Consumer medicine information

DBL Vincristine Sulfate Injection

Vincristine sulfate

BRAND INFORMATION

Brand name

DBL Vincristine Sulfate Injection

Active ingredient

Vincristine sulfate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using DBL Vincristine Sulfate Injection.

What is in this leaflet

This leaflet answers some common questions about DBL Vincristine Sulfate Injection. This medicine is also called vincristine.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor or pharmacist has weighed the risks of you being given DBL Vincristine Sulfate Injection against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine. You may need to read it again.

What DBL Vincristine Sulfate Injection is used for

Vincristine belongs to a group of medicines known as antineoplastic or cytotoxic agents. You may also hear it referred to as chemotherapy.

Vincristine is classified as a vinca alkaloid. It interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by vincristine, other effects may also occur (see Side Effects).

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.

Vincristine is not addictive.

This medicine is available only with a doctor’s prescription.

Before you are given DBL Vincristine Sulfate Injection

When you must not be given it

You must not be given DBL Vincristine Sulfate Injection if you have an allergy to vincristine or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction to vincristine may include:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

You must not be given vincristine if you have an allergy to any of the Vinca Alkaloids medicines eg. Vinblastine and Vindesine

You must not be given vincristine if you have the demyelinating form of Charcot-Marie-Tooth-Syndrome.

You must not be given DBL Vincristine Sulfate Injection if you are currently receiving radiotherapy to areas that include the liver.

You must not be given DBL 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 DBL 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.

If you are not sure whether you should be given DBL Vincristine Sulfate Injection, talk to your doctor or pharmacist.

Before you are given it

Tell your doctor or pharmacist if you have allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes

Tell your doctor or pharmacist if you have or have had any medical conditions, especially the following:

  • gout
  • kidney stones
  • liver problems or jaundice
  • any infections, especially chicken pox or shingles
  • nerve or muscle disease.

If you have not told your doctor or pharmacist about any of the above, tell them before you are given DBL Vincristine Sulfate Injection.

Taking other medicines

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

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

  • other anti-cancer drugs eg. Bleomycin, methotrexate, doxorubicin, asparaginase and mitomycin-C
  • some medicines used to treat infections eg. itraconazole, fluconazole, voriconazole, isoniazid, ciprofloxacin, norfloxacin, ofloxacin
  • some heart medications eg. nifedipine, digoxin
  • medicines to treat gout e.g. allopurinol, colchicine, probenecid or sulfinpyrazone
  • phenytoin, a medicine to prevent seizures/ fits/epilepsy
  • vaccines
  • St John's wort.

These medicines may be affected by DBL Vincristine Sulfate Injection, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Your doctor or pharmacist will advise you.

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 and pharmacist may have more information on medicines to be careful with or avoid while being given vincristine.

How DBL Vincristine Sulfate Injection is given

How much is given

Your doctor will decide what dose you will receive. 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.

Vincristine is usually given as a course of injections at weekly intervals.

How it is given

DBL Vincristine Sulfate Injection is given as a slow injection into a vein. Vincristine must only be given by a doctor or nurse.

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)

As DBL Vincristine Sulfate Injection is given to you under the supervision of your doctor, it is very unlikely that you will receive too much. However, if you experience any severe side effects after being given this medicine, tell your doctor or nurse immediately.

In case of overdose, immediately contact the Poisons Information Centre for advice (telephone 13 11 26 in Australia). Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of vincristine overdose include some of those listed in the ‘Side Effects’ section but are usually of a more severe nature.

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

While you are being given DBL Vincristine Sulfate Injection

Things you must do

DBL 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.

DBL 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 DBL Vincristine Sulfate Injection.

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

If you plan to be vaccinated within a year of being given DBL 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 DBL Vincristine Sulfate Injection, tell your doctor or pharmacist.

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, pharmacist or nurse as soon as possible if you do not feel well while you are being given DBL Vincristine Sulfate Injection, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like other medicines, vincristine may have unwanted side effects. Some of these side effects may be prevented or treated by therapy with other medicines. If side effects do occur, their severity usually depends on the dose of vincristine you receive.

The effects of DBL Vincristine Sulfate Injection may take some time to occur and therefore some side effects may be delayed. It is possible that the unwanted side effects may not occur until months after vincristine is given.

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

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

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

Tell your doctor or nurse as soon as possible if you notice any of the following:

  • dizzy or light-headed when getting up from lying or sitting position
  • constipation
  • loss of feeling, hearing or taste
  • difficulty in walking
  • muscle wasting
  • mouth ulcers
  • different urination frequency
  • jaw, bone, limb or back pain
  • muscle aches
  • partial loss of sight, blurred or double vision
  • trouble in sleeping, depression, nervousness, hallucinations, confusion and personality changes

Tell your doctor immediately or go to the Accident and Emergency department of your nearest hospital if you notice any of the following:

  • tightness or pain in the chest, neck, back or arms as well as abnormal heartbeat
  • wheezing or difficulty breathing, skin rash or swelling
  • signs of infection such as fever or chills, cough, hoarseness and sore throat
  • unusual bleeding or bruising
  • abdominal or stomach cramps
  • abdominal pain or swelling, sudden weight gain
  • yellowing of the skin and eyes
  • loss of movement or coordination
  • muscle spasms
  • fits, seizures or convulsions

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

Treatment with vincristine may cause changes in your blood cells which may be serious. Vincristine may also affect how your kidneys and liver work. Your doctor will arrange regular blood tests and checks to detect any changes.

Other side effects not listed above may occur in some patients. Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

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

After being given DBL Vincristine Sulfate Injection

The benefits and side effects of this medicine may take some time to occur. Therefore, even after you have finished receiving your vincristine treatment you should tell your doctor immediately if you notice any of the side effects listed above.

Storage

DBL Vincristine Sulfate Injection will be stored in the pharmacy or on the ward. It must be kept in a refrigerator, where the temperature stays between 2-8°C.

After use, any unused portion of the injection will be discarded.

Product description

What it looks like

DBL Vincristine Sulfate Injection is a clear, colourless solution.

Ingredients

Active ingredient

  • vincristine sulfate

Other ingredients

  • mannitol
  • water

DBL Vincristine Sulfate Injection does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

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

DBL Vincristine Sulfate Injection comes in the following sizes:

  • 1 mg/1 mL vial AUST R 16308
  • 2 mg/2 mL vial AUST R 47249

™ = Trademark

This leaflet was prepared in September 2023.

Published by MIMS November 2023

BRAND INFORMATION

Brand name

DBL Vincristine Sulfate Injection

Active ingredient

Vincristine sulfate

Schedule

S4

 

1 Name of Medicine

Vincristine sulfate.

2 Qualitative and Quantitative Composition

DBL Vincristine Sulfate Injection:
1 mg/1 mL and 2 mg/2 mL injections contains vincristine sulfate 1 mg/mL and mannitol in water for injections. The solutions do not contain any preservative.
Vincristine sulfate occurs as a white or slightly yellow, hygroscopic, amorphous or crystalline powder and is freely soluble in water and slightly soluble in alcohol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
DBL Vincristine Sulfate Injection is a clear colourless solution. The solutions do not contain any preservative.

4 Clinical Particulars

4.1 Therapeutic Indications

Vincristine sulfate is indicated in acute leukaemia.
Current practices of cancer chemotherapy involve the simultaneous use of several agents. For enhanced therapeutic effect without additive toxicity, agents with different dose limiting clinical toxicities and different mechanisms of action are generally selected. It is rarely possible to achieve equally good results with single agent treatment. Thus vincristine sulfate is often chosen as part of polychemotherapy because of lack of significant bone marrow suppression (at recommended doses) and because of its unique clinical toxicity (neuropathy). See Section 4.2 Dose and Method of Administration for possible increased toxicity when used in combination therapy.
It has been shown to be useful in combination with other oncolytic agents in Hodgkin's disease, non-Hodgkin's malignant lymphomas (lymphocytic, mixed cell, histiocytic, undifferentiated, nodular and diffuse types), rhabdomyosarcoma, neuroblastoma, Wilms' 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.
In recent years, multiple agent regimens have been developed for the treatment of a variety of malignant disorders in children. Paediatric patients with neuroblastoma, osteogenic sarcoma, Ewing's sarcoma, rhabdomyosarcoma, Wilms' tumour, Hodgkin's disease, non-Hodgkin's lymphomas, embryonal carcinoma of the ovaries and rhabdomyosarcoma of the uterus should be considered candidates for such polychemotherapy treatment. Close co-operation among oncologists, paediatricians, radiologists and surgeons is required in order to achieve the best possible results.
Patients with true idiopathic thrombocytopenic purpura refractory to splenectomy and short-term treatment with adrenocortical steroids may respond to vincristine sulfate, but the drug is not recommended as primary treatment for this disorder.
Recommended weekly doses of vincristine sulfate given for 3 to 4 weeks have produced permanent remissions in some patients. If patients fail to respond after 3 to 6 doses, it is unlikely that there will be any results with additional doses.

4.2 Dose and Method of Administration

Dosage.

Neurotoxicity appears to be dose related. Extreme care must be used in calculating and administering the dose of vincristine sulfate, since overdosage may have a very serious or fatal outcome.
Vincristine has been given by many different dosing schemes and in combination with many other medicines. Because of the narrow range between therapeutic and toxic levels and variations in response, the dosage must always be carefully adjusted according to the needs of the individual. Vincristine is usually administered at weekly intervals.
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 to 2.0 mg/m2 body surface area (BSA).
For children weighing 10 kg or less, or having a BSA less than 1 m2, the starting dose should be 0.05 mg/kg administered once a week.

Adults.

The usual dose is 0.4 to 1.4 mg/m2 BSA.
Elderly patients and those with underlying neurological disease may be more susceptible to the neurotoxic effects of vincristine. Dosage modification may also be required in patients with liver disease or jaundice.
As stated under Section 4.3 Contraindications, vincristine should not be given to patients receiving radiation therapy through ports that include the liver. When used in combination with L-asparaginase, vincristine sulfate should be given 12 to 24 hours before 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.

Method of administration.

This preparation is for intravenous use only (see caution below) by individuals experienced in administration of vincristine sulfate. The intrathecal administration of vincristine sulfate is usually fatal.
DBL Vincristine Sulfate Injection should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit.
The diluted DBL Vincristine Sulfate Injection must be infused via a flexible plastic container (e.g. infusion bag) into a free flowing intravenous 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.
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 DBL Vincristine Sulfate Injection administration. Preparation must be by dilution in small volume intravenous bags (the 'minibag' technique), to protect against accidental administration via a spinal route.

Handling precautions.

As with all antineoplastic agents, trained personnel should prepare DBL 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 sulfate. 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 sulfate.
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 DBL Vincristine Sulfate Injection, or articles associated with body waste should be disposed of by placing in a double sealed polythene bag and incinerated at 1100°C.
When handling urine and faeces from patients receiving vincristine, protective clothing should be worn for up to 4 to 7 days, respectively after therapy (see Section 6.6 Special Precautions for Disposal).

Dosage adjustment.

A 50% reduction in the dose of vincristine sulfate is recommended for patients having a serum bilirubin value above 3 mg/100 mL for both children and adults.

4.3 Contraindications

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 should not be given vincristine sulfate.
Careful attention should be given to those conditions listed under Section 4.4 Special Warnings and Precautions for Use.
DBL Vincristine Sulfate Injection is contraindicated in patients who are hypersensitive to vincristine, vinca alkaloids or any other ingredient in the preparation.
Vincristine should not be administered to patients while they are receiving radiation therapy through ports that include the liver.
Vincristine should not be administered to women while they are breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation).

4.4 Special Warnings and Precautions for Use

Vincristine should be used only by physicians experienced in cytotoxic chemotherapy.

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 very irritating 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: "Warning - For intravenous use only - Fatal if given by other routes".

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, and 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:
1. As much spinal fluid was removed as could be safely done through lumbar access.
2. 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/hour. The fluid was removed through a lumbar access.
3. 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/hour, with removal through the lumbar access. The rate of infusion was adjusted to maintain a protein level in the spinal fluid of 150 mg/dL.
4. Glutamic acid, 10 grams was given intravenously over 24 hours followed by 500 mg 3 times daily by mouth for 1 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 should occur during intravenous administration of vincristine, 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 heat has been used to disperse the drug in order to minimise discomfort and the possibility of tissue damage.

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.

Urate nephrotoxicity.

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

Treatment of central nervous system leukaemia.

As vincristine penetrates the blood brain barrier poorly, additional agents and routes of administration may be required for central nervous system leukaemia. Vincristine must not be administered intrathecally.

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.
Particular attention should be given to dosage and neurologic side effects if vincristine is administered to patients who have had previous cytotoxic drug therapy or irradiation and in those with pre-existing neuromuscular disease (including sensory peripheral neuropathy and steroid induced myopathy), and also when other drugs with neurotoxic potential are being used. The neurotoxic effect of vincristine may be additive with other neurotoxic agents or increased by spinal cord irradiation and neurological disease. Care should also be taken in elderly patients, who may be more susceptible to neurotoxicity (see Section 4.2 Dose and Method of Administration).

Respiratory.

Acute shortness of breath and severe bronchospasm have 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 and may require aggressive treatment, particularly when there is pre-existing pulmonary dysfunction. The onset of these reactions may be within minutes or several hours after the vinca is administered and may occur up to 2 weeks following the dose of mitomycin. Progressive dyspnoea requiring chronic therapy may occur. Vincristine should not be readministered.

Optic.

Care should be taken to avoid accidental contamination of the eyes, because vincristine is highly irritant and can cause corneal ulceration. The eyes should be washed with water immediately and thoroughly.

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.

Because of the hepatic metabolism and biliary excretion of vincristine, a dosage reduction may be required in patients with liver disease or jaundice. 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 4.2 Dose and Method of Administration.

Paediatric use.

No data available.

Effects on laboratory tests.

Because dose limiting clinical toxicity is manifested as neurotoxicity, clinical evaluation (e.g. history, physical examination) is necessary to detect the need for dosage modification. Following administration of vincristine sulfate, 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 (see Section 4.8 Adverse Effects (Undesirable Effects)). 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. Liver function tests are therefore recommended when vincristine therapy is initiated and at periodic intervals during therapy, depending on the patient's clinical state, the dosage used and any 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 asparaginase (see Section 4.2 Dose and Method of Administration), isoniazid and other medicines acting on the peripheral nervous system.

Doxorubicin.

The concurrent use of doxorubicin with vincristine and prednisone may produce increased myelosuppression; it is recommended that the 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 CSF occurred when vincristine was given 23 hours after high dose methotrexate therapy was initiated. The effect lasted approximately 3 hours.

Vaccines.

Because normal defence mechanisms may be suppressed by vincristine sulfate therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, and 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 may also be decreased. Immunisation of a patient who is receiving or who has received vincristine should be undertaken only with extreme caution after careful review of the patient's haematologic status and only with the knowledge and consent of the physician managing the 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.

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.

Phenytoin.

The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included vincristine sulfate has been reported to reduce blood levels of the anticonvulsant and to increase seizure activity. Dosage adjustment should be based on serial blood level monitoring. The contribution of vincristine sulfate 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.

Nifedipine.

Nifedipine decreases the clearance of vincristine.

CYP 3A4 inhibitors/inducers.

Vincristine should be administered cautiously with drugs which inhibit or induce the cytochrome P450 isoenzyme CYP3A, as these drugs may decrease or increase vincristine metabolism, thereby increasing its toxicity. Concurrent administration with itraconazole or fluconazole (known inhibitors of this metabolic pathway) have been reported to cause an earlier onset and/or increased severity of neuromuscular side effects. This interaction is presumed to be related to inhibition of vincristine metabolism. Inducers like St. John's wort should be given cautiously.

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.

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 the treatment of vincristine sulfate for malignant disease has not been studied in humans. Clinical reports of both male and female patients who have received multiple agent chemotherapy that included vincristine indicate that azoospermia and amenorrhoea can occur in post pubertal 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. When pregnant mice and hamsters were given doses of vincristine sulfate that caused resorption of 23% to 85% of fetuses, fetal malformations were produced in those that survived. Five monkeys were given single doses of vincristine sulfate between days 27 and 34 of their pregnancies; 3 of the fetuses were normal at term, and 2 viable fetuses had grossly evident malformations at term. In several animal species, vincristine sulfate can induce teratogenesis as well as embryo death with doses that are non-toxic 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 apprised 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 breastfeed 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)

Prior to the use of vincristine, patients and or parents/ guardians should be advised of the possibility of untoward symptoms.
In general, adverse effects are reversible and are related to dosage. The most common adverse effect is hair loss; the most troublesome adverse effects 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 following adverse effects have been reported:

Immune system disorders.

Rare cases of allergic type reactions, such as anaphylaxis, rash, oedema and angioedema, that are temporarily related to vincristine therapy, have been reported in patients receiving vincristine as a part of multidrug chemotherapy regimens.

Gastrointestinal disorders.

Autonomic toxicity such as 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.
Paralytic ileus (which mimics the 'surgical abdomen') may occur, particularly in young children and in the elderly. The ileus will reverse itself with temporary discontinuance of vincristine and with symptomatic care.
Nausea, vomiting, diarrhoea, anorexia, stomatitis, oral ulceration, intestinal necrosis and/or perforation, abdominal cramps and abdominal distension occur occasionally.

Hepatobiliary disorders.

Veno-occlusive liver disease has been reported, especially in children.

Renal and urinary disorders.

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). Allopurinol may be preferred to minimise hyperuricaemia, because of the risk of uric acid nephropathy with uricosuric antigout agents.
Polyuria, oliguria, nocturia, dysuria, and urinary retention due to bladder atony have occurred. Other drugs known to have caused urinary retention (particularly in the elderly) should, if possible, be discontinued for the first few days following administration of vincristine sulfate. Increased urinary retention is especially likely to occur in elderly male patients with varying degrees of obstructive uropathy. Urinary incontinence has also been reported.

Cardiac and vascular disorders.

Hypertension and hypotension have occurred. Chemotherapy combinations that have included vincristine sulfate, when given to patients previously treated with mediastinal radiation, have been associated with coronary artery disease and myocardial infarction. Causality has not been established. Thromboembolism has been reported when bleomycin has been administered with vinca alkaloids and other agents such as cisplatin or etoposide; such combinations have also been implicated in producing Raynaud's syndrome.

Nervous system disorders.

Neurotoxicity is the most common dose limiting side effect of vincristine. Frequently, there is a sequence to the development of neuromuscular side effects. Initially, only sensory impairment and paraesthesia may be encountered. With continued treatment, neuritic pain and, later, motor difficulties may occur. There have been no reports made of any agent that can reverse the neuromuscular manifestations that may accompany therapy with vincristine. Vincristine may exacerbate the signs and symptoms in patients with pre-existing neurological disorders. Consideration should be given to discontinuing treatment if neuromuscular effects continue to be a problem.
Loss of deep tendon reflexes, foot drop, wrist drop, ataxia, and paralysis have been reported with continued administration. Cranial nerve manifestations, including isolated paresis and/or paralysis of muscles controlled by cranial motor nerves, may occur in the absence of motor impairment elsewhere; extra-ocular and laryngeal muscles are those most commonly involved. Numbness of the fingers and toes, atrophy, cramps, slapping gait, and difficulty in walking or inability to walk, may occur. Jaw pain, pharyngeal pain, salivary gland pain, bone pain, back pain, limb pain, testicular pain and myalgias have been reported; pain in these areas may be severe. Convulsions, frequently with hypertension, have been reported in a few patients receiving vincristine sulfate. Several instances of convulsions followed by coma have been reported in children.
Sympathetic neuropathy may occur. Peripheral neuritis and neuralgia occur frequently.
Peroneal nerve palsy (manifesting as foot drop and slapping gait), areflexia, nerve injury have been reported.
Treatment with vinca alkaloids has resulted very rarely (< 0.01%) in vestibular and auditory damage to the eighth cranial nerve. Manifestations include partial or total deafness, which may be permanent or temporary, and difficulties with balance including dizziness, nystagmus and vertigo. Vincristine should only be used concurrently with other potentially ototoxic drugs, such as the platinum containing antineoplastic agents, with extreme caution.
Patients with existing neurological disorders such as poliomyelitis or Charcot-Marie-Tooth syndrome may be at increased risk of neurotoxicity.

Psychiatric disorders.

Depression, agitation, insomnia, hallucinations and altered state of consciousness have been reported.

Eye disorders.

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

Respiratory, thoracic and mediastinal disorders.

Oropharyngeal pain, acute respiratory distress syndrome and bronchospasm can occur (see Section 4.4 Special Warnings and Precautions for Use).

Endocrine, metabolism and nutrition disorders.

Hypersecretion of antidiuretic hormone (SIADH) has occurred rarely 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. Decreased appetite is also very common.

Blood and lymphatic system disorders.

Vincristine sulfate does not appear to have any constant or significant effect on platelets or red blood cells. Serious bone marrow depression is usually not a major dose limiting event.
However, anaemia, leucopenia and thrombocytopenia have been reported.
Thrombocytopenia, if present when therapy with vincristine is begun, may actually improve before the appearance of bone marrow remission. Granulocytopenia can also occur.

Skin and subcutaneous tissue disorders.

Alopecia is reported to occur in about 20% to 70% of patients who receive vincristine. It is reversible when vincristine is discontinued. Rash has also been reported, as have photosensitivity reactions.
Vincristine may cause a severe local reaction, resulting in pain and cellulitis, on extravasation (see Section 4.4 Special Warnings and Precautions for Use).

Other.

Fever and headache have occurred. Also, other side effects include defective sweating, myoclonic jerks, abnormal Valsalva response, impotence and diminished libido. Weight loss has been reported at high doses.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs and symptoms.

Overdosage with vincristine produces adverse reactions that are mainly extensions of the common adverse effects as these are dose related. As no antidote for vincristine has been found to date, treatment is purely supportive and symptomatic.
In children under 13 years of age, death has occurred following doses of vincristine that were ten 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 (see Section 4.8 Adverse Effects (Undesirable Effects)).

Treatment.

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 GI tract may be necessary). Routine monitoring of the cardiovascular system is also recommended together with daily blood counts as an indicator for transfusion requirements.
Folinic acid has been observed to have a protective effect in normal mice which were administered lethal doses of vincristine sulfate. Isolated 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. Theoretically, based on pharmacokinetic data, tissue levels of vincristine can be expected to remain significantly elevated for at least 72 hours. Treatment with folinic acid does not eliminate the need for the above-mentioned supportive measures.
Most of the intravenous dose of vincristine sulfate is excreted into the bile after rapid tissue binding (see Section 5.2 Pharmacokinetic Properties). Because only very small amounts of the drug appear in dialysate, haemodialysis is not likely to be helpful in cases of overdosage. 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.
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.

The precise mechanism of action of vincristine sulfate remains under investigation. It appears to bind to or crystallise critical microtubular proteins of the mitotic spindle, thus preventing their proper polymerisation and causing metaphase arrest. The antineoplastic effects of the vinca alkaloids are related to their ability to bind specifically with the intracellular protein tubulin, a key component of cellular microtubules.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Distribution.

Distribution of vincristine and its metabolites into human body tissue and fluids has not been fully characterised, but the drug is rapidly and apparently widely distributed following intravenous administration.
Vincristine sulfate is extensively protein bound (75%) and is reported to be concentrated in blood platelets. Within 15 to 30 minutes after intravenous administration, over 90% of the drug is distributed from the blood into tissue, where it remains tightly, but not irreversibly, bound.
Vincristine sulfate and its metabolites are rapidly and extensively distributed into bile, with peak biliary concentrations occurring within 2 to 4 hours after rapid intravenous administration.
Central nervous system leukaemia has been reported in patients undergoing otherwise successful therapy with vincristine sulfate. This suggests that vincristine sulfate does not penetrate well into cerebrospinal fluid.

Excretion.

Pharmacokinetic studies in patients with cancer have shown a triphasic serum decay pattern following rapid intravenous administration. The initial, middle, and terminal half-lives are 5 minutes, 2.3 hours and 85 hours, respectively; however, the range of the terminal half-life in humans is from 19 to 155 hours.
The liver is the major excretory organ in humans and animals; about 80% of an intravenous dose of vincristine sulfate appears in the faeces and 10% to 20% can be found in the urine.

5.3 Preclinical Safety Data

Genotoxicity.

Neither in vivo nor in vitro laboratory tests have conclusively demonstrated the mutagenicity of vincristine sulfate. 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.

Patients who receive vincristine sulfate chemotherapy in combination with anticancer drugs known to be carcinogenic have developed second malignancies. The contributing role of vincristine sulfate in this development has not been determined. 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 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 injection or 5% glucose injection.

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 can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2 to 8°C. (Refrigerate. Do not freeze.) Protect from light.

6.5 Nature and Contents of Container

DBL Vincristine Sulfate Injection is available in clear Type 1 glass vials with Type 1888 rubber closures in the following presentations (see Table 1).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.
If spill occurs, restrict access to the affected area. Wear two pairs of latex rubber gloves, a suitable mask, a protective gown and safety glasses. Limit the spread of the spill by covering with a suitable material such as absorbent towels or adsorbent granules. Spills may also be treated with 5% sodium hypochlorite. Collect the absorbent/ adsorbent and other debris from the spill and place in a leakproof plastic container and label accordingly. Cytotoxic waste should be regarded as toxic and hazardous and clearly labelled 'Cytotoxic waste for incineration at 1100°C'. Waste material should be incinerated at 1100°C for at least 1 second. Clean the remaining spill area with copious amounts of water.

6.7 Physicochemical Properties

Chemical structure.

Vincristine sulfate, the salt of an alkaloid obtained from the periwinkle plant (Catharanthus roseus).
The chemical structure of vincristine sulfate is:
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