should be given 12 - 24 hours before administration of the enzyme, in order to minimise toxicity, since administering L-asparaginase first may reduce hepatic clearance of vincristine.

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

Severe hepatotoxicity, including veno-occlusive disease has been reported in patients treated with a combination of vincristine and dactinomycin for renal carcinoma.


4.6 Fertility, pregnancy and lactation

Use in Pregnancy

Caution is necessary with the use of all oncolytic drugs during pregnancy. Both men and women receiving vincristine should be informed of the potential risk of adverse effects.

There are no or limited amount of data from the use of Vincristine Sulphate in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Vincristine Sulphate is not recommended during pregnancy. Both women of childbearing potential and men should be advised to use reliable methods of contraception or abstinence.

If vincristine is used during pregnancy or if the patient becomes pregnant while receiving this medicinal product she should be informed of the potential hazard to the fetus.

Use in Breast-feeding

There is insufficient information on the excretion of Vincristine Sulphate in human milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Vincristine Sulphate therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.


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4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.


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4.8 Undesirable effects

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, related to the total accumulated dose given.

System Organ Class

Undesirable Effect

Infections and infestations

Infection, sepsis, neutropenic sepsis

Neoplasms benign, malignant and unspecified

The occurrence of secondary malignancies has been reported rarely in patients treated with vincristine in association with other anticancer drugs known to be carcinogenic.

Blood and lymphatic system disorders

Leucopenia and neutropenia; vincristine does not appear to have any constant or significant effect upon the platelets or the red blood cells, however, anaemia, haemolytic anaemia and thrombocytopenia have been reported. If thrombocytopenia is present when treatment with vincristine sulphate is begun, it may actually improve before the appearance of marrow remission. Clinical consequences of leucopenia may be fever, infections and sepsis. There have been occasional reports of fatal infections during vincristine therapy.

Immune system disorders

Rare cases of allergic-type reactions, such as anaphylaxis, rash and oedema, temporally related to vincristine therapy have been reported in patients receiving vincristine as a part of multi-drug chemotherapy regimens.

Endocrine disorders

Rare occurrences of a syndrome attributable to inappropriate anti-diuretic hormone secretion have been observed in patients treated with vincristine. There is a high urinary sodium excretion in the presence of hyponatraemia; renal or adrenal disease, hypotension, dehydration, azotaemia and clinical oedema are absent. With fluid deprivation, improvement occurs in the hyponatraemia and in the renal loss of sodium.

Metabolism and nutrition disorders

Anorexia.

Nervous system disorders

Neuropathic pain, sensory loss, difficulty in walking, loss of deep tendon reflexes, Ataxia, paresis, foot drop and cranial nerve palsies, especially ocular palsies and laryngeal nerve paralysis. Frequently, there appears to be a sequence in the development of neuromuscular side effects. Initially, one may encounter only sensory impairment and paraesthesiae. With continued treatment, neuritic pain may appear and later, motor difficulties. No reports have yet been made of any agent that can reverse the neuromuscular manifestations of vincristine sulphate. Convulsions, frequently with hypertension, have been reported in a few patients receiving vincristine. Several instances of convulsions followed by coma have been reported in children. Leukoencephalopathy, encephalopathy.

Eye disorders

Transient cortical blindness and optic atrophy with blindness have been reported.

Ear and labyrinth disorders

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 vincristine sulphate is used in combination with other agents known to be ototoxic, such as platinum-containing oncolytics.

Cardiac disorders

Chemotherapy combinations which have included vincristine, when given to patients previously treated with mediastinal radiation, have been associated with coronary artery disease and myocardial infarction. Causality has not been established.

Vascular disorders

Hypertension and hypotension

Respiratory, thoracic and mediastinal disorders

Acute shortness of breath and severe bronchospasm. Pharyngeal pain has also been reported.

Gastrointestinal disorders

Constipation (which may take the form of upper colon impaction and include colicky abdominal pain), abdominal cramps, paralytic ileus, diarrhoea, nausea, vomiting, oral ulceration, intestinal necrosis and/or perforation have occurred. Parotid gland pain has also been reported.

Paralytic ileus may occur, particularly in young children.

Skin and subcutaneous tissue disorders

Alopecia, rash.

Musculoskeletal and connective tissue disorders

Muscle wasting, jaw pain, bone pain, back pain, limb pain and myalgias have been reported; pain in these areas may be severe.

Renal and urinary disorders

Polyuria, dysuria and urinary retention due to bladder atony have occurred. Other drugs known to cause urinary retention (particularly in the elderly) should, if possible, be discontinued for the first few days following administration of vincristine.

General disorders and administration site conditions

Fever, headache, injection site reaction (see section 4.2), slapping gait.

Investigations

Weight loss

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:

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie


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4.9 Overdose

Side effects of Vincristine Sulphate are dose related and are exaggerated by overdosage. There is, as yet, no antidote for Vincristine Sulphate. In children under 13 years of age, death has occurred following doses of vincristine that were 10 times those recommended for therapy. Severe symptoms may occur in this patient group following dosages of 3 to 4 mg/m2. Adults can be expected to experience severe symptoms after single doses of 3 mg/m2 or more. Therefore, following administration of doses higher than those recommended patients can be expected to experience side-effects in an exaggerated fashion.

Support 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 seizure and cathartics administered to prevent ileus. Use of enemas or cathartics to prevent ileus (in some instances, decompression of the gastrointestinal tract may be necessary.

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

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

Most of an intravenous dose of vincristine is excreted into the bile after rapid tissue binding. Because only very small amounts of the drug appear in dialysate, hemodialysis is not likely to be helpful in cases of overdosage.

There are no published clinical data on the consequences of oral ingestion of vincristine. Should oral ingestion occur, the stomach should be evacuated followed by oral administration of activated charcoal and a cathartic.


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agent - vinca alkaloid.

ATC code: L01CA02

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 immuno-suppressive activity.


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5.2 Pharmacokinetic properties

Vincristine is not reliably absorbed from the gastro-intestinal tract. After intravenous administration 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 I.V. administration of Vincristine, serum concentrations of the drug appear to decline in a triphasic manner. The terminal elimination half-life of Vincristine has ranged from 10.5-155 hours.


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5.3 Preclinical safety data

In several animal species, vincristine can induce teratogenic effects as well as embryolethality with doses that are non-toxic to the pregnant animal.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Mannitol

Water for Injections


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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.


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6.3 Shelf life

Unopened: 2 years

Once opened: use immediately.


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6.4 Special precautions for storage

Store in a refrigerator (2°C - 8°C).

Keep vial in the outer carton in order to protect from light.

For storage after opening, see section 6.3.


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6.5 Nature and contents of container

2 ml Type I clear glass vials with rubber stoppers containing 2 ml of solution in packs of 5 vials.

2 ml Type I clear Onco-Tain® vials with rubber stoppers containing 2 ml of solution in packs of 5 vials.


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6.6 Special precautions for disposal and other handling

For single use only, discard any unused contents.

Further Information

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)

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 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 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.


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7. MARKETING AUTHORISATION HOLDER

Hospira UK Limited

Horizon

Honey Lane

Hurley

Maidenhead

SL6 6RJ

United Kingdom


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8. MARKETING AUTHORISATION NUMBER(S)

PA 437/8/5


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 05 May 1987

Date of last renewal: 05 May 2007


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10. DATE OF REVISION OF THE TEXT

May 2016



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Active Ingredients

 
   Vincristine sulphate