Consumer medicine information

Vincristine Sulfate Injection (Pfizer)

Vincristine sulfate

BRAND INFORMATION

Brand name

Pfizer (Australia) Vincristine Sulfate

Active ingredient

Vincristine sulfate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Vincristine Sulfate Injection (Pfizer).

What is in this leaflet

This leaflet answers some common questions about Vincristine Sulfate Injection. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Vincristine Sulfate Injection against the benefits this medicine is expected to have for you.

This medicine is likely to be used while you are at the clinic or in hospital. If possible, please read this leaflet carefully before this medicine is given to you. In some cases this leaflet may be given to you after the medicine has been used.

If you have any concerns about taking this medicine, ask your doctor, nurse or pharmacist.

Keep this leaflet. You may need to read it again.

What Vincristine Sulfate Injection is used for

Vincristine sulfate belongs to a group of anticancer medicines called Vinca alkaloids. It is used for the treatment of various cancers. Vincristine stops the cancer cells growing and eventually kills them.

Vincristine is used to treat certain cancers, including:

  • acute leukaemia
  • Hodgkin’s disease
  • non-Hodgkin’s disease
  • rhabdomyosarcoma
  • neuroblastoma
  • Wilm’s tumour
  • bone cancer
  • mycosis fungoides
  • Ewing’s sarcoma
  • uterine or cervical cancer
  • breast cancer
  • malignant melanoma
  • lung cancer
  • gynaecological childhood tumours

Your doctor may have prescribed vincristine for another reason.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Before you are given Vincristine Sulfate Injection

When you must not be given it

Do not use Vincristine Sulfate Injection if:

  • you have an allergy to vincristine or any of the ingredients listed at the end of this leaflet
  • you have an allergy to any of the Vinca Alkaloids medicines eg. Vinblastine and Vindesine
  • you suffer from Charcot-Marie-Tooth-Syndrome. This is a type of hereditary nerve disease.
  • you are receiving or have received radiation therapy

If you are not sure whether any of these apply to you, check with your doctor.

You must not be given Vincristine Sulfate Injection if you are pregnant or intend to become pregnant. Vincristine may affect your developing baby if you are given it during pregnancy.

It is recommended that you and your doctor discuss the need for vincristine treatment during pregnancy, and the possible risks and benefits of using vincristine during pregnancy.

Vincristine may cause birth defects if either the male or the female is undergoing treatment at the time of conception, or if the female is receiving vincristine during early pregnancy.

Women of childbearing potential should use effective contraception during treatment with Vincristine Sulfate injection and for at least 7 months after the last dose.

Male patients being treated with Vincristine Sulfate injection should use effective contraception during treatment and for at least 4 months after the last dose if their female partner is of child bearing potential.

Many cancer medicines can cause infertility. Your doctor should discuss this issue with you before you begin therapy with vincristine.

You should not be given Vincristine Sulfate Injection if you are breast-feeding or plan to breast-feed. It is not known whether vincristine passes into breast milk. Do not breastfeed while being treated with Vincristine Sulfate injection and for one month after the last dose.

Before you are given it

Tell your doctor if:

  1. you have any allergies to:
  • any other medicine
  • any other substances, such as foods, preservatives or dyes
  1. you are pregnant or intend to become pregnant
  2. you are breastfeeding or plan to breastfeed
  3. you have or have had any medical conditions, especially the following:
  • Gout
  • Kidney stones
  • Any infections
  • Liver disease or jaundice
  • Nerve or muscle disease.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and vincristine may interfere with each other. These include:

  • Medicines to treat gout eg. Allopurinol, colchicine, probenecid or sulfinpyrazone
  • Heart medicines eg. Nifedipine or digoxin
  • Phenytoin, a medicine used to prevent seizures, fits or epilepsy
  • Vaccines
  • Medicines used to treat infections eg. Itraconazole, fluconazole, voriconazole, isoniazid, ciprofloxacin, norfloxacin and ofloxacin
  • St John's wort
  • Any other anti-cancer medicines eg. Bleomycin, methotrexate, doxorubicin, asparaginase and mitomycin-C.

In some cases, two different medicines may be used together by your doctor even if an interaction might occur. In these cases, your doctor may change your dose.

Do not have any vaccinations (immunisations) without your doctor's approval while you are being treated with vincristine, and for up to 12 months after you stop treatment with it. Vincristine may lower your body's resistance to infection and there is a chance that you may get the infection the immunisation is meant to prevent.

In addition, other people living in your household should not take oral polio vaccine (sabin) since there is a chance they could pass the polio virus on to you.

Your doctor will advise you about continuing to take other medicines while you are receiving Vincristine Sulfate Injection.

How Vincristine Sulfate Injection is given

This medicine is given as a slow injection into a vein. Sometimes, it is diluted and given as a long injection. Vincristine Sulfate Injection must only be given by a doctor or nurse.

Your doctor will decide what dose, how often and how long you will receive it. This depends on your condition and other factors, such as your weight, age, blood tests, how well your liver is working, and whether or not other medicines are being given at the same time.

Several courses of vincristine therapy may be needed, depending on your response to treatment.

Additional treatment should not be repeated until your blood cell numbers return to acceptable levels and any unwanted effects have been controlled.

If you are given too much (overdose)

This rarely happens as Vincristine Sulfate Injection is administered under the care of a highly trained doctor.

However, if you are given too much vincristine, you may experience some of the effects listed under "Side Effects" below.

Your doctor has information on how to recognise and treat an overdose. Ask your doctor if you have any concerns.

While you are being given Vincristine Sulfate Injection

Things you MUST do

Vincristine Sulfate Injection can temporarily lower the number of white blood cells in your blood, increasing the chance of you getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

  • If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection, or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
  • Check with your doctor immediately if you notice any unusual bleeding or bruising, black stools, blood in urine or stools or pinpoint red spots on your skin.
  • Be careful when using a regular toothbrush, dental floss or toothpick. Your doctor or nurse may recommend other ways to clean your teeth and gums.
  • Check with your doctor before having any dental work done.
  • Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
  • Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
  • Avoid contact sports or other situations where bruising or injury could occur.
  • Be sure to keep all of your doctors' appointments so that your progress can be checked.
  • If you become pregnant while under vincristine treatment, tell your doctor immediately.

Vincristine Sulfate Injection and its breakdown products may be excreted in body fluids and waste, including blood, urine, faeces, vomitus and semen.

In general, precautions to protect other people should be taken while you are receiving chemotherapy and for one week after the treatment period:

  • Flush the toilet twice to dispose of any body fluids and waste
  • Wear gloves to clean any spill of body fluid or waste. Use paper towels or old rags, a strong solution of non-bleaching detergent and large amounts of water to mop up the spill. Discard the towels or rags into a separate waste bag and dispose of fluids in the toilet.
  • Wash linen or clothing that is heavily contaminated by body fluids or waste separately from other items. Use a strong solution of non-bleaching detergent and large amounts of water.
  • Place soiled disposable nappies and other pads in a plastic bag, seal and dispose into the garbage.
  • For sexual intercourse, use a barrier method such as a condom.

Tell your doctor, nurse or pharmacist if you have any concerns before, during or after administration of Vincristine Sulfate Injection.

Tell any other doctors, dentists, and pharmacists who are treating you that you are being given Vincristine Sulfate Injection.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are being given Vincristine Sulfate Injection.

If you plan to be vaccinated within a year of being given Vincristine Sulfate Injection, tell the doctor before you are vaccinated.

If you or your partner become pregnant while being given or soon after being given Vincristine Sulfate Injection, tell your doctor or pharmacist.

Things you MUST NOT do

  • Do not have any immunisations or vaccinations without your doctor's approval and for up to 12 months after you stopped treatment with it.

Things to be careful of

Be careful driving or operating machinery until you know how vincristine affects you. This medicine may cause dizziness, tiredness or affect vision or movement in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are using vincristine.

Like other medicines, vincristine can cause some side effects. If they occur, most are likely to be minor or temporary. However, some may be serious and need medical attention.

Ask your doctor, nurse or pharmacist to answer any questions that you may have.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • hair loss
  • diarrhoea, nausea, vomiting, loss of appetite and weight loss
  • headache
  • unusual perspiration
  • increase in sunburn
  • tingling or burning sensation
  • inflamed gums
  • impotence or reduced sexual drive

Check with your doctor or nurse as soon as possible if any of the following side effects occur:

  • dizzy or light-headed when getting up from lying or sitting position
  • loss of feeling, hearing or taste
  • eye sight problems: blurred or double vision, temporary blindness
  • trouble in sleeping, depression, nervousness, hallucinations, confusion and personality changes
  • increased frequency, difficulty or pain in passing urine, or incontinence
  • constipation or cramps
  • hair loss
  • mouth ulcers
  • muscle wasting, difficulty in walking
  • jaw, bone, limb or back pain
  • muscle aches

Tell your doctor immediately if you notice any of the following:

These are serious side effects. You may need urgent medical attention. Serious side effects are rare.

  • Pain or redness at place of injection
  • Allergies
    An allergy may appear as an itchy rash, high temperature after the injection, swelling of the face, lips, tongue or throat and/or difficulty in breathing.
  • Effects on the heart
    Symptoms to look for are, tightness or pain in the chest, neck, back or arms as well as abnormal heartbeat.
  • Effects on nerves and muscles
    Vincristine sometimes affects nerves in the hands and feet. This may appear as numbness, tingling, pain or weakness in the fingertips. Other symptoms are loss of movement, muscle control and reflexes, jaw pain, back pain, arm and leg pain, face pain, fits and coma.
  • Bleeding disorders
    Symptoms to look for are black, tarry stools; or blood in stools or urine; pinpoint red spots on skin and any unusual bleeding or bruising.
  • Infection
    Symptoms to look for are fever, chills, cough, hoarseness and sore throat.
  • Effects on the liver
    Symptoms to look for are abdominal pain or swelling, sudden weight gain or yellowing of the skin and eyes

Other side effects not listed above may also occur in some patients. If you notice any other effects, check with your doctor. Some side effects may only be seen by your doctor.

Product description

What it looks like

Vincristine Sulfate Injection is a clear, colourless solution in a plastic vial.

AUST R 48055 Vincristine Sulfate Injection 2mg in 2mL (sterile) Plastic Vial

Ingredients

Vincristine Sulfate Injection contains Vincristine Sulfate, Mannitol and Water for Injections. It does not contain a preservative.

Supplier

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizermedicalinformation.com.au

This leaflet was prepared in September 2023.

Published by MIMS November 2023

BRAND INFORMATION

Brand name

Pfizer (Australia) Vincristine Sulfate

Active ingredient

Vincristine sulfate

Schedule

S4

 

1 Name of Medicine

Vincristine sulfate.

2 Qualitative and Quantitative Composition

Vincristine Sulfate Injection contains 1 mg/mL of vincristine sulfate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Vincristine Sulfate Injection is a sterile, hypertonic, preservative-free solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Vincristine is used primarily in the treatment of acute leukaemia, usually as a component of various chemotherapeutic regimens. It has also been used as part of combination therapy in the treatment of Hodgkin's disease, non-Hodgkin's malignant lymphomas, rhabdomyosarcoma, neuroblastoma, Wilm's tumour, osteogenic sarcoma, mycosis fungoides, Ewing's sarcoma, carcinoma of the uterine cervix, breast cancer, malignant melanoma, oat cell carcinoma of the lung and gynaecological tumours of childhood.
Vincristine may be useful in patients with true idiopathic thrombocytopenic purpura resistant to the usual treatment, but is not recommended as primary treatment for this disorder.

4.2 Dose and Method of Administration

This preparation is for intravenous use only and is usually administered at weekly intervals. It can be fatal if administered intrathecally (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Vincristine should not be given intramuscularly, subcutaneously or intrathecally. Intrathecal use of vincristine usually results in death. When dispensed, flexible plastic containers containing this product should be labelled: For intravenous use only. Fatal if given by any other route.

Dosage.

Neurotoxicity appears to be dose related. Extreme care must be used in calculating and administrating the dose of vincristine since overdosage may have very serious or fatal outcome (see Section 4.9 Overdose).
Vincristine has been given by many different dosing schemes and in combination with many other drugs. As the range between therapeutic and toxic levels is narrow and the response is varied, the dosage must always be carefully adjusted according to the needs of the individual.
The calculated dose of the vincristine solution should be administered only through a vein by intravenous infusion (IV) according to the treatment protocol and under constant supervision for signs of extravasation.

Children.

The usual dose is 1.5-2.0 mg/m2 body surface area.
For children < 10 kg or body surface area < 1 m2 0.05 mg/kg weekly.

Adults.

The usual dose is 0.4-1.4 mg/m2 body surface area.

Method of administration.

The diluted Vincristine Sulfate Injection must be infused via a flexible plastic container (e.g. infusion bag) into a free flowing IV infusion of 0.9% sodium chloride or 5% glucose, or directly into an intravenous catheter/needle, whichever is more suitable for the patient (see Section 6.2 Incompatibilities). It is recommended to administer the solution over 5 to 10 minutes after dilution in a 50 mL infusion bag (50 mL sodium chloride or other compatible diluent). After administration the vein must be flushed through thoroughly. Care should be taken to avoid extravasation as this may cause local ulceration. Vincristine Sulfate Injection should not be diluted in solutions that raise or lower the pH outside the range of 3.5 to 5.5. It should not be mixed with anything other than 0.9% sodium chloride or 5% glucose.
To reduce the potential for fatal medication errors due to incorrect route of administration, Vincristine Sulfate Injection is recommended to be diluted in a flexible plastic container and prominently labeled as indicated For intravenous use only - Fatal if given by other routes (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Always check the needle position before intravenously administering vincristine. If there is a swelling or other evidence of injection site leakage, it may cause considerable irritation. Cease the infusion immediately and give the remaining dose at another site. Immediately apply local measures (hyaluronidase, local heat) to try to reduce both discomfort and the risk of cellulitis.
Syringes should not be used for Vincristine Sulfate Injection administration. Preparation must be by dilution in small volume intravenous bags (the 'minibag' technique), rather than in a syringe, to protect against accidental administration via a spinal route.

Handling precautions.

As with all antineoplastic agents, trained personnel should prepare Vincristine Sulfate Injection. This should be performed in a designated area (preferably a cytotoxic laminar flow cabinet). Protective gown, mask, gloves and appropriate eye protection should be worn when handling vincristine. Where solution accidentally contacts skin or mucosa, the affected area should be immediately washed thoroughly with soap and water. It is recommended that pregnant personnel not handle cytotoxic agents such as vincristine. Luer-Lock fitting syringes are recommended. Large bore needles are recommended to minimise pressure and possible formation of aerosols. Aerosols may also be reduced by using a venting needle during preparation.
Do not add extra fluid to the vial prior to removal of the dose. Withdraw the solution of vincristine sulfate into an accurate syringe, measuring the dose carefully. Do not add extra fluid to the vial in an attempt to empty it completely.
Items used to prepare vincristine, or articles associated with body waste, should be disposed of by placing in a double sealed polythene bag and incinerating at 1100°C. When handling urine and faeces from patients receiving vincristine, protective clothing should be worn for up to 4-7 days respectively after therapy.

Spills and disposal.

If spills occur, restrict access to the affected area. Wear two pairs of gloves (latex rubber), a respirator mask, a protective gown and safety glasses. Limit the spread of the spill by covering with a suitable material such as absorbent towel or adsorbent granules. Spills may also be treated with 5% sodium hydroxide. Collect up absorbent/ adsorbent material and other debris from spill and place in a leak proof plastic container and label accordingly. Cytotoxic waste should be regarded as hazardous or toxic and clearly labelled 'Cytotoxic waste for incineration at 1100°C'. Waste material should be incinerated at 1100°C for at least 1 second. Cleanse the remaining spill area with copious amounts of water.

Dosage adjustment.

Patients with biliary obstruction; pre-existing neuropathies; liver dysfunction or jaundice; and the elderly.
A direct serum bilirubin > 3 mg/100 mL should prompt a 50% reduction in dosage.
When used in combination with L-asparaginase, vincristine sulfate should be given 12 to 24 hours before the administration of the enzyme in order to minimise toxicity (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions); administering L-asparaginase before vincristine may reduce hepatic clearance of vincristine sulfate.

4.3 Contraindications

Known hypersensitivity to vincristine sulfate, other vinca alkaloids or any of the excipients.
Intrathecal administration, as usually results in death (see Section 4.4 Special Warnings and Precautions for Use).
Patients with the demyelinating form of Charcot-Marie-Tooth syndrome.
Patients receiving radiation therapy through ports that include the liver.

4.4 Special Warnings and Precautions for Use

Vincristine should be used only by physicians experienced in therapy with cytotoxic agents.

Precautions for administration.

This preparation is for intravenous use only. Can be fatal if administered intrathecally (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications).
Vincristine is an irritant and should not be given intramuscularly, subcutaneously or intrathecally. Intrathecal administration of vincristine is usually fatal.
When dispensed, flexible plastic containers containing this product should be labelled: For intravenous use only. Fatal if given by any other route.

Emergency treatment of accidental intrathecal administration.

Treatment of patients following accidental intrathecal administration of vincristine has included immediate removal of spinal fluid and flushing with lactated Ringer's solution, as well as other solutions, but this has not prevented ascending paralysis and death. In one case, progressive paralysis in an adult was arrested by the following treatment initiated immediately after the intrathecal injection.
a) As much spinal fluid was removed as could be safely done through lumbar access.
b) The subarachnoid space was flushed with lactated Ringer's solution infused continuously through a catheter in a cerebral lateral ventricle at the rate of 150 mL/h. The fluid was removed through a lumbar access.
c) As soon as fresh frozen plasma became available, the fresh frozen plasma, 25 mL, diluted in 1 L of lactated Ringer's solution was infused through the cerebral ventricular catheter at the rate of 75 mL/h with removal through the lumbar access. The rate of infusion was adjusted to maintain a protein level in the spinal fluid of 150 mL/dL.
d) Glutamic acid 10 g was given intravenously over 24 hours followed by 500 mg three times daily by mouth for one month or until neurological dysfunction stabilised. The role of glutamic acid in this treatment is not certain and may not be essential.

Extravasation.

Vincristine is a vesicant and may cause a severe local reaction on extravasation. If leakage into the surrounding tissue occurs, the infusion 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 moderate heat has been used to disperse the drug and minimise discomfort and tissue damage.

Neurotoxicity.

Neurotoxicity is the most common dose limiting side effect (see Section 4.8 Adverse Effects (Undesirable Effects)). The development of neuromuscular effects is generally sequential with initial sensory impairment and paraesthesia. With further treatment neuritic pain may develop and, later, motor difficulties. There have been no reports of any agent that can reverse these neuromuscular manifestations. Exacerbation of pre-existing neurological disorders may occur. Discontinuation of treatment should be considered if neuromuscular effects continue to be a problem.
Neurologic side effects of vincristine may be increased with the concomitant use of other neurotoxic agents, patients with pre-existing neuromuscular disease, in the elderly or in patients who have had previous irradiation. Particular attention should be given to dosage and neurological side effects in these patients.

Haematological.

Effective therapy with vincristine is less likely to be followed by granulocytopenia than is the case with vinblastine and other oncolytic agents. A study of the side effects of vincristine injection solution in all age groups reveals that it is usually neuromuscular rather than bone marrow toxicity that limits dosage. Leucopoenia is not common following therapy, however because of the possibility of granulocytopenia, both physician and patient should remain alert for signs of any complicating infection.
Although pre-existing granulocytopenia does not necessarily contraindicate the administration of vincristine, the appearance of granulocytopenia and/or a complicating infection during treatment warrants careful consideration before giving the next dose.

Genito-urinary.

Hyperuricaemia may occur in some patients receiving vincristine, especially those with non-Hodgkin's lymphomas or leukaemia. In some patients uric acid nephropathy may result. These effects may be minimised by adequate hydration, alkalinisation of the urine and/or administration of allopurinol (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Urate nephrotoxicity.

Acute urate nephropathy, which may occur after the administration of oncolytic agents, has been reported with vincristine. The risk/ benefit should be considered in patients with a history of gout or urate renal stones.

Treatment of central nervous system leukaemia.

Vincristine penetrates the blood brain barrier poorly, so alternate chemotherapeutic agents or routes of administration may be required for central nervous system leukaemia. Vincristine must not be administered intrathecally.

Alopecia.

Alopecia is the most common adverse effect associated with vincristine therapy, occurring in 20-70% of patients. It is reversible upon discontinuation of the drug.

Optic.

Avoid accidental contamination of the eyes, as vincristine is highly irritant and may cause corneal ulceration. The eyes should be washed with water immediately and thoroughly.

Respiratory.

Acute shortness of breath, severe bronchospasm and respiratory distress syndrome has been reported following the 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 of dyspnoea may occur minutes to several hours after the vinca alkaloid is administered, and may occur up to two weeks following the dose of Mitomycin-C. Progressive dyspnoea requiring chronic therapy may occur. Vincristine therapy should be discontinued and should not be readministered.

Secondary malignancies.

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.

Gastrointestinal.

Constipation and paralytic ileus are not uncommon and are frequently associated with abdominal cramps. Stool softeners, mild laxatives and enemas may be helpful. A routine prophylactic regimen of laxative and enemas is usually recommended for patients receiving vincristine. Constipation may take the form of upper colon impaction, and on physical examination, the rectum may be empty. Colicky abdominal pain coupled with an empty rectum may mislead the physician. A flat film of the abdomen is useful in demonstrating this condition. All cases have responded to high enemas and laxatives. Paralytic ileus (which mimics the 'surgical abdomen') may occur, particularly in young children and the elderly. The ileus will reverse itself with temporary discontinuance of vincristine and with symptomatic care.

Endocrine.

Hypersecretion of antidiuretic hormone has been reported in patients receiving vincristine therapy. In these patients hyponatraemia associated with increased urinary sodium excretion occurs without evidence of renal or adrenal disease, hypotension, dehydration, azotaemia or clinical oedema. With fluid deprivation, improvement occurs in the hyponatraemia and in the renal loss of sodium.

Infection.

The risks and benefits should be considered before vincristine is administered to patients with an infection, due to its immunosuppressive effects. It should be administered with caution to patients with herpes zoster or with existing or recent chicken pox (including recent exposure), as there is a risk of severe generalised disease developing.

Immunisation.

Immunisation of patients being treated with vincristine should only be undertaken with extreme caution (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). People in close contact with the patient, especially family members, should postpone immunisation with oral polio vaccines.

Use in hepatic impairment.

Impaired hepatic function or jaundice may warrant dosage adjustments, as vincristine is metabolised in the liver and excreted in the bile. An increase in the severity of side-effects may be experienced by patients with liver disease sufficient to decrease biliary excretion.

Use in renal impairment.

No data available.

Use in the elderly.

See Section 4.4 Special Warnings and Precautions for Use, Neurotoxicity, Gastrointestinal; Section 4.2 Dose and Method of Administration, Dosage adjustment.

Paediatric use.

See Section 4.4 Special Warnings and Precautions for Use, Gastrointestinal.

Effects on laboratory tests.

Because dose limiting clinical toxicity is manifested as neurotoxicity, clinical evaluation (e.g. history, physical evaluation) is necessary to detect the need for dosage modification. Following administration of Vincristine Sulfate Injection, some individuals may have a fall in the white blood cell count or platelet count, particularly when previous therapy or the disease itself has reduced bone marrow function. Therefore, a complete blood count should be done before administration of each dose. Acute elevation of serum uric acid may also occur during induction of remission in acute leukaemia; thus, such levels should be determined frequently during the first 3 to 4 weeks of treatment or appropriate measures taken to prevent uric acid nephropathy. The laboratory performing these tests should be consulted for its range of normal values.
Hepatocellular dysfunction has been noted in some patients treated with vincristine sulfate. It is therefore recommended that liver function tests be performed on initiation of vincristine therapy and at periodic intervals during therapy depending on the patients clinical state, dosage and concomitant therapy.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Anti-gout agents.

Allopurinol may increase the incidence of cytotoxic induced bone marrow depression. The mechanism for this potentiation has not been fully classified.
Dosage adjustment of anti-gout agents (e.g. allopurinol, colchicine, probenecid or sulfinpyrazone) may be necessary to control hyperuricaemia and gout, since vincristine may raise the concentration of blood uric acid.

Drugs acting on the peripheral nervous system.

The neurotoxicity of vincristine may be additive with that of other drugs acting on the peripheral nervous system (e.g. asparaginase and isoniazid) (see Section 4.2 Dose and Method of Administration).

Doxorubicin.

The concurrent use of doxorubicin with vincristine and prednisolone may produce increased myelosuppression; it is recommended that this combination be avoided.

Methotrexate.

Vincristine appears to increase the cellular uptake of methotrexate by malignant cells and this principle has been applied in high dose methotrexate therapy. The clinical importance of this interaction is not known however. It has also been reported that a 2.5-fold increase of methotrexate levels in C.S.F. occurred when vincristine was given 23 hours after high dose methotrexate therapy was initiated. The effect lasted approximately 3 hours.

Oral quinolones.

Due to decreased absorption of the antimicrobial agent, the antimicrobial effect of oral quinolones (ciprofloxacin, norfloxacin and ofloxacin) may be decreased by administration of vincristine.

Nifedipine.

Nifedipine decreases the clearance of vincristine.

Phenytoin.

The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included vincristine has been reported to reduce blood levels of the anticonvulsant and to increase seizure activity. Dosage adjustment of phenytoin, based on serial blood level monitoring, should be made when it is used in combination with vincristine. The contribution of vincristine to this interaction is not certain. The interaction may result from reduced absorption of phenytoin and an increase in the rate of its metabolism and elimination.

Vaccines.

Because normal defence mechanisms may be suppressed by vincristine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine. The patient's antibody response to killed virus vaccine may also be decreased. Immunisation of these patients should be undertaken only with extreme caution after careful review of the patient's haematological status and only with the knowledge and consent of the physician managing vincristine therapy. The interval between discontinuation of medications that cause immune suppression and restoration of the patient's ability to respond to the vaccine depends on many factors; estimates vary from 3 months to 1 year.

Voriconazole.

Although not studied in vitro or in vivo, voriconazole may increase the plasma concentrations of vinca alkaloids including vincristine sulfate and lead to neurotoxicity. Therefore, it is recommended that dose adjustment of vincristine sulfate be considered.

CYP 3A4 inhibitors/inducers.

Caution should be exercised in patients concurrently taking drugs known to inhibit/induce drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily or in patients with hepatic dysfunction. Concurrent administration of vincristine sulfate with itraconazole or fluconazole (known inhibitors of the same metabolic pathway) has been reported to cause an earlier onset and/or increased severity of neuromuscular side effects. Inducers like St. John's wort should be given cautiously.

Digoxin.

Studies have shown that cancer chemotherapy and radiation therapy have resulted in decreased absorption of the digitalis glycosides digoxin and B-acetyldigoxin administered in tablet forms. Serial monitoring of digoxin blood levels before, during and after chemotherapy should be initiated so that any necessary dosage adjustment can be made.

Mitomycin.

Concurrent administration of mitomycin with vincristine may increase the incidence of acute shortness of breath and severe bronchospasm (see Section 4.4 Special Warnings and Precautions for Use).

Ototoxic drugs.

Vincristine should be used with extreme caution with potentially ototoxic drugs such as the platinum-containing antineoplastic agents, as temporary or permanent hearing impairment has been reported in patients receiving vinca alkaloids (see Section 4.8 Adverse Effects (Undesirable Effects)).

Bleomycin.

Thromboembolism or Raynaud's syndrome may occur if bleomycin is used with vinca alkaloids and other agents such as cisplatin or etoposide (see Section 4.8 Adverse Effects (Undesirable Effects)).

Radiation therapy.

When chemotherapy is being given in conjunction with radiation therapy the use of vincristine should be delayed until radiation therapy has been completed.

4.6 Fertility, Pregnancy and Lactation

Women of childbearing potential/contraception in males and females.

Women of childbearing potential should be advised to avoid becoming pregnant while receiving vincristine sulfate. Due to the potential for genotoxicity, teratogenicity, and embryo toxicity, female patients of reproductive potential are advised to use highly effective contraception during treatment and for at least 7 months following last dose of vincristine sulfate.
Due to the potential for genotoxicity, male patients with female partners of reproductive potential are advised to use highly effective contraception during treatment and for at least 4 months following the last dose of vincristine sulfate.

Effects on fertility.

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, permanent azoospermia and amenorrhoea are much less likely.
Based on these clinical reports, male and female fertility may be compromised. It is recommended to discuss fertility preservation with men and women prior to treatment.
(Category D)
Vincristine can cause fetal harm when administered to a pregnant woman. In several animal species vincristine is embryotoxic and teratogenic with doses that are nontoxic to the pregnant animal. There are no adequate and well controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while receiving this drug, she should be advised of the potential hazard to the fetus.
 It is not known whether vincristine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions due to vincristine in breastfed infants, the mother should be advised not to breast-feed while on vincristine sulfate therapy and for 1 month following last dose of treatment. Alternatively, discontinue treatment taking into account the importance of the drug to the mother.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration. However, adverse effects of vincristine sulfate (with unknown frequency) may include dizziness, visual disturbances and neuromuscular effects which could affect the ability to drive or use machines. See Section 4.8 Adverse Effects (Undesirable Effects).

4.8 Adverse Effects (Undesirable Effects)

In general, adverse reactions are reversible and are related to dosage and cumulative dosage. The use of small amounts of vincristine daily for long periods is not advised. The most common adverse reaction is alopecia, the most troublesome adverse reactions are neuromuscular in origin.
When single, weekly doses of the drug are employed, the adverse effects of leucopenia, neuritic pain, and constipation occur but are of short duration (i.e. less than 7 to 10 days). When the dosage is reduced, these effects may lessen or disappear. The severity of such effects seems to increase when the calculated amount of vincristine is given in divided doses. Other adverse effects such as hair loss, sensory loss, paraesthesia, difficulty in walking, slapping gait, loss of deep-tendon reflexes and muscle wasting may persist for at least as long as therapy is continued. Generalised sensorimotor dysfunction may become progressively more severe with continued treatment. Although most such symptoms usually disappear by about the sixth week after discontinuance of treatment, some neuromuscular difficulties may persist for prolonged periods in some patients. Regrowth of hair may occur while maintenance therapy continues.
The reported adverse reactions are listed in Table 1 by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10; ≥ 10%), common (≥ 1/100 to < 1/10; ≥ 1% to < 10%), uncommon (≥ 1/1,000 to < 1/100; ≥ 0.1% to < 1%), rare (≥ 1/10,000 to < 1/1,000; ≥ 0.01% to < 0.1%), very rare (< 1/10,000; < 0.01%), and frequency not known (cannot be estimated from the available data).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Overdosage with vincristine produces reactions that are mainly extensions of the adverse effects, as these are dose related. Therefore, following administration of doses higher than those recommended, patients can be expected to experience side effects in an exaggerated fashion. The treatment of vincristine overdosage is purely supportive and symptomatic, as no antidote has yet been found.
Adults may experience severe symptoms after single doses of 3 mg/m2 or more. In children under 13 years death has occurred following doses ten times those recommended for therapy. Severe symptoms may occur in this patient group following dosages of 3 to 4 mg/m2.
Anticonvulsants such as phenobarbitone may be beneficial in controlling seizures. If profound neutropenia develops, surveillance for the presence of infection by culture, protective isolation and early treatment with antibiotics when infection is suspected may be necessary. Fluid restriction and possibly the use of an appropriate diuretic may have to be instituted to prevent side effects resulting from hypersecretion of antidiuretic hormone. Enemas or cathartics may be used to prevent ileus (in some cases decompression of the G.I. tract may be necessary). Routine monitoring of the cardiovascular system is also recommended together with daily blood counts as an indicator for transfusion requirements.
Isolated case reports suggest that folinic acid may be helpful in treating humans who have received an overdose of vincristine. A suggested schedule is to administer 15 mg of folinic acid intravenously every 3 hours for 24 hours and then every 6 hours for at least 48 hours. Theoretical tissue levels of vincristine derived from pharmacokinetic data are predicted to remain significantly elevated for at least 72 hours. Treatment with folinic acid does not eliminate the need for supportive measures.
An increase in the severity of side effects may be experienced in patients with liver disease with diminished biliary excretion.
Enhanced faecal excretion of parenterally administered vincristine has been demonstrated in dogs pretreated with cholestyramine. There are no published clinical data on the use of cholestyramine as an antidote in humans. Nor is there published clinical data on the consequences of oral ingestion of vincristine. Should oral ingestion occur the stomach should be evacuated, and activated charcoal administered orally as a cathartic.
Most of an intravenous dose of vincristine is excreted in the bile after rapid tissue binding. Because only very small amounts of the drug appear in dialysate, haemodialysis is not likely to be helpful in cases of overdosage.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Antineoplastic agent. Antimitotic.
The precise mechanism of action of vincristine sulfate remains under investigation. Vincristine appears to affect cell mitosis by interfering with microtubular proteins and causing an arrest of cell division during the metaphase. It is cell cycle phase specific.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Distribution.

After intravenous administration, vincristine is rapidly distributed to body tissues. Vincristine is extensively protein bound (75%) and is reported to be concentrated in blood platelets. Vincristine does not penetrate the central nervous system to any significant degree.

Metabolism and excretion.

Vincristine is extensively metabolised in the liver. The main route of elimination is via the bile into the faeces. About 80% of an intravenous dose of vincristine appears in the faeces and 10-20% is excreted in the urine.

5.3 Preclinical Safety Data

Genotoxicity.

Neither in vivo nor in vitro laboratory tests have conclusively demonstrated the mutagenicity of this product. As a classic tubulin binder, the primary mode of action of vincristine is aneugenicity, but at higher doses and over prolonged dosing intervals, the expression of clastogenicity becomes a possibility.

Carcinogenicity.

No evidence of carcinogenicity was found following intraperitoneal administration of vincristine in rats and mice, although this study was limited.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, sodium hydroxide, sulfuric acid, water for injections.
See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Vincristine Sulfate Injection should not be diluted in solutions that raise or lower the pH outside the range of 3.5 to 5.5. It should not be mixed with anything other than 0.9% sodium chloride or 5% glucose. See Section 4.2 Dose and Method of Administration, Method of administration.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date (month/year) is stated on the package after EXP.

6.4 Special Precautions for Storage

Store between 2-8°C. Refrigerate, do not freeze. Protect from light. Single use only. Discard unused portion.

6.5 Nature and Contents of Container

Vincristine Sulfate Injection 1 mg in 1 mL (sterile) Plastic Vial (5's).
Vincristine Sulfate Injection 2 mg in 2 mL (sterile) Plastic Vial (5's).
*Vincristine Sulfate Injection 5 mg in 5 mL (sterile) Plastic Vial (5's).
*For Hospital Use Only.

6.6 Special Precautions for Disposal

See Section 4.2 Dose and Method of Administration, Handling precautions, Spills and disposal.

6.7 Physicochemical Properties

Vincristine sulfate is the salt of an alkaloid obtained from the periwinkle plant Vinca rosea (Catharanthus roseus).

Chemical structure.


Molecular formula.

C46H56N4O10,H2SO4.

Molecular weight.

923.1.

CAS number.

2068-78-2.

7 Medicine Schedule (Poisons Standard)

(S4) Prescription Only Medicine.

Summary Table of Changes