Consumer medicine information

Vinorelbine Ebewe

Vinorelbine

BRAND INFORMATION

Brand name

Vinorelbine Ebewe

Active ingredient

Vinorelbine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Vinorelbine Ebewe.

SUMMARY CMI

Vinorelbine Ebewe®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Vinorelbine Ebewe?

Vinorelbine Ebewe contains the active ingredient vinorelbine tartrate. Vinorelbine Ebewe is used to treat lung cancer and advanced breast cancer. For more information, see Section 1. Why am I using Vinorelbine Ebewe? in the full CMI.

2. What should I know before I use Vinorelbine Ebewe?

Do not use if you have ever had an allergic reaction to vinorelbine or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Vinorelbine Ebewe? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Vinorelbine Ebewe and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Vinorelbine Ebewe?

Vinorelbine Ebewe is given as a slow infusion (drip) into your veins. Vinorelbine Ebewe must only be given by a doctor or nurse.

More instructions can be found in Section 4. How do I use Vinorelbine Ebewe? in the full CMI.

5. What should I know while using Vinorelbine Ebewe?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Vinorelbine Ebewe.
  • Keep all appointments with your doctor to check on your progress and monitor side effects.
  • If you become pregnant while taking Vinorelbine Ebewe, tell your doctor immediately.
Things you should not do
  • You should not breast-feed while you are being treated with Vinorelbine Ebewe.
  • Do not use if you have or have had an infection or high temperature in the last 2 weeks.
  • Do not use if you are currently receiving radiation therapy.
  • Do not use if you have recently had a yellow fever vaccination or plan to have one.
  • Do not use if you have severe liver problems or if you have a reduced number of platelets of red blood cells.
Driving or using machines
  • Be careful driving or operating machinery until you know how Vinorelbine Ebewe affects you.
Drinking alcohol
  • Fatigue is a common side effect of Vinorelbine Ebewe. Drinking alcohol may make the tiredness worse.
Looking after your medicine
  • If you are storing Vinorelbine Ebewe at home:
  • Store Vinorelbine Ebewe in the refrigerator (2 to 8°C). Do not freeze it.
  • Keep away from light and where children cannot reach

For more information, see Section 5. What should I know while using Vinorelbine Ebewe? in the full CMI.

6. Are there any side effects?

Common side effects include nausea, vomiting, diarrhoea, unusual tiredness, weakness, sleepiness, drowsiness or lack of energy, unusual hair loss, constipation, aching muscles, chest pain, jaw pain, painful swollen joints, injection site reactions, shortness of breath and high or low blood pressure.

Serious side effects include difficulty breathing, pain in bladder or back, blood in urine, chest pain, fast or irregular heartbeat, rash, itching or hives on the skin, swelling of the feet and ankles, face, lips, tongue or other parts of the body. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Vinorelbine Ebewe®

Active ingredient(s): Vinorelbine tartrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Vinorelbine Ebewe. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Vinorelbine Ebewe.

Where to find information in this leaflet:

1. Why am I using Vinorelbine Ebewe?
2. What should I know before I use Vinorelbine Ebewe?
3. What if I am taking other medicines?
4. How do I use Vinorelbine Ebewe?
5. What should I know while using Vinorelbine Ebewe?
6. Are there any side effects?
7. Product details

1. Why am I using Vinorelbine Ebewe?

Vinorelbine Ebewe contains the active ingredient vinorelbine tartrate. Vinorelbine belongs to a family of medicines called vinca alkaloids.

Vinorelbine Ebewe belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these medicines being called chemotherapy.

Vinorelbine Ebewe is used treat lung cancer and advanced breast cancer.

Vinorelbine Ebewe may be used on its own or in combination with other medicines to treat cancer. Vinorelbine Ebewe works by stopping cancer cells from growing and multiplying causing the cells to die.

2. What should I know before I use Vinorelbine Ebewe?

Warnings

Do not use Vinorelbine Ebewe if:

  • you are allergic to vinorelbine, or to the other vinca alkaloids, (vinblastine, vincristine, vindesine, vinflunine); or to any of the ingredients listed at the end of this leaflet. Symptoms of an allergic reaction to Vinorelbine Ebewe may include:
    - shortness of breath
    - wheezing, difficulty breathing or a tight feeling in your chest
    - swelling of the face, lips, tongue or other parts of the body
    - rash, itching, hives or flushed, red skin
    - dizziness or lightheadedness
  • you have or have had an infection or high temperature in the last 2 weeks. Your doctor may decide to delay your treatment until the infection has gone.
  • you have recently had a yellow fever vaccination or plan to have one.
  • you are currently receiving radiation therapy to your liver.
  • you have, or had any of the following medical conditions:
    - severe liver problems
  • a reduced number of white blood cells (known as neutropenia) which you may notice as frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • a reduced number of platelets (blood cells which help the blood to clot) which you may notice as bleeding or bruising more easily than normal.

Check with your doctor if you:

  • have allergies to any other medicines or substances, such as foods, preservatives or dyes
  • if you have, or have had, any of the following medical conditions:
    - heart problems (including chest pain and heart attack)
    - liver problems
    - a low white blood cell count which you may notice as signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers
    - lung problems, including asthma take any medicines for any other condition or treatments for cancer, including radiation therapy. Vinorelbine Ebewe must not be administered if you are currently receiving radiation therapy to your liver.
  • if you have recently had or plan to have a vaccination. Live attenuated vaccines (eg. measles vaccine, mumps vaccine, rubella vaccine) are not recommended while having Vinorelbine Ebewe.

Vinorelbine Ebewe is a potent cytotoxic drug that results in a decrease in blood cells. Your blood count will be carefully monitored before and during your treatment.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Vinorelbine Ebewe should not be administered if you are pregnant or intend to become pregnant.

Check with your doctor if you are pregnant or intend to become pregnant.

Like most medicines used to treat cancer, Vinorelbine Ebewe is not recommended for use during pregnancy.

Vinorelbine Ebewe may affect your developing baby if you take it during pregnancy.

If you are a fertile man or woman, you should use an effective method of contraception during your treatment with Vinorelbine Ebewe for three months after your last dose of Vinorelbine Ebewe.

Men being treated with Vinorelbine Ebewe are advised not to father a child during and up to a minimum of 3 months after treatment. Prior to treatment, men are advised to seek advice on conserving sperm due to the chance of irreversible fertility resulting from treatment with Vinorelbine Ebewe.

If there is a need to consider Vinorelbine Ebewe during your pregnancy, your doctor will discuss with you the benefits and risks of using it.

Do not breastfeed while being treated with Vinorelbine Ebewe.

Vinorelbine Ebewe may pass into breast milk and therefore there is a possibility that the breast-fed baby may be affected.

Talk to your doctor if you are breastfeeding or intend to breastfeed. Do not breastfeed while being treated with Vinorelbine Ebewe.

Use in Children

Vinorelbine Ebewe is not recommended for use in children as there is no information on its effects in children.

3. What if I am taking other medicines?

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

Some medicines may interfere with Vinorelbine Ebewe and affect how it works. These include:

  • medicines used to prevent blood clots (anticoagulants) eg. phenindione, warfarin, heparin
  • phenytoin, a medicine used to treat epilepsy
  • cyclosporin, tacrolimus, medicines which lower your immunity
  • itraconazole and ketoconazole, medicines used to treat fungal infections
  • mitomycin, lapatinib, medicines used to treat cancer
  • medicines with known bone marrow toxicity (causing a reduced number of red or white blood cells or platelets)
  • other medicines used to treat cancer such as cisplatin
  • ritonavir, a medicine used to treat AIDS
  • rifampicin, a medicine used to treat tuberculosis.

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

Your doctor and pharmacist may have more information on medicines to be careful with or to avoid while having Vinorelbine Ebewe.

If you have not told your doctor about any of the above, do so before you begin treatment with Vinorelbine Ebewe.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Vinorelbine Ebewe.

4. How do I use Vinorelbine Ebewe?

How much to take

  • Your doctor will decide what dose you will receive. This depends on your body surface area, your condition and factors such as your liver function and whether you are receiving any other chemotherapy medicines. Your doctor may adjust your dose during treatment.
  • Vinorelbine Ebewe may be given alone or in combination with other drugs.
  • Several courses of Vinorelbine Ebewe therapy may be needed depending on your response to treatment.
  • Vinorelbine Ebewe reduces the number of white blood cells in the body. Your doctor will check these levels regularly. Further doses of Vinorelbine Ebewe may be delayed until your blood cell numbers return to acceptable levels.

How to use Vinorelbine Ebewe

  • Vinorelbine Ebewe is given as a slow infusion (drip) into your veins.
  • Vinorelbine Ebewe must only be given by a doctor or nurse.

How to long to use Vinorelbine Ebewe

Vinorelbine Ebewe is usually given every week, but it may be given less often if you are also having other medicines to treat cancer. Your doctor will decide how many doses you will need.

If you forget to use Vinorelbine Ebewe

Tell your doctor as soon as possible if you realise that you have missed an appointment for receiving your dose of Vinorelbine Ebewe.

If you have problems remembering when your next dose is due, use a diary or calendar or ask a friend to remind you.

If you use too much Vinorelbine Ebewe

As Vinorelbine Ebewe 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 side effects while or after being given Vinorelbine Ebewe, tell your doctor, nurse, or pharmacist.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Vinorelbine Ebewe?

Things you should do

  • Tell your doctor or nurse immediately if you feel any pain or discomfort during the infusion.
  • Keep all appointments with your doctor. Your doctor may want to do some blood and other tests from time to time to check on your progress and monitor any unwanted side effects.
  • Keep follow up appointments with your doctor. It is important to have your follow-up doses of Vinorelbine Ebewe at the appropriate times to get the best effects from your treatments.
  • If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are having treatment with Vinorelbine Ebewe.
  • If you become pregnant while taking Vinorelbine Ebewe, tell your doctor immediately.
  • Vinorelbine Ebewe can lower the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding.
    Take the following precautions to reduce your risk of infection or bleeding:
    - Check with your doctor immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, lower back or side pain or find it painful or difficult to urinate;
    - Avoid people who have infections.
    - Be careful when using a toothbrush, toothpick or dental floss. Your doctor, dentist, nurse or pharmacist may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work.
    - Be careful not to cut yourself when you are using sharp objects such as a razor or nail cutters.
    - Avoid contact sports or other situations where you may bruise or get injured.

Call your doctor straight away if you:

  • are feeling unwell after taking Vinorelbine Ebewe.

Remind any doctor, dentist or pharmacist you visit that you are having treatment with Vinorelbine Ebewe.

Things you should not do

  • You should not breast-feed while you are being treated with Vinorelbine Ebewe. Breastfeeding must be discontinued before starting treatment with Vinorelbine Ebewe.
  • Men being treated with Navelbine IV are advised not to father a child during and up to a minimum of 3 months after treatment. Prior to treatment, men are advised to seek advice on conserving sperm due to the chance of irreversible fertility resulting from treatment with Vinorelbine Ebewe.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Vinorelbine Ebewe affects you.

If you experience symptoms that affect your ability to concentrate and react, do not drive a car or operate machinery. Fatigue is a common side effect of Vinorelbine Ebewe. Make sure you know how Vinorelbine Ebewe affects you before you drive a car, operate machinery or do anything else that could be dangerous if you are feeling tired.

Drinking alcohol

Tell your doctor if you drink alcohol.

Drinking alcohol may make the tiredness worse.

Looking after your medicine

Vinorelbine Ebewe is usually stored in the hospital, or at the pharmacy. However, if you are storing at home:

  • Store Vinorelbine Ebewe in the refrigerator (2 to 8°C).
    Do not freeze it.
  • Protect Vinorelbine Ebewe from light

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If your doctor stops your treatment with Vinorelbine Ebewe, or it has passed its expiry date, return any leftover vials to your pharmacist. Do not dispose of Vinorelbine Ebewe via wastewater or household waste. This will help to protect the environment.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Pain related
  • aching muscles, muscle tenderness or weakness, not caused by exercise
  • pain, including pain at the tumour site
  • jaw pain
  • painful swollen joints
Skin related
  • skin rash
  • unusual hair loss or thinning
Head and neurology related
  • unusual tiredness, weakness, sleepiness, drowsiness or lack of energy
Gastrointestinal/Gut related
  • nausea
  • vomiting
  • diarrhoea
  • constipation
  • upset stomach
Infection related
  • fever
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Breathing problems
  • difficulty breathing, short of breath
  • breathlessness, which may be very severe and usually worse on lying down
Head and neurology related
  • tiredness, headaches, being short of breath when exercising, dizziness and looking pale (symptoms of a decreased number of red blood cells)
  • numbness + tingling of fingers and toes
  • lack of muscle control, which may be associated with abnormal gait, and speech changes
  • weakness of legs or feet
Infection related
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers (symptoms of a lack of white blood cells)
  • sore mouth
Bleeding related
  • bleeding or bruising more easily than normal or nosebleeds (symptoms of a low blood platelet count)
  • blood infection (sepsis) with symptoms such as a high fever and deterioration in general health
Eye problems
  • changes in your vision
Gastrointestinal/ Gut problems
  • stomach pain with bloating, gut cramps and vomiting which may be symptoms of the small bowel not working properly
  • severe upper stomach pain
Skin related
  • irritation, pain, swelling or colouring of the skin around the needle or along the vein during the infusion
Liver disease related
  • weakness, tiredness, loss of appetite, weight loss or stomach pain that may be symptoms of liver disease.
Urinary related
  • pain or burning feeling when passing urine
  • pain in bladder or back, blood in urine
Heart related
  • chest pain
  • palpitations, fast or irregular heart beat
  • severe chest pain which is not normal for you, the symptoms may be due to disturbance in the heart function following insufficient blood flow, so called ischemic heart disease such as for example angina pectoris and myocardial infarction (sometimes with fatal outcome)
Allergy related
  • rash, itching or hives on the skin swelling of the feet and ankles, face, lips, tongue or other parts of the body.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What Vinorelbine Ebewe contains

Active ingredient
(main ingredient)		Vinorelbine tartrate
Other ingredients
(inactive ingredients)
  • water for injections
  • nitrogen

Vinorelbine Ebewe does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Vial stopper is not made with natural rubber latex.

Do not take this medicine if you are allergic to any of these ingredients.

What Vinorelbine Ebewe looks like

Vinorelbine Ebewe - clear, colourless to pale yellow solution. It comes in a clear glass vial with a rubber stopper and a cap. Each vial is packed in a carton.

10 mg in 1 mL injection (Aust R 126693) (vial)

50 mg in 5 mL injection (Aust R 99724) (vial)

Who distributes Vinorelbine Ebewe

Sandoz Pty Ltd
100 Pacific Highway
North Sydney, NSW 2060
Tel: 1800 726 369

This leaflet was revised in November 2024.

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Vinorelbine Ebewe

Active ingredient

Vinorelbine

Schedule

S4

 

1 Name of Medicine

Vinorelbine tartrate.

2 Qualitative and Quantitative Composition

1 mL of Vinorelbine Ebewe contains 13.85 mg of vinorelbine tartrate (equivalent to 10 mg vinorelbine).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Vinorelbine Ebewe is available as a concentrated injection for intravenous use.
Vinorelbine Ebewe is a clear, colourless to pale yellow solution in a clear glass vial.

4 Clinical Particulars

4.1 Therapeutic Indications

Vinorelbine Ebewe is indicated for the treatment of advanced breast cancer after failure of standard therapy, as a single agent or in combination; and as first line treatment for advanced non-small cell lung cancer, as a single agent or in combination.

4.2 Dose and Method of Administration

Dosage.

Adults.

Single agent treatment is usually given at 25 - 30 mg/m2 weekly.
In combination chemotherapy, the dose may be the same and the frequency of administration reduced, i.e. days 1 and 8 or days 1 and 5 every three weeks.

Method of administration.

Vinorelbine Ebewe should be administered either by slow bolus over 6 to 10 minutes after dilution in 50 mL of a normal saline solution or by a short infusion over 20 to 30 minutes after dilution in 125 mL of normal saline solution. Administration should always be followed by at least 250 mL normal saline infusion to flush the vein and prevent phlebitis. Vinorelbine Ebewe is a moderate vesicant. Insertion of a central venous line may be necessary (see Section 4.8 Adverse Effects (Undesirable Effects)).

Caution.

Vinorelbine Ebewe must only be administered intravenously through an infusion line. It is extremely important that the intravenous needle or catheter be properly positioned before any vinorelbine is injected. Leakage into surrounding tissue during intravenous administration of Vinorelbine Ebewe may cause considerable irritation, local tissue necrosis and/or thrombophlebitis.
If extravasation occurs, the injection should be discontinued immediately, and any remaining portion of the dose should then be introduced into another vein. Since there are no established guidelines for the treatment of extravasation injuries with vinorelbine, institutional guidelines may be used.
As with other toxic compounds, caution should be exercised in handling and preparation of the solution of Vinorelbine Ebewe. Skin effects may occur with accidental exposure. The use of gloves is recommended. If the solution of Vinorelbine Ebewe contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water. Severe irritation of the eyes has been reported with accidental contamination of the eye with another vinca alkaloid. If this happens with Vinorelbine Ebewe, the eye should be flushed with water immediately and thoroughly.
Procedures for proper handling and disposal of anticancer medicines should be used. Several guidelines on this subject have been published.
Vinorelbine Ebewe injection is a clear, colourless to pale yellow solution. Parenteral medicine products should be visually inspected for particulate matter and discolouration prior to administration whenever solution and container permit. If particulate matter is seen, Vinorelbine Ebewe should not be administered.
Vinorelbine Ebewe is for intravenous use by infusion only. Fatal if given by any other route.

Preparation for administration.

Vinorelbine Ebewe injection must be diluted in either a syringe or intravenous bag using one of the recommended solutions. The volume of dilution depends on the mode of administration: 50 mL for a bolus injection; 125 mL for an infusion.
Administration of Vinorelbine Ebewe must be followed by infusion of at least 250 mL of one of the recommended solutions.
Diluted Vinorelbine Ebewe is chemically and physically stable for up to 24 hours under normal room light below 30°C when stored in polypropylene syringes, polyvinyl chloride bags and clear glass vials. However, to reduce microbiological hazard, use as soon as practicable after dilution. If storage is necessary, hold at 2°C to 8°C for not more than 24 hours.

Syringe.

The calculated dose of Vinorelbine Ebewe should be diluted to a concentration between 1.5 and 3.0 mg/mL. The following solutions may be used for dilution: Glucose 5% Injection USP and Sodium Chloride 0.9% Injection USP.

Intravenous bag.

The calculated dose of Vinorelbine Ebewe should be diluted to a concentration between 0.5 and 2 mg/mL. The following solutions may be used for dilution: Glucose 5% Injection USP; Sodium Chloride 0.9% Injection USP; Sodium Chloride 0.45% Injection USP; Glucose 5% and Sodium Chloride 0.45% Injection USP; Ringer's Injection USP and Lactated Ringer's Injection (Compound Sodium Lactate Injection) USP.
After diluting Vinorelbine Ebewe in normal saline or glucose solution, the shelf-life in the clear glass vials or in PVC perfusion bags is 24 hours at storage below 30°C.
To reduce microbiological hazard, use as soon as practicable after preparation. If storage is necessary, hold at 2 to 8°C for not more than 24 hours.
Vinorelbine Ebewe contains no antimicrobial agent. Product is for single use in one patient only. Discard any residue.
As with all parenteral medicine products, intravenous admixtures should be inspected visually for clarity, particulate matter, discolouration and leakage prior to administration, whenever solution and container permit. If particulate matter, discolouration or leakage is seen, the admixture should not be used.

Pharmaceutical precautions.

The following protective recommendations are given due to toxic nature of this substance:
personnel should be trained in good technique for handling;
pregnant staff should be excluded from working with this medicine;
personnel handling Vinorelbine Ebewe should wear protective clothing: goggles, gowns and disposable gloves and masks;
a designated area should be defined for reconstruction (preferably under a laminar flow containment system). The work surface should be protected by disposable plastic backed absorbent paper;
all items used for administration of cleaning, including gloves should be placed in high risk, waste disposable bag for high temperature incineration;
spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water;
all cleaning materials should be disposed of as indicated previously;
accidental contact with the eyes or skin should be treated immediately. Copious lavage with water is appropriate treatment for contact with eyes, whereas water or soap and water, or sodium bicarbonate solution may be used on the skin; medical attention should be sought.

Dosage adjustment.

Haematological toxicity.

Neutrophil counts should be ≥ 1 x 109 cells/L prior to the administration of Vinorelbine Ebewe. Adjustments in the dosage of Vinorelbine Ebewe should be based on neutrophil counts obtained on the day of treatment (see Table 1).

Hepatic impairment.

Vinorelbine Ebewe should be administered with caution to patients with hepatic insufficiency. In patients who develop hyperbilirubinaemia during treatment with Vinorelbine Ebewe, the dose should be adjusted on the basis of total bilirubin, as a measure of hepatic function (see Table 2).
For patients with both haematological toxicity and hepatic insufficiency, the lower of the doses listed above should be administered.

4.3 Contraindications

Known hypersensitivity to vinorelbine or to any of the excipients or to other vinca alkaloids.
Neutrophil counts < 1,500 cells/mm3 or severe infection, current or recent (within 2 weeks).
Platelet count < 100,000/mm3.
Severe hepatic insufficiency.
Pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Lactation (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).
In combination with yellow fever vaccine (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Administration.

Vinorelbine is for intravenous use by infusion only. Fatal if given by any other route.
Vinorelbine injection should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Vinorelbine Ebewe must only be administered by the intravenous route. Intrathecal administration of other vinca alkaloids has resulted in death. Improper administration of Vinorelbine Ebewe may result in extravasation causing local tissue necrosis and/or thrombophlebitis (see Section 4.2 Dose and Method of Administration, Caution).

Myelosuppression.

Since inhibition of the hematopoietic system is the main risk associated with vinorelbine, patients treated with vinorelbine should be frequently monitored for myelosuppression both during and after therapy, with determination of haemoglobin level and the leukocyte, neutrophil and platelet counts on the day of each new administration.
Neutropenia is dose limiting. Neutrophil nadirs occur between 5 and 10 days after dosing, depending on whether vinorelbine is used as single agent or in combination, with neutrophil count recovery usually within 7 to 14 days after administration. Complete blood counts with differentials should be performed and results reviewed prior to administering each dose of Vinorelbine Ebewe. Vinorelbine Ebewe should not be administered to patients with neutrophil counts < 1,500 cells/mm3. Patients developing severe neutropenia should be monitored carefully for evidence of infection and/or fever.
If patients present signs or symptoms suggestive of infection, a prompt investigation should be carried out (see Section 4.2 Dose and Method of Administration, Dose adjustment, Haematological toxicity).
Vinorelbine Ebewe should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy, or whose marrow function is recovering from the effects of previous chemotherapy (see Section 4.2 Dose and Method of Administration).

Respiratory system, thoracic and mediastinal disorders.

Pulmonary toxicity, including severe acute bronchospasm, interstitial pneumonitis, acute respiratory distress syndrome (ARDS) occurring with use of Vinorelbine Ebewe intravenous pharmaceutical form has been reported. The mean time to onset of ARDS after vinorelbine administration was one week (range 3 to 8 days).
The infusion must be immediately interrupted in patients who develop unexplained dyspnoea or have any evidence of pulmonary toxicity. Vinorelbine Ebewe must be permanently discontinued for confirmed interstitial pneumonitis.

Nervous system disorders.

Peripheral neuropathy.

The effects are dose dependent but usually reversible when treatment is discontinued.

Autonomic neuropathy.

Treatment may be resumed after recovery of normal bowel motility.

General.

Most medicine related adverse events of vinorelbine are reversible. If severe adverse events occur, Vinorelbine Ebewe should be reduced in dosage or discontinued and appropriate corrective measures taken. Reinstitution of therapy with vinorelbine should be carried out with caution and alertness as to possible recurrence of toxicity.
Special care should be taken when prescribing for patients with a history of ischaemic heart disease. Patients presenting with ischaemic cardiac disease should be carefully monitored (see Section 4.8 Adverse Effects (Undesirable Effects)).
This product is specifically contra-indicated with yellow fever vaccine and its concomitant use with other live attenuated vaccines is not recommended.
Acute shortness of breath and severe bronchospasm have been reported infrequently following the administration of vinorelbine and other vinca alkaloids, most commonly when the vinca alkaloid was used in combination with mitomycin. These adverse events may require treatment with supplemental oxygen, bronchodilators, and/or corticosteroids, particularly when there is a pre-existing pulmonary dysfunction.
Care must be taken to avoid contamination of the eye with concentrations of vinorelbine used clinically. Severe irritation of the eye has been reported with accidental exposure to another vinca alkaloid, and even corneal ulceration if the medicine is sprayed under pressure. If exposure occurs, the eye should immediately be thoroughly flushed with water or sodium chloride 9 mg/mL (0.9%) solution for injection.
Vinorelbine Ebewe should not be given concomitantly with radiotherapy if the treatment field includes the liver.
Caution must be exercised when combining vinorelbine and strong inhibitors or inducers of CYP3A4 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Interactions specific to vinorelbine), and its combination with phenytoin (like all cytotoxics) and with itraconazole (like all vinca alkaloids) is not recommended.
Interstitial lung disease has been reported more frequently in the Japanese population.

Use in hepatic impairment.

There is no evidence that the toxicity of vinorelbine is enhanced in patients with elevated liver enzymes. No data are available for patients with severe baseline cholestasis, but the liver plays an important role in the metabolism of vinorelbine. Because clinical experience in patients with severe liver disease is limited, caution should be exercised when administering vinorelbine to patients with severe hepatic injury or impairment.

Use in renal impairment.

Because of the low level of renal excretion, no dose modification is necessary in patients with renal impairment (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

Clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Paediatric use.

Safety and effectiveness have not been established.

Effects on laboratory tests.

Since dose limiting clinical toxicity is the result of depression of the white blood cell count, it is imperative that complete blood counts with differentials be obtained and reviewed on the day of treatment prior to each dose of vinorelbine.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interactions common to all cytotoxics.

Due to the increase of thrombotic risk in case of tumoral diseases, the use of anticoagulative treatment is frequent. As the intra-individual variability of the coagulability during diseases, is high and there is the risk of interaction between oral anticoagulants and anticancer therapy, if the patient is treated with oral anticoagulants, increasing the frequency of INR (International Normalised Ratio) monitoring is recommended.
Concomitant use contraindicated.

Yellow fever vaccine.

Risk of fatal generalised vaccine disease (see Section 4.3 Contraindications).
Concomitant use not recommended.

Live attenuated vaccines.

Risk of generalised vaccine disease, possibly fatal. This risk is increased in patients already immunodepressed by their underlying disease. The use of an inactivated vaccine where one exists is recommended (e.g. poliomyelitis).

Phenytoin.

Risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic medicine or risk of toxicity enhancement or loss of efficacy of the cytotoxic medicine due to increased hepatic metabolism by phenytoin.
Concomitant use with caution.

Ciclosporin, tacrolimus.

Excessive immunodepression with risk of lymphoproliferation.

Interactions specific to vinca alkaloids.

Concomitant use not recommended.

Itraconazole.

Increased neurotoxicity of vinca alkaloids due to the decrease of their hepatic metabolism.
Concomitant use with caution.

Mitomycin.

Acute pulmonary effects have been reported with vinorelbine and other vinca alkaloids used in conjunction with mitomycin: risk of bronchospasm and dyspnoea are increased; in a rare case, an interstitial pneumonitis was observed. Vinorelbine should be administered with caution in combination with mitomycin.
As vinca alkaloids are known as substrates for P-glycoprotein, and in the absence of specific study, caution should be exercised when combining vinorelbine with strong modulators of this membrane transporter.

Interactions specific to vinorelbine.

The combination of vinorelbine with other medicines with known bone marrow toxicity is likely to exacerbate the myelosuppressive adverse effects.
Acute pulmonary effects have been reported with vinorelbine and other vinca alkaloids used in conjunction with mitomycin. The risk of bronchospasm and dyspnoea is increased, in rare case interstitial pneumonitis was observed. Vinorelbine Ebewe should be administered with caution in combination with mitomycin.
Although the pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin, the incidence of toxicities, specifically granulocytopenia, with the combination of vinorelbine and cisplatin is significantly higher than with single agent vinorelbine.
In studies with rats, the anticoagulant effect of phenindione was potentiated when given in combination with high doses of vinorelbine (30 mg/m2/day for 4 consecutive days or 15 mg/m2/day for 5 consecutive days) but combination treatment with sodium valproate did not cause any increase in anticonvulsant activity.
Vinorelbine is metabolised by cytochrome CYP3A4. Although interaction studies have not been performed, it is expected that inhibitors of CYP3A4 such as ketoconazole, itraconazole, ritonavir etc. would result in elevated blood concentrations of vinorelbine. Inducers of CYP3A4 such as rifampicin and phenytoin may reduce concentrations of vinorelbine. Since the magnitude of the inducing or inhibiting effects is unknown, such drug combinations should be avoided.
An increased incidence of grade 3/4 neutropenia has been suggested when intravenous vinorelbine and lapatinib were associated in one clinical phase I study. In this study, the recommended dose of intravenous form of vinorelbine in a 3-weekly schedule on day 1 and day 8 was 22.5 mg/m2 when combined with daily lapatinib 1000 mg. This type of combination should be administered with caution.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Adverse effects on the male reproductive system were observed in repeat dose toxicity studies in animals, including decreased spermatogenesis in rats dosed twice weekly at 2.1 - 7.2 mg/m2 for 13 weeks, reduced prostate/ seminal vesicle secretion in rats dosed twice weekly at 3 mg/m2 for 26 weeks, reduced testicular weight in mice dosed at 19 mg/m2/day for three 5 day cycles, and reduced epididymal weight in dogs dosed at 5 mg/m2 for 26 weeks. Vinorelbine tartrate did not affect fertility when administered to male and female rats prior to and during mating; however, the doses used in these studies (9 mg/m2 once weekly or up to 4.2 mg/m2 at 3-day intervals) were lower than the human dose.
Men being treated with vinorelbine are advised not to father a child during and minimally up to 3 months after treatment. Prior to treatment, advice should be sought for conserving sperm due to the chance of irreversible infertility as a consequence of treatment with vinorelbine.
(Category D)
Vinorelbine may cause foetal harm if administered to a pregnant woman. When given every three days during organogenesis, vinorelbine tartrate has been shown to be teratogenic in rats and rabbits at doses of 3 and 7.7 mg/m2, respectively. A single 9 mg/m2 dose of vinorelbine tartrate caused embryogenic deaths in mice. Doses causing adverse foetal effects in animals were lower than the human dose. There are no studies in pregnant women. If Vinorelbine Ebewe is used during pregnancy, or if the patient becomes pregnant while receiving this medicine, the patient should be apprised of the potential hazard to the foetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Vinorelbine Ebewe. Women of childbearing potential must use effective contraception during treatment and up to 3 months after treatment.
 It is not known whether vinorelbine is excreted in the milk of animals or humans. A study in rats showed that growth of the offspring was suppressed when vinorelbine tartrate was administered to lactating dams at 6 mg/m2 every three days. Because many medicines are excreted in human milk, and because of the potential for serious adverse effects in nursing infants from vinorelbine, breastfeeding must be discontinued before starting treatment with Vinorelbine Ebewe.

4.7 Effects on Ability to Drive and Use Machines

The effect of vinorelbine on the ability to drive and use machines has not been studied. However, patients should be advised not to drive or operate machinery if they experience any adverse reactions with a potential impact on their ability to perform these activities (e.g. dizziness and fatigue are common).

4.8 Adverse Effects (Undesirable Effects)

Adverse effects reported as more than isolated cases are listed below, by system organ class and by frequency. Frequencies are defined as: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000, < 1/100), rare (> 1/10,000, < 1/1,000), very rare (< 1/10,000), according to the MedDRA frequency convention and system organ classification.
Some effects were previously described using the WHO classification (grade 1 = G1; grade 2 = G2; grade 3 = G3; grade 4 = G4; grade 1-4 = G1-4; grade 1-2 = G1-2; grade 3-4 = G3-4).
The most commonly reported adverse medicine effects are bone marrow depression with neutropenia, anaemia, neurologic disorders, gastrointestinal toxicity with nausea, vomiting, stomatitis and constipation, transient elevations of liver function tests, alopecia and local phlebitis.

Infections and infestations.

Common: infection bacterial, viral or fungal at different localisation (respiratory, urinary, GI tract) mild to moderate and usually reversible with an appropriate treatment.
Uncommon: severe sepsis with other visceral organ failure, septicaemia.
Very rare: complicated septicaemia and sometimes fatal.

Blood and lymphatic system disorders.

Very common: bone marrow depression. Neutropenia is the major dose limiting toxicity with vinorelbine. Neutropenia (G3: 25.2%, G4: 28.4%) is rapidly reversible (7 to 14 days) and noncumulative. It is maximal between five and fourteen days after administration, depending on whether vinorelbine is used as single agent or in combination. Further treatment may be given after recovery of the neutrophil count. Anaemia (G3-4: 8%).
Common: thrombocytopenia (G3-4: 2.3%) can also occur. Dose adjustments are required for haematological toxicity and hepatic insufficiency (see Section 4.2 Dose and Method of Administration).

Immune system disorders.

Not known: systemic allergic reactions as anaphylaxis, anaphylactic shock or anaphylactoid type reaction.

Nervous system disorders.

Very common: mild to moderate peripheral neuropathy manifested as paraesthesia, hyperaesthesia and loss of deep tendon reflexes (G3: 2.5%, G4: 0.2%). After prolonged treatment, weakness of the lower extremities has also been reported. The effects are dose dependent but usually reversible when treatment is discontinued.
In autonomic neuropathy, the main symptom is intestinal paresis causing constipation which rarely progresses to paralytic ileus (G3: 2%, G4: 0.6%), weakness of the lower extremities. Treatment may be resumed after recovery of normal bowel mobility.
Uncommon: severe paraesthesias with infrequent sensory and motor symptoms. These effects are generally reversible.
Rare: paralytic ileus, treatment may be resumed after recovery of normal bowel mobility.

Gastrointestinal disorders.

Very common: constipation (see Nervous system disorders, above), mild to moderate nausea occurred in 25.5% of patients treated with vinorelbine.
Stomatitis (as single agent).
Nausea and vomiting (G3: 2%, G4: 0.3%). Anti-emetic therapy may reduce their occurrence.
Constipation is the main symptom which rarely progresses to paralytic ileus with vinorelbine as single agent and with the combination of vinorelbine and other chemotherapeutic agents.
Common: diarrhoea, (usually mild to moderate), severe nausea and vomiting.
Rare: pancreatitis, paralytic ileus.

Skin and subcutaneous tissue disorders.

Very common: alopecia is mild and may appear progressively with extended courses of treatment.
Vinorelbine may produce generalised cutaneous effects.
Like other anticancer vinca alkaloids, vinorelbine is a moderate vesicant.
Injection site reactions, including erythema, pain at injection site, and vein discolouration occurred in approximately one third of patients (5% were severe). Chemical phlebitis along the vein proximal to the site of injection was reported in 10% of patients. In rare cases local tissue necrosis has been observed. Bolus injection followed by liberal flushing of the vein can limit this effect. Insertion of a central venous line may be necessary.
Common: severe injection site reactions.
Rare: generalised cutaneous reactions, tissue necrosis at injection site.

Hepatobiliary disorders.

Very common: transient elevations of liver enzymes.

Respiratory system, thoracic and mediastinal disorders.

Common: shortness of breath (reported in 3% of patients), bronchospasm.
Vinorelbine, like other vinca alkaloids, may produce dyspnoea.
Rare: interstitial pneumopathy (in particular, with vinorelbine and mitomycin combinations), sometimes fatal.

Cardiac disorders.

Common: chest pain was reported in 5% of patients. Most reports of chest pain were in patients who had either a history of cardiovascular disease or tumour within the chest.
Rare: myocardial infarction, angina pectoris, transient ECG changes.
Very rare: cardiac failure, pulmonary oedema, tachycardia, palpitation and heart rhythm disorders.

Vascular disorders.

Uncommon: hypotension, hypertension, flushing and peripheral coldness.
Rare: severe hypotension, collapse.

Musculoskeletal and connective tissue disorders.

Common: jaw pain, myalgia, arthralgia.

Endocrine disorders.

Uncommon: Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Renal and urinary disorders.

Uncommon: Haemorrhagic cystitis.

Metabolism and nutrition disorders.

Rare: severe hyponatremia.

General disorders and administration site conditions.

Very common: Fatigue occurred in 27% of patients. It was usually mild or moderate but tended to increase with cumulative dosing. Effects at the injection site may include erythema, burning pain, vein discoloration and local phlebitis with vinorelbine as single chemotherapeutic agent.
Common: pain at the tumour site, chest pain of non-cardiac origin, asthenia, fever.
Rare: local necrosis (proper positioning of the intravenous needle or catheter and bolus injection followed by liberal flushing of the vein can limit these effects).

Adverse events observed in pivotal phase III studies (metastatic).

See Table 3.

Post-marketing experience.

The following additional adverse reactions have been reported from post marketing experience according to the MedDRA classification with the frequency 'not known'.
The reactions were described using CTCAE classification which provide a terminology for AE's and a grading scale of the severity of AEs (grade 1 = G1; grade 2 = G2, grade 3 = G3, grade 4 = G4; grade 1-4 = G1-4; grade 1-2 = G1-2, grade 3-4 = G3-4).

Infections and infestations.

Neutropenic sepsis. Neutropenic infection G3-4.

Blood and lymphatic system disorders.

Febrile neutropenia, pancytopenia, leucopenia G1-4.

Immune system disorders.

Systemic allergic reactions including anaphylaxis, anaphylactic shock or anaphylactoid type reactions.

Metabolism and nutrition disorders.

Anorexia.

Skin and subcutaneous tissue disorders.

Palmer-plantar erythrodysesthesia syndrome.

Nervous system disorders.

Headache, dizziness, ataxia.

Cardiac disorders.

Heart failure.

Respiratory system.

Cough G1-2. Acute respiratory distress syndrome (ARDS) sometimes fatal (see Section 4.4 Special Warnings and Precautions for Use).

Gastrointestinal disorders.

Gastrointestinal bleeding, severe diarrhoea, abdominal pain.

Hepatobiliary disorders.

Hepatic disorders.

General disorders.

Chills G1-2.

Investigations.

Weight loss.

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

Symptoms.

Overdosage with vinorelbine could produce bone marrow hypoplasia sometimes associated with infection, fever and paralytic ileus.

Emergency procedure.

General supportive measures together with blood transfusion, growth factors and broad spectrum antibiotic therapy should be instituted as deemed necessary by the physician.
There is no known antidote for overdoses of vinorelbine. The primary anticipated complications of overdosage would consist of bone marrow suppression and peripheral neurotoxicity. If overdosage occurs, general supportive measures together with appropriate blood transfusions and antibiotics should be instituted as deemed necessary by the doctor.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Vinorelbine is a cytostatic antineoplastic medicine. It is a semisynthetic member of the vinca alkaloid family that interferes with microtubule assembly. The vinca alkaloids are structurally similar compounds comprised of two multiringed units, vindoline and catharanthine. Unlike other vinca alkaloids, the catharanthine unit is the site of structural modification for vinorelbine. The antitumour activity of vinorelbine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. In intact tectal plates from mouse embryos, vinorelbine, vincristine, and vinblastine inhibited mitotic microtubule formation at the same concentration (2 micromolar), including a blockade of cells at metaphase. Vincristine produced depolymerisation of axonal tubules at 5 micromolar, but vinblastine and vinorelbine did not have this effect until concentrations of 30 and 40 micromolar, respectively. These data suggest relative selectivity of vinorelbine for mitotic microtubules.
Vinorelbine has an active metabolite, 17-deacetylvinorelbine, low levels of which are recovered in humans. Its toxicity and activity are slightly higher than those of vinorelbine.

Clinical trials.

Advanced breast cancer, second line.

Twenty phase II studies of IV vinorelbine monotherapy have been performed as second line or subsequent treatment of advanced breast cancer patients. The response rate and duration of response to chemotherapy declines as patients progress through first, second and third line chemotherapy. Thirteen of these phase II studies were in mixed anthracycline pretreated and anthracycline naïve populations, entering 494 patients and reporting overall response rates of 14 to 45% (patients weighted average = 29.2%) and median survival times of 58 to 69 weeks. The remaining seven phase II studies were in anthracycline pretreated patients, entering a total of 339 patients, reporting response rates of 16 to 64% (patient weighted average = 30.9%) and median survival was 24 to 82 weeks.
The demonstration of vinorelbine activity as a single agent in the treatment of advanced breast cancer is based on eight phase II studies and one phase III study, totalling 577 patients. In the four trials where vinorelbine was used as first line treatment, the overall response rate ranged from 41 to 60%. Of the total 283 evaluable patients, 128 had objective responses (i.e. response rate of 45.2%, 95% confidence interval 39.4 to 51%, duration of response 8.7 months). In the three phase II studies of vinorelbine administered weekly in second or third line treatment of advanced breast cancer, the response rate ranged from 19.6 to 30.3%. Based on an intention to treat analysis of evaluable patients in the two studies which used the recommended dose of 30 mg/m2 weekly, the overall response rate was 24% and median duration 4.4 months. Results of the eighth phase II study are not presented here because of the different mode of administration used.
In a randomised phase III study conducted to investigate efficacy in anthracycline refractory advanced breast cancer, 115 patients received vinorelbine as a single agent versus 64 patients who received intravenous melphalan. The median dose, number of doses and duration of treatment for vinorelbine were 27.5 mg/m2, nine doses and 12 weeks, respectively and for melphalan, 25 mg/m2, two doses and 8 weeks respectively. Of those receiving vinorelbine, 13 of 84 (15.5%) patients with measurable disease achieved an objective response compared with 4 of 46 (8.7%) receiving melphalan. Overall survival was 35 weeks for patients receiving vinorelbine compared with 31 weeks for those receiving melphalan (log rank p = 0.023). Neither treatment had an adverse effect on quality of life.
Vinorelbine has also been studied in combination with other agents in the second line treatment of advanced breast cancer. Results from trials are summarised in the following table (see Table 4).
Vinorelbine was also investigated in combination with other chemotherapy agents in advanced breast cancer. In a phase II study, a combination of vinorelbine plus doxorubicin resulted in an overall response rate of 74% (66 objective responses out of 89 evaluable patients), with an overall median duration of response of 12 months and a median time to progression of 13.2 months. The median survival of patients attaining complete response had not yet been reached with a median follow-up of 30 months. The median survival of patients attaining a partial response was 22.4 months. The overall median survival was 27.5 months.
In a phase II study of the combination of vinorelbine plus fluorouracil, an overall response rate of 64% was found (40 out of 63 evaluable patients), with an overall median duration of response of 12.3 months, median time to progression of 12.7 months and an overall median survival of 23 months (28.1 months for responding patients).

Non-small cell lung cancer (NSCLC).

The activity of vinorelbine was investigated in a series of phase II trials. The overall response rate to vinorelbine single agent in NSCLC patients ranged from 8 to 33% in previously untreated patients. In the two major phase II trials with more than 60 evaluable patients, the overall response rate was over 30% in chemotherapy naive patients. The high activity of vinorelbine as single agent in non-small cell lung cancer which was observed in noncontrolled phase II studies has also been confirmed in three randomised phase III trials. In one prospective randomised study with 216 stage IV patients, vinorelbine was compared to fluorouracil with calcium folinate (considered equivalent to best supportive care for the purposes of the study). The median survival time of patients who received vinorelbine was 30 weeks compared to 22 weeks for those on the fluorouracil/ calcium folinate arm (log rank p = 0.03). The response rates were 12% for the vinorelbine arm and 3% for the fluorouracil/ calcium folinate arm.
The activity of vinorelbine in combination with cisplatin has been investigated in two randomised phase III trials in a total of 782 patients. In a two arm trial, vinorelbine was compared to vinorelbine with cisplatin. The overall response rate to vinorelbine as single agent was 16% while that of the combination vinorelbine/ cisplatin was 43%. The median survival time for patients receiving vinorelbine as single agent was similar to that observed with vinorelbine and cisplatin.
In a large European clinical trial, 612 patients with stage III or IV non-small cell lung cancer, no prior chemotherapy and WHO performance status of 0, 1 or 2 were randomised to treatment with single agent vinorelbine (30 mg/m2/week), vinorelbine (30 mg/m2/week) plus cisplatin (120 mg/m2 days 1 and 29 then every six weeks), and vindesine (3 mg/m2/week for seven weeks, then every second week) plus cisplatin (120 mg/m2 days 1 and 29 then every six weeks). Vinorelbine plus cisplatin produced longer survival times than vindesine plus cisplatin (median survival 40 weeks versus 32 weeks, p = 0.03). The median survival time for patients receiving single agent vinorelbine was similar to that observed with vindesine plus cisplatin (31 weeks versus 32 weeks). The one year survival rates were 36% for vinorelbine plus cisplatin, 27% for vindesine plus cisplatin, and 30% for single agent vinorelbine. The overall objective response rate (all partial responses) was significantly higher in patients treated with vinorelbine plus cisplatin (28%) than in those treated with vindesine plus cisplatin (19%, p = 0.03) and in those treated with single agent vinorelbine (14%, p < 0.001). The response rates reported for vindesine plus cisplatin and single agent vinorelbine were not significantly different. Significantly, less nausea, vomiting, alopecia, and neurotoxicity were observed in patients receiving single agent vinorelbine compared to those receiving the combination of vindesine and cisplatin.

5.2 Pharmacokinetic Properties

Absorption.

Vinorelbine demonstrated high binding to human platelets and lymphocytes. The binding to plasma constituents in cancer patients ranged from 79.6 to 92.2%. Vinorelbine binding was not altered in the presence of cisplatin, 5-fluorouracil or doxorubicin.

Distribution.

Following intravenous administration of vinorelbine to patients at 30 mg/m2, vinorelbine concentration in plasma decays in a triphasic manner. The initial rapid decline primarily represents distribution of medicine to peripheral compartments followed by metabolism and excretion of the medicine during subsequent phases.
Penetration of vinorelbine into pulmonary tissue is significant with tissue/plasma concentration ratios of greater than 300 in a study involving surgical biopsy.

Metabolism.

One active metabolite, deacetylvinorelbine, has been detected but not quantified in human plasma.

Excretion.

The prolonged terminal phase is due to relatively slow efflux of vinorelbine from peripheral compartments. The terminal phase half-life averages 27.7 to 43.6 hours and the mean clearance ranges from 0.6 to 1.3 L/h/kg.
Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in faeces after intravenous administration to humans. The effects of renal or hepatic dysfunction on the disposition of vinorelbine have not been assessed, but based on experience with other anticancer vinca alkaloids, dose adjustments are recommended for patients with impaired hepatic function (see Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

Vinorelbine tartrate has been shown to affect chromosome number and possibly structure in vivo (polyploidy in bone marrow cells from Chinese hamsters and a positive micronucleus test in mice).
It was not mutagenic or cytotoxic in a reverse histidine mutation (Ames) test but showed mutagenic potential in a mouse forward mutation (TK locus) test.

Carcinogenicity.

Carcinogenicity studies in mice and rats showed no tumorigenic activity at dose levels up to 2.4 mg/m2 given by intravenous injection every two weeks for 18 months or two years, respectively. However, the positive findings in genetic toxicity assays suggest that the medicine may have carcinogenic potential at the higher dose level used in humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Water for injection, nitrogen.

6.2 Incompatibilities

Vinorelbine Ebewe should not be diluted in alkaline solutions due to the risk of precipitation. Vinorelbine Ebewe should not be mixed with other agents. Vinorelbine Ebewe is not absorbed to or affected by either PVC or clear neutral glass.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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°C to 8°C. Refrigerate. Do not freeze. Protect from light.

6.5 Nature and Contents of Container

Vinorelbine Ebewe is available in clear glass vial (single use vial) with a grey rubber closure and aluminium crimp cap.
Vial stopper is not made with natural rubber latex.
Vinorelbine Ebewe 10 mg/1 mL vial is available in pack sizes of 1 vial and 5 vials.
Vinorelbine Ebewe 50 mg/5 mL vial is available in pack size of 1 vial.
Not all strengths or presentations may be marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

The pH of Vinorelbine Ebewe injection concentrate is approximately 3.5 and the aqueous solubility is > 1,000 mg/mL in distilled water.

Chemical structure.


Chemical name: 3',4'-didehydro-4'- deoxy-C'- norvincaleukoblastine [R-(R*,R*)-2,3 dihydroxybutanedioate (1:2)(salt)].
Molecular formula: C45H54N4O8.2C4H6O6.
Molecular weight: 1,079.12.

CAS number.

Vinorelbine tartrate.

125317-39-7.

Vinorelbine.

71486-22-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes