Consumer medicine information

Navelbine Oral

Vinorelbine

BRAND INFORMATION

Brand name

Navelbine Oral

Active ingredient

Vinorelbine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Navelbine Oral.

SUMMARY CMI

Navelbine Oral

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 Navelbine Oral?

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

2. What should I know before I use Navelbine Oral?

Do not use if you have ever had an allergic reaction to 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 Navelbine Oral? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Navelbine Oral 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 Navelbine Oral?

Navelbine Oral is given as a capsule. Swallow your Navelbine Oral capsule whole with a full glass of water, without chewing or sucking the capsule. More instructions can be found in Section 4. How do I use Navelbine Oral? in the full CMI.

5. What should I know while using Navelbine Oral?

Things you should do
  • Keep all appointments with your doctor to check on your progress and monitor side effects.
  • If you become pregnant while taking Navelbine Oral, tell your doctor immediately.
Things you should not do
  • You should not breast-feed while you are being treated with Navelbine Oral.
  • Men being treated with Navelbine Oral are advised not to father a child during and up to a minimum of 3 months after treatment.
  • 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, if you have a reduced number of platelets of red blood cells, if you have stomach or intestinal disorders or if you have any condition requiring long-term oxygen therapy
Driving or using machines
  • Be careful driving or operating machinery until you know how Navelbine Oral affects you.
Drinking alcohol
  • Fatigue and Dizziness are common side effects of Navelbine Oral. Drinking alcohol may make these symptoms worse.
Looking after your medicine
  • Store Navelbine Oral 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 Navelbine Oral? in the full CMI.

6. Are there any side effects?

Common side effects include nausea, vomiting, diarrhoea, loss of appetite, unusual tiredness, weakness, sleepiness, drowsiness or lack of energy, unusual hair loss, constipation, aching muscles, skin reactions, fever, jaw pain, painful swollen joints, weight loss, weight gain and high or low blood pressure. Serious side effects include difficulty breathing, 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

Navelbine Oral

Active ingredient(s): vinorelbine tartrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Navelbine Oral. 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 Navelbine Oral.

Where to find information in this leaflet:

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

1. Why am I using Navelbine Oral?

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

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

Navelbine Oral is used treat lung cancer and advanced breast cancer.

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

Navelbine Oral is not recommended for use in children and adolescents aged less than 18 years as there is no information on its effects in these age groups.

2. What should I know before I use Navelbine Oral?

Warnings

Do not use Navelbine Oral if:

  • you are allergic to vinorelbine; or to the other vinca alkaloids, (vinblastine, vincristine, vindesine, vinflunine); or any of the ingredients listed at the end of this leaflet.
Symptoms of an allergic reaction to Navelbine Oral 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
  • if you have or have had (within the last two weeks), a severe infection. Your doctor may decide to delay your treatment until the infection has gone.
  • if you plan to have a yellow fever vaccine or have just had one.
  • if you are currently receiving radiation therapy to your liver.
  • if you have or have had any of the following medical conditions:
    - severe liver problems
    - a low white blood cell and/or platelet count which you may notice as signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers
    - surgery on your stomach or small bowel
    - stomach or intestinal disorders
    - any condition requiring long-term oxygen therapy
  • Always check the ingredients to make sure you can use this medicine.

Do not take Navelbine Oral if you are pregnant or intend to become pregnant.

Like most medicines used to treat cancer, Navelbine Oral is not recommended for use in pregnancy. Navelbine Oral may affect your developing baby if you take it during pregnancy. If there is a need to consider Navelbine Oral during your pregnancy, your doctor will discuss with you the benefits and risks of using it.

Do not breastfeed while being treated with Navelbine Oral.

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

Check with your doctor if you:

  • have or have had a severe infection in the last 2 weeks. Your doctor may decide to delay your treatment until the infection has gone.
  • have allergies to:
    - any other medicines
    - any other 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 and/or platelet count which you may notice as signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers
    - stomach problems (including surgery on your stomach)
    - lung problems, including asthma
    - the rare hereditary problem of fructose intolerance (due to the presence of sorbitol).
  • take any medicines for any other condition or treatments for cancer, including radiation therapy.
Navelbine Oral must not be taken if you are currently receiving radiation therapy to your liver.
  • if you plan to have a vaccination. Having a live attenuated vaccine (eg: measles, mumps, rubella vaccine) is not recommended while taking Navelbine Oral as they may increase the risk of life-threatening vaccine disease.
  • if your ability to carry out activities of daily living is strongly reduced.

Navelbine Oral 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

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

Like most medicines used to treat cancer, Navelbine Oral is not recommended for use in pregnancy. Navelbine Oral 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 Navelbine Oral and for three months after your last dose of Navelbine Oral.

Men being treated with Navelbine Oral are advised not to father a child during and up to a minimum of 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 Navelbine Oral.

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

Talk to your doctor if you are breastfeeding or intend to breastfeed. You must stop breast-feeding before starting treatment with Navelbine Oral.

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 Navelbine Oral and affect how it works. These include:

  • mitomycin and lapatinib, medicines used to treat cancer;
  • warfarin, phenindione and other medicines used to prevent blood clots;
  • other medicines used to treat cancer such as cisplatin;
  • ketoconazole and itraconazole, medicines used to treat fungal infections;
  • retonavir, a medicine used to treat HIV and AIDS;
  • rifampicin, a medicine used to treat tuberculosis or meningitis;
  • cyclosporin and tacrolimus, drugs which reduce the body's ability to fight illness/disease (known as immunosuppressants).
  • phenytoin, a medicine used to treat epilepsy or fits.

These medicines may be affected by Navelbine Oral 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 Navelbine Oral.

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

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

4. How do I use Navelbine Oral?

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.
  • Navelbine Oral may be given alone or in combination with other drugs.
  • Several courses of Navelbine Oral therapy may be needed depending on your response to treatment.
  • Navelbine Oral reduces the number of white blood cells in the body. Your doctor will check these levels regularly. Further doses of Navelbine Oral may be delayed until your blood cell numbers return to acceptable levels.

How to take Navelbine Oral

  • Navelbine Oral is given as a capsule.
  • Swallow your Navelbine Oral capsule whole with a full glass of water, without chewing or sucking the capsule. The liquid inside Navelbine Oral is an irritant and may cause damage if it comes in contact with your skin, mucosa or eyes.
  • Damaged capsules should not be swallowed.
  • If contact with the contents of the capsule does occur, wash the affected area thoroughly with water or a normal saline solution.
  • Navelbine Oral should be taken with food.
  • If vomiting occurs within a few hours of taking Navelbine Oral, the dose of Navelbine Oral should not be repeated. Your doctor may prescribe a medication to help with vomiting if it is a problem.
  • To open the child resistant packaging:
    - Cut the blister along the black dotted line;
    - Peel off the soft plastic foil;
    - Push the capsule through the aluminium foil.

How long is it given

  • Navelbine Oral 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 Navelbine Oral

Tell your doctor as soon as possible if you realise that you have missed your dose of Navelbine Oral.

If you have problems remembering when your next dose is due, use a diary or calendar or ask a friend to remind you. Please also refer to your Navelbine Oral 'Patient Booklet'.

If you use too much Navelbine Oral

If you think that you have used too much Navelbine Oral, you may need urgent medical attention.

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 Navelbine Oral?

Things you should do

  • 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.
  • If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are having treatment with Navelbine Oral.
  • If you become pregnant while taking Navelbine Oral, tell your doctor immediately. Navelbine Oral 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 Navelbine Oral.

Remind any doctor, dentist or pharmacist you visit that you are having treatment with Navelbine Oral.

Things you should not do

  • You should not breast-feed while you are being treated with Navelbine Oral. Breastfeeding must be discontinued before starting treatment with Navelbine Oral.
  • Men being treated with Navelbine Oral are advised not to father a child during and up to a minimum of 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 Navelbine Oral.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Navelbine Oral affects you.

If you experience symptoms that affect your ability to concentrate and react, do not drive a car or operate machinery. Dizziness and fatigue are common side effects of Navelbine Oral. Make sure you know how Navelbine Oral affects you before you drive a car, operate machinery or do anything else that could be dangerous if you are feeling tired or dizzy.

Drinking alcohol

Tell your doctor if you drink alcohol.

Drinking alcohol may make the tiredness and dizziness worse.

Looking after your medicine

  • If you are storing Navelbine Oral at home:
    - Store Navelbine Oral in the refrigerator (2 to 8°C) in the original packaging. Do not freeze it.
    - Protect Navelbine Oral from light.

Do not store Navelbine Oral or any other medicine in the bathroom or near a sink. Do not leave it on a windowsill or in the car

Heat and dampness will destroy the medicine.

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

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If your doctor stops your treatment with Navelbine Oral, or it has passed its expiry date, return any leftover capsules to your pharmacist. Do not dispose of Navelbine Oral 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
Problems with skin and hair
  • skin reactions
  • unusual hair loss or thinning
Head and neurology related
  • unusual tiredness, weakness, sleepiness, drowsiness or lack of energy
  • trouble sleeping
  • dizziness
  • headache
Gastrointestinal upset
  • nausea
  • vomiting
  • diarrhoea
  • constipation
  • upset stomach
  • loss of appetite
  • indigestion
  • weight loss
  • weight gain
Respiratory related
  • coughing
  • change in or loss of taste
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
Infection related
  • frequent infections or signs of infection such as fever, severe chills, sore throat or mouth ulcers (symptoms of a lack of white blood cells)
  • sore mouth
  • mouth ulcers and cold sores
  • viral, bacterial or fungal infections
  • blood infections (sepsis) symptoms such as high fever and deterioration in general health
Head and neurology related
  • tiredness, headaches, dizziness and looking pale (symptoms of a decreased number of red blood cells)
  • Lack of muscle control may be associated with abnormal gait, speech changes and abnormalities in eyes movement
Bleeding related
  • bleeding or bruising more easily than normal or nosebleeds (symptoms of a low blood platelet count)
Eye problems
  • changes in your vision
Throat related
  • difficulty swallowing
Urinary related
  • pain or burning feeling when passing urine or other urinary problems.
Heart related
  • chest pain
  • palpitations, fast or irregular heart beat
  • high blood pressure
  • low blood pressure
Allergy related
  • rash, itching or hives on the skin
  • swelling of the feet and ankles, face, lips, tongue or other parts of the body
Liver related
  • liver disorders (abnormal liver test).
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 Navelbine Oral contains

Active ingredient
(main ingredient)		vinorelbine tartrate
Other ingredients
(inactive ingredients)
  • ethanol
  • purified water
  • glycerol
  • macrogol 400
  • gelatin
  • anidrisorb 85/70
  • phosal 53 MCT
  • medium-chain triglycerides
  • edible ink red
  • titanium dioxide
  • iron oxide yellow
  • iron oxide red
Potential allergensNo

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

What Navelbine Oral looks like

Navelbine Oral soft capsules are available in four strengths: 20 mg, 30 mg, 40 mg* and 80 mg*.

Navelbine Oral 20 mg soft capsules are light brown and printed N20.

Navelbine Oral 30 mg soft capsules are pink and printed N30.

Navelbine Oral 40 mg soft capsules are brown and printed N40.

Navelbine Oral 80 mg soft capsules are pale yellow and printed N80.

Navelbine Oral comes in blister packs of 1 tablet.

*These pack sizes are not available in Australia.

Australian Registration Number:
20 mg: AUST R 99498
30 mg: AUST R 99558
40 mg: AUST R 99561
80 mg: AUST R 99564

Who distributes Navelbine Oral

Pierre Fabre Australia Pty Limited
Level 7, 32 Walker St
North Sydney NSW 2060

This leaflet was prepared in July 2021

Published by MIMS February 2022

BRAND INFORMATION

Brand name

Navelbine Oral

Active ingredient

Vinorelbine

Schedule

S4

 

1 Name of Medicine

Vinorelbine tartrate.

2 Qualitative and Quantitative Composition

Capsules contain 20 mg, 30 mg and 80 mg vinorelbine (as tartrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Soft capsule.

20 mg soft capsule.

Light brown soft capsule printed N20.

30 mg soft capsule.

Pink soft capsule printed N30.

80 mg soft capsule*.

Pale yellow soft capsule printed N80.
*Not marketed.

4 Clinical Particulars

4.1 Therapeutic Indications

Non-small cell lung cancer.

Navelbine Oral is indicated for the first line treatment of advanced non-small cell lung cancer, as a single agent or in combination.

Breast cancer.

Navelbine Oral is indicated for the treatment of advanced breast cancer after failure of standard therapy as a single agent or in combination.

4.2 Dose and Method of Administration

Adults.

Single agent. The recommended regimen is:

First three administrations.

60 mg/m2, administered once weekly.

Subsequent administrations.

Beyond the third administration, increasing the dose of Navelbine Oral to 80 mg/m2 once weekly is recommended, except in those patients for whom the neutrophil count has dropped once below 500/mm3 or more than once between 500 and 1000/mm3 during the first 3 administrations at 60 mg/m2.
Dose modifications according to haematological status. If the neutrophil count is below 1500/mm3 and/or the platelet count is below 100,000/mm3, then treatment should be delayed until recovery. See Table 1.
For any administration planned at the 80 mg/m2/week dose, if the neutrophil count falls below 500/mm3 or more than once between 500 and 1000/mm3, the dose must be delayed until recovery and reduced from 80 to 60 mg/m2 per week during the 3 subsequent administrations. See Table 2.
It is possible to re-escalate the dose from 60 to 80 mg/m2/week if the neutrophil count does not drop below 500/mm3, or more than once between 500 and 1000/mm3, during the three administrations given at the 60 mg/m2 dose.
Dose modification for hepatic impairment. Vinorelbine is contraindicated in patients with severe hepatic impairment. In patients with moderate hepatic impairment (serum bilirubin between 1.5 and 3 x ULN, independent of ALT and AST concentrations), Navelbine Oral monotherapy should be administered at a dose of 50 mg/m2/week. In patients with mild hepatic impairment (serum bilirubin < 1.5 x ULN and ALT and/or AST between 1.5 and 2.5 x ULN), Navelbine Oral may be administered at the standard dose of 60 mg/m2/week. Haematological toxicity should be closely monitored. Hepatic impairment has not been studied in combination chemotherapy.
Combination chemotherapy.

General.

The use of oral vinorelbine in combination regimens has not been extensively studied. However, based on pharmacokinetic studies, the oral dose of 80 mg/m2 was demonstrated to correspond to 30 mg/m2 of the IV form and 60 mg/m2 orally to 25 mg/m2 IV.
In combination regimens, intravenous vinorelbine dosing may be replaced with oral vinorelbine therapy. The recommended dose is 60 mg/m2. The safety of higher doses of oral vinorelbine (e.g. 80 mg/m2) in combination regimens has not been established, except for use with capecitabine in advanced breast cancer (see below).

Combination with capecitabine in advanced breast cancer.

In combination with capecitabine for the treatment of advanced breast cancer, the administration of Navelbine Oral is recommended on days 1 and 8 for three week cycles at 60 mg/m2 for the first cycle, then increased to 80 mg/m2 for subsequent cycles, except in patients for whom the neutrophil count has dropped below 500/mm3 or more than once between 500 and 1000/mm3 during the first administration at 60 mg/m2. Capecitabine should be administered at a dose of 1000 mg/m2, twice daily on days 1-14 of the three week cycle.
Table 3 gives the dose required for appropriate ranges of body surface area (BSA).
Even for patients with a body surface area (BSA) ≥ 2 m2, the dose should never exceed 120 mg per week at 60 mg/m2 and 160 mg per week at 80 mg/m2.
Procedures for proper handling and disposal of anticancer drugs should be used. Several guidelines on this subject have been published.

Method of administration.

Navelbine Oral must be given strictly by the oral route. They should be swallowed whole with water and should not be chewed or sucked. It is recommended that the capsule be taken with food.

4.3 Contraindications

Known hypersensitivity to vinorelbine or to other vinca alkaloids or to any of the excipients listed, see Section 6.1 List of Excipients.
Disease significantly affecting absorption.
Previous significant surgical resection of stomach or small bowel.
Neutrophil counts < 1500 cells/mm3, or current or recent severe infection due to neutropenia (within 2 weeks).
Platelet count < 100,000 cells/mm3.
Pregnancy.
Lactation (see Section 4.6 Fertility, Pregnancy and Lactation).
Patients requiring long-term oxygen therapy.
Severe hepatic insufficiency.
In combination with yellow fever vaccine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Administration.

Navelbine Oral should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents with facilities for monitoring cytotoxic drugs.
If the patient chews or sucks the capsule by mistake, rinse mouth with water or preferably a normal saline solution.
In the event of the capsule being cut or damaged, the liquid content is an irritant, and so may cause damage if in contact with skin, mucosa or eyes. Damaged capsules should not be swallowed and should be returned to the pharmacy or to the physician in order to be properly destroyed. If any contact occurs, immediate thorough washing with water or preferably with normal saline solution should be undertaken.
If vomiting occurs within a few hours of drug intake, administration of the dose should not be repeated. Prophylactic treatment such as 5HT3 antagonists (e.g. ondansetron, granisetron) may reduce the incidence. Navelbine Oral is associated with a higher incidence of nausea/ vomiting than the i.v formulation. A primary prophylaxis with antiemetics is recommended. It is recommended that the capsule be taken with food.
Constipation is a very common gastrointestinal disorder. The prescription of laxatives may be appropriate for patients with a prior history of constipation and/or are receiving concomitant treatment with opiates.

Myelosuppression.

Neutropenia is dose limiting. Complete blood counts with differentials should be performed and results reviewed prior to administering each dose of Navelbine Oral. Patients treated with Navelbine Oral should be frequently monitored for myelosuppression both during and after therapy. Navelbine Oral should not be administered to patients with neutrophil counts < 1500 cells/mm3 and/or platelet counts below 100,000 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 modification for haematological toxicity).
Navelbine Oral 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).
During clinical trials, where treatment was initiated at a weekly dose of 80 mg/m2 (corresponding to an IV dose of 30 mg/m2 in terms of systemic exposure), febrile neutropenia, in some cases fatal, was encountered in about 15% of patients. Therefore, it is recommended that the starting dose should be 60 mg/m2 and increased to 80 mg/m2 only if the dose is tolerated (see Section 4.2 Dose and Method of Administration).

General.

Most drug related adverse events of Navelbine Oral are reversible. If severe adverse events occur, Navelbine Oral should be reduced in dosage or discontinued and appropriate corrective measures taken. Reinstitution of therapy with Navelbine Oral 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;
with poor performance status.
Patients presenting with ischaemic cardiac disease should be carefully monitored (see Section 4.8 Adverse Effects (Undesirable Effects)).
This product is specifically contraindicated with yellow fever vaccine. Its concomitant use with other live attenuated vaccines is not recommended.
Acute shortness of breath and severe bronchospasm have been reported infrequently along with rare cases of interstitial pneumopathy following the administration of Navelbine 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.
Due to the presence of sorbitol, patients with the rare hereditary problem of fructose intolerance should not take this medicine.
Navelbine Oral contains small amounts of ethanol (alcohol), less than 100 mg per dose. The small amount of alcohol in this medicine will not have any noticeable effects.
Navelbine Oral should not be given concomitantly with radiotherapy if the treatment field includes the liver.

Use in hepatic impairment.

Vinorelbine is contraindicated in patients with severe hepatic impairment. In patients with moderate hepatic impairment (serum bilirubin between 1.5 and 3 x ULN, independent of ALT and AST concentrations), dose reduction is recommended (see Section 4.2 Dose and Method of Administration). In patients with mild hepatic impairment (serum bilirubin < 1.5 x ULN and ALT and/or AST between 1.5 and 2.5 x ULN), no dose reduction is required. Haematological toxicity should be closely monitored.

Use in renal impairment.

Because of the low level of renal excretion, no dose modification is necessary in patients with renal impairment.

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. Use in children and adolescents aged < 18 years is therefore not recommended.

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 Navelbine Oral. If the neutrophil count is below 1500/mm3 and/or the platelet count is below 100,000/mm3, then treatment should be delayed until recovery.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interactions common to all cytotoxics.

Due to the increase of thrombotic risk in the 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.
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 in phenytoin absorption by the cytotoxic drug or loss of efficacy of the cytotoxic drug 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 in their hepatic metabolism.
Concomitant use with caution.

Mitomycin.

Acute pulmonary reactions have been reported with Navelbine 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. Navelbine Oral should be administered with caution in combination with mitomycin.
As vinca alkaloids are known as substrates for P-glycoprotein, and in the absence of a specific study, caution should be exercised when combining Navelbine with strong modulators of this membrane transporter.

Interactions specific to vinorelbine.

The combination of Navelbine Oral and other drugs with known bone marrow toxicity is likely to exacerbate the myelosuppressive adverse effects.
In the absence of specific studies evaluating drug-drug interaction with warfarin, the patient should be cautiously monitored when vinorelbine is given in combination with warfarin.
Although the pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin, the incidence of toxicities, specifically granulocytopenia, with the combination of Navelbine Oral and cisplatin is significantly higher than with single agent Navelbine Oral.
In studies with rats, the anticoagulant effect of phenindione was potentiated when given in combination with a high dose 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 the 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.

Food.

Simultaneous intake of a low fat standard meal does not modify exposure to vinorelbine.

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 Navelbine Oral are advised not to father a child during and up to a minimum of 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 Navelbine Oral.
(Category D)
Navelbine Oral 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 embryonic deaths in mice. Doses causing adverse foetal effects in animals were lower than the human dose. There are no studies in pregnant women. If Navelbine Oral is used during pregnancy, or if the patient becomes pregnant while receiving this drug, 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 Navelbine Oral. Effective contraception must be used during treatment and up to 3 months after the treatment.
 It is not known whether vinorelbine is excreted in 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 drugs are excreted in human milk, and because of the potential serious adverse reactions in nursing infants from Navelbine Oral, breastfeeding must be discontinued in women before starting treatment with Navelbine Oral.

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)

The overall reported incidence of adverse effects was determined from clinical studies in 316 patients (132 patients with non-small cell lung cancer and 184 patients with breast cancer) who received the recommended regimen of Navelbine (first three administrations at 60 mg/m2/week followed by 80 mg/m2/week).
Adverse reactions reported are listed below by MedDRA body system organ class and the frequency convention.
Frequency of adverse reactions is defined as: very common (≥ 1/10); common (≥ 1/100 and < 1/10); uncommon (≥ 1/1000 and < 1/100); rare (≥ 1/10,000 and < 1/1000) and very rare (< 1/10, 000). Additional adverse reactions pooled from postmarketing experience and clinical trials have been added according to the MedDRA classification with the frequency ‘not known’.
The reactions were described using the Common Terminology Criteria for Adverse Events (CTCAE) classification which provides a terminology for adverse events (AEs) and a grading scale 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).

Adverse effects reported with Navelbine Oral.

Premarketing experience. The most commonly reported adverse drug reactions are bone marrow depression with neutropenia, anaemia and thrombocytopenia, gastrointestinal toxicity with nausea, vomiting, diarrhoea, stomatitis and constipation. Gastrointestinal adverse events occur more commonly with oral vinorelbine than with intravenous administration. Fatigue and fever were also very commonly reported.
Postmarketing experience. Navelbine Oral is used as a single agent or in combination with other chemotherapeutic agents or targeted therapy agents such as cisplatin or capecitabine. The most common system organ classes involved from postmarketing experience are: ‘blood and lymphatic system disorders’, ‘gastrointestinal disorders’, ‘infections and infestations’ and ‘general disorders and administration site conditions’. This information is consistent with premarketing experience. See Table 4.

Adverse effects with Navelbine IV.

In addition, some adverse effects have been observed with Navelbine IV from pre- and postmarketing experience which were not reported with Navelbine Oral. It cannot be ruled out that these effects may also be experienced with the use of Navelbine Oral as with other vinca alkaloids. See Table 5.

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

There is no known antidote for overdoses of Navelbine Oral. No case of overdosage has been reported with Navelbine Oral, however 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, growth factors and antibiotics should be instituted as deemed necessary by the physician. A close monitoring of hepatic function is recommended.
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.

Vinorelbine is an antineoplastic drug. 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 antitumor 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 micromolar and 40 micromolar, respectively. These data suggest relative selectivity of vinorelbine for mitotic microtubules.

Clinical trials.

Navelbine IV.

Non-small cell lung cancer.

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 5-fluorouracil with leucovorin (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 5-fluorouracil/ leucovorin arm (log rank p = 0.03). The response rates were 12% for the vinorelbine arm and 3% for the fluorouracil/ leucovorin 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), cisplatin (120 mg/m2 days 1 and 29 then every 6 weeks), and vindesine (3 mg/m2/week for 7 weeks, then every second week) plus cisplatin (120 mg/m2 days 1 and 29 then every 6 weeks). Vinorelbine plus cisplatin produced longer survival times than vindesine plus cisplatin (median survival 40 weeks vs 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 vs 32 weeks). The 1-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.

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 naive populations, entering 494 patients and reporting overall response rates of 14-45% (patients weighted average = 29.2%) and median survival times of 58-69 weeks.
The remaining seven phase II studies were in anthracycline pretreated patients, entering a total of 339 patients, reporting response rates of 16-64% (patient weighted average = 30.9%) and median survival was 24-82 weeks.
In a randomised phase III study conducted to investigate efficacy in anthracycline refractory advanced breast cancer, 115 patients received IV vinorelbine as a single agent versus sixty four patients who received intravenous melphalan. The median dose, number of doses and duration of treatment for vinorelbine were 27.5 mg/m2, 9 doses and 12 weeks respectively and for melphalan, 25 mg/m2, 2 doses and 8 weeks respectively. Of those receiving vinorelbine, thirteen of 84 (15.5%) patients with measurable disease achieved an objective response compared with four 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.
IV 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 Table 6.
Navelbine Oral. Oral vinorelbine has been developed as a line extension of the IV dosage form. Hence the primary objective of the clinical program was to demonstrate bioequivalence between the oral and intravenous formulations on the basis of pharmacokinetic studies. An oral dose of 80 mg/m2 was demonstrated to correspond to 30 mg/m2 of the IV formulation and 60 mg/m2 orally to 25 mg/m2 given by the IV route. Subsequent phase II studies were conducted to examine the efficacy and tolerance of oral vinorelbine.

Non-small cell lung cancer.

One randomised phase II study (97 CA 205) with the recommended oral dose regimen was conducted, comparing oral and IV vinorelbine in patients with advanced or metastatic NSCLC who had not previously been treated with cytotoxic chemotherapy. The results are summarised in Table 7.
In a multicentre, phase II study of 56 patients in combination with cisplatin 100 mg/m2 (day 1 q 4 weeks), the weekly administration of vinorelbine (IV vinorelbine 25 mg/m2 day 1, oral vinorelbine 60 mg/m2 days 8, 15 and 22) produced a response rate of 30% for all registered patients and 33% for evaluable patients in the first line treatment of unresectable, localised or metastatic NSCLC. Median progression free survival and survival were 5.5 and 8.9 months, respectively.

Advanced breast cancer. As a single agent.

Two noncomparative multicentre phase II studies (96 CA 201 and 97 CA 206) of oral vinorelbine given weekly at a dose of 60 mg/m2 for the first 3 weeks and then increased to 80 mg/m2 as a single agent, were conducted in the first line treatment of advanced breast cancer. A total of 184 patients were enrolled.
The majority of patients had metastatic disease at study entry, visceral lesions and had received prior hormonotherapy. The proportion of patients having received prior neo/adjuvant chemotherapy was 49.2% (96 CA 201) and 26.5% (97 CA 206). No patient had received prior chemotherapy for advanced/ metastatic disease.
The efficacy results are summarised in Table 8.
A response rate of 30% was reported in study 97 CA 206 and 21% in study 96 CA 201. The lower response rate observed in the latter study could be explained by the very poor prognosis features in the patients having received no prior adjuvant chemotherapy: 57% of patients had stage IIIB-IV disease, 67% had a disease free interval less than 2 years and 62% had at least 3 organs involved. In this subset of patients, the response rate was only 14%.
Median durations of progression free survival and overall survival were consistent in the 2 studies: 4.6 and 4.2 months; and 19.3 and 23.9 months respectively.
A randomised phase II trial (CA221) assessed in parallel the efficacy and safety of oral vinorelbine at 60 mg/m2 on days 1 and 8 every 3 weeks for the first cycle then increased to 80 mg/m2 on days 1 and 8 every 3 weeks for subsequent cycles; and IV vinorelbine at 25 mg/m2 on days 1 and 8 every 3 weeks for the first cycle then increased to 30 mg/m2 on days 1 and 8 every 3 weeks for subsequent cycles. The study was closed 2.5 years after its initiation due to low accrual (85 patients enrolled out of 230 planned). Premature closure of the study did not allow for the accurate assessment of the efficacy of oral vinorelbine. The following results were observed: response rate of 7% and disease control rate of 47.4% in the oral arm; response rate of 22% and disease control rate of 51.9% in the IV arm. Median overall survival was similar in the 2 study arms: 9.4 months and 10.2 months respectively.

In combination.

A randomised phase II study (CA 222) of the combination of oral vinorelbine with capecitabine versus a sequential regimen of oral vinorelbine and capecitabine versus the combination of docetaxel and capecitabine was carried out in 139 metastatic breast cancer patients previously treated with anthracyclines.
In combination with capecitabine, oral vinorelbine was given on days 1 and 8 of three week cycles at 60 mg/m2 for the first cycle and then at 80 mg/m2. In the sequential regimen, patients received oral vinorelbine 60 then 80 mg/m2/week for a total of 3 three week cycles and then 3 cycles of capecitabine. In the control arm, the standard regimen of docetaxel 75 mg/m2 on day 1 and capecitabine every 3 weeks was used. In the 3 study arms, the dose of capecitabine was 2000 mg/m2/day administered from days 1 to 14 every 3 weeks.
Efficacy results in the 3 study arms are summarised in Table 9.
The two combination arms, oral vinorelbine plus capecitabine and docetaxel plus capecitabine, produced similar disease control rates (70.5% vs 70.8% in the ITT population), similar response rates (31.8% vs 35.4%), similar progression free survival (7.2 months vs 8.9 months) and similar time to treatment failure (5.6 months vs 4.3 months). In comparison, the sequential regimen of oral vinorelbine followed by capecitabine was inferior to the combination regimens for all the efficacy parameters considered.
Oral vinorelbine in combination with other cytotoxics was assessed in three phase I/II studies: with epirubicin (study CA 205); docetaxel (CA 101); and paclitaxel (CA 102).
The efficacy results of these studies are summarised in Table 10.
The two regimens alternating oral and IV vinorelbine in combination with epirubicin or docetaxel gave similar response rates of approximately 50%. Median durations of overall survival tended to be longer for the taxane combinations than for the combination with epirubicin.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, Navelbine is promptly absorbed and the Tmax is reached within 1.5 to 3 hours with a blood concentration peak (Cmax) of approximately 130 nanogram/mL after dosing at 80 mg/m2. The absolute bioavailability is about 40% and simultaneous intake of a low fat standard meal does not modify the area under the concentration time curve (AUC). The effect of a high fat meal on absorption has not been studied.
Navelbine Oral 60 and 80 mg/m2 leads to a comparable AUC to that obtained from 25 and 30 mg/m2 of the IV formulation, respectively. Interindividual variability of the AUC is similar after administration by both the IV and oral routes. There is a proportional increase between the AUC and dose.

Distribution.

The mean pharmacokinetic parameters were evaluated in blood. After intravenous administration, the terminal half-life averaged 38 hours. Blood clearance was high, approached liver blood flow and averaged 0.72 L/hr/kg (range 0.32-1.26 L/hr/kg), while steady state volume of distribution was large, averaged 21.2 L/kg (range 7.5-39.7 L/kg), and indicated extensive tissue distribution.
Vinorelbine binds extensively to blood cells and especially platelets (70-80%), but less extensively (about 15%) to plasma proteins. There is a significant uptake of Navelbine in lungs, as assessed by pulmonary surgical biopsies showing up to a 300-fold greater concentration than in serum. Navelbine has not been detected in the central nervous system.

Metabolism.

Navelbine is mostly metabolised by the CYP3A4 isoform of the cytochrome P450. All the metabolites have been identified, and none are active except 4-O-deacetylvinorelbine, which is the main metabolite in blood. No sulfo or glucuronoconjugates are observed.

Excretion.

Renal elimination is low (< 20% of the dose) and consists mostly of the parent compound. Biliary excretion is the predominant elimination route of both metabolites and unchanged Navelbine, which is the main recovered compound.

Renal impairment.

The effect of renal dysfunction on Navelbine disposition has not been assessed, however, dose reduction, in the presence of renal insufficiency is not indicated with Navelbine due to its low renal elimination.

Hepatic impairment.

Vinorelbine is cleared from the circulation primarily by the liver and, therefore, elevated blood concentrations may be expected in patients with hepatic impairment. In a phase I pharmacokinetic study, 6 subjects with severe hepatic impairment were treated with 20 mg/m2 intravenously. Blood concentrations were elevated compared to historical data from patients with normal hepatic function. Oral vinorelbine is contraindicated in patients with severe hepatic impairment. In studies in patients with mild and moderate hepatic impairment, the pharmacokinetics of orally administered vinorelbine were not modified after administration of: 60 mg/m2 in patients with mild hepatic impairment (bilirubin < 1.5 x ULN and ALT and/or AST between 1.5 and 2.5 x ULN) and 50 mg/m2 in patients with moderate hepatic impairment (bilirubin between 1.5 and 3 x ULN, independent of ALT and AST levels). Haematological toxicity should be closely monitored.

Pharmacokinetics/pharmacodynamic relationships.

A strong relationship was demonstrated between AUC and leucocyte or PMN decreases.

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 IV injection every two weeks for 18 months or two years respectively. However, the positive findings in genetic toxicity assays suggest that the drug may have carcinogenic potential at the higher dose level used in humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Navelbine Oral also contains the following excipients: ethanol, purified water, glycerol and macrogol 400. The capsule shell contains: gelatin, Anidrisorb 85/70, Phosal 53 MCT, medium-chain triglycerides, glycerol, edible ink red, titanium dioxide, iron oxide yellow or iron oxide red.

6.2 Incompatibilities

Not applicable.

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) in the original container. Protect from light.

6.5 Nature and Contents of Container

PVC/PVDC/Al blister packs.
Pack size: 1 capsule.

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

Vinorelbine tartrate is a semi-synthetic vinca alkaloid with antitumor activity. The chemical name is 3',4'-didehydro-4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*) - 2,3 dihydroxybutanedioate (1:2) (salt)]. Vinorelbine tartrate is a white to yellow or light brown amorphous powder with the molecular formula C45H54N4O8.2C4H6O6 and a molecular weight of 1079.12. The aqueous solubility is > 1000 mg/mL in distilled water.

Chemical structure.


CAS number.

125317-39-7.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes