Consumer medicine information

DBL Vinorelbine Injection Concentrate

Vinorelbine

BRAND INFORMATION

Brand name

DBL Vinorelbine Injection Concentrate

Active ingredient

Vinorelbine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using DBL Vinorelbine Injection Concentrate.

What is in this leaflet

This leaflet answers some common questions about DBL™ Vinorelbine Injection Concentrate (vinorelbine). It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given vinorelbine against the benefits they expect it will have for you.

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

Keep this leaflet.

You may need to read it again.

What DBL™ Vinorelbine Injection Concentrate is used for

This medicine is used to treat:

  • advanced breast cancer
  • non-small cell lung cancer.

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

It works by stopping cancer cells from growing and multiplying. It may be used alone or in combination with other medicines to treat cancer.

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

Your doctor may have prescribed it for another reason.

This medicine is not addictive.

It is available only with a doctor’s prescription.

There is not enough information to recommend the use of this medicine for children.

Before you are given DBL™ Vinorelbine Injection Concentrate

When you must not be given it

You must not be given DBL™ Vinorelbine Injection Concentrate if you have an allergy to:

  • any medicine containing vinorelbine
  • any other similar medicines, such as vinblastine, vincristine or vindesine.

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Tell your doctor if you have an infection or high temperature.

Your doctor may decide to delay your treatment until the infection has gone. A mild illness, such as a cold, is not usually a reason to delay treatment.

Females: tell your doctor or pharmacist if you are pregnant or intend to become pregnant.

Like most cytotoxic medicines vinorelbine is not recommended for use during pregnancy. If there is any need to consider vinorelbine during your pregnancy, your doctor or pharmacist will discuss with you the benefits and risks of using it.

Males: tell your doctor or pharmacist if your partner intends to become pregnant while you are being given vinorelbine or shortly after you have stopped treatment with vinorelbine.

Vinorelbine may cause birth defects if either the male or female is using it at the time of conception. It is recommended that you use some kind of birth control while you are using vinorelbine and for at least 12 weeks after you stop treatment. A barrier method of birth control, such as a condom, should be used while you are being given vinorelbine and for the first week of this 12 week period. Your doctor will discuss this with you.

Do not breast-feed if you are being treated with this medicine.

Vinorelbine passes into breast milk and there is a possibility that your baby may be affected.

You must not be given this medicine if you have any of the following medical conditions:

  • very low numbers of neutrophils (a type of white blood cell)
  • severe infection due to your neutrophil numbers being low
  • severe liver problems.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have any of the following medical conditions:

  • heart problems, including angina
  • liver problems
  • lung problems, including asthma.

Tell your doctor if you are receiving radiotherapy that involves the abdominal or stomach area.

If you have not told your doctor about any of the above, tell him/her before you are given vinorelbine.

Taking other medicines

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

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

  • some other medicines used to treat cancer, such as mitomycin and cisplatin
  • phenindione, a medicine used to treat blood clots or prevent them from forming
  • some medicines used to treat viral or fungal infections
  • rifampicin, a medicine used to treat bacterial infections, including tuberculosis
  • medicines used to treat epilepsy (seizures), such as phenytoin and carbamazepine
  • St John’s wort (Hypericum perforatum), a herbal remedy.

These medicines may be affected by vinorelbine or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using this medicine.

How DBL™ Vinorelbine Injection Concentrate is given

How much is given

Your doctor will decide what dose you will receive. This depends on several factors including your height, weight, white blood cell count, liver function, and whether or not other chemotherapy medicines are also being given.

Vinorelbine may be given alone or in combination with other medicines to treat cancer.

Vinorelbine is usually given once a week, but 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.

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

Vinorelbine reduces the number of white blood cells in the body. Your doctor will check your blood cell numbers regularly.

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

Ask your doctor if you want to know more about the dose of vinorelbine you will be receiving.

How it is given

DBL™ Vinorelbine Injection Concentrate is given as a slow injection or infusion (‘drip’) into a vein. It must only be given by a nurse or doctor.

If you receive too much (overdose)

As DBL™ Vinorelbine Injection Concentrate is given to you under the supervision of your doctor, it is very unlikely that you will receive an overdose. However if you experience severe side effects tell your doctor immediately.

Symptoms of an overdose may include the side effects listed below in the 'Side effects' section, but are usually of a more severe nature.

Ask your doctor or pharmacist if you have any concerns.

In case of overdose, immediately contact the Poisons Information Centre for advice (telephone 13 11 26 in Australia, or call 0800 764 766 in New Zealand).

While you are being given DBL™ Vinorelbine Injection Concentrate

Things you must do

Tell your doctor immediately if you feel unexpected pain or discomfort during the injection.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are being given vinorelbine.

Tell any other doctors, dentists, and pharmacists who treat you that you are being given this medicine.

If you become pregnant while you are being treated with this medicine, tell your doctor immediately.

Keep all of your doctor’s appointments so your progress can be checked.

Your doctor may want to do some blood and other tests from time to time, to check on your progress and to detect any unwanted side effects.

Keep follow up appointments with your doctor.

It is important to have your follow-up doses of vinorelbine at the appropriate times to get the best effects from your treatments.

This medicine 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. The following precautions should be taken to reduce your risk of infection or bleeding:

  • Avoid people who have infections. 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.
  • 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.

Your body breaks down vinorelbine and uses it to fight cancer. The breakdown products may be excreted in body fluids and waste, including blood, urine, faeces, vomitus and semen.

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

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

Things to be careful of

Be careful driving or operating machinery until you know how vinorelbine affects you.

This medicine may cause dizziness or light-headedness in some people. If you have any of these symptoms, do not drive, operate machinery, or do anything else that could be dangerous.

Be careful when drinking alcohol while you are taking this medicine.

If you drink alcohol, dizziness or light-headedness, and tiredness may be worse.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are being treated with vinorelbine.

Like other medicines used to treat cancer, vinorelbine may have unwanted side effects, some of which may be serious. You may need medical attention if you get some of the side effects.

If you are over 65 years of age you may have an increased chance of getting side effects.

Do not be alarmed by the following lists of side effects.

You may not experience any of them.

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

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

  • nausea (feeling sick) or vomiting
  • diarrhoea
  • constipation
  • hair loss
  • sore mouth, mouth ulcers
  • mild redness, discomfort or discolouration of the vein near the injection site
  • fatigue (tiredness).

The above list includes side effects which are usually mild or short-lived.

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

  • tingling or numbness in the hands or feet
  • increased feeling of sensitivity, especially in the skin
  • weakness in the arms or legs
  • pain in the jaw, bones, muscles, or at the tumour site
  • tiredness, headaches, being short of breath when exercising, dizziness and looking pale.

The above list includes serious side effects, which may require medical attention.

If any of the following happen, tell your doctor or nurse immediately, or go to Accident and Emergency at your nearest hospital:

  • severe pain near the injection site
  • any signs of infection such as fever, chills, sore throat or cough, low back or side pain, painful or difficult urination
  • severe stomach pain, which may be accompanied by nausea and vomiting
  • signs of an allergic reaction, such as shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin
  • unusual bleeding or bruising (such as bloody or black stools, blood in urine)
  • pain in the bladder or back
  • breathlessness, which may be severe and worse on lying down
  • chest pain
  • swelling of the feet or legs due to fluid build-up.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor, nurse or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may occur in some people. Some of these side effects can only be found when your doctor does tests from time to time to check your progress.

The benefits and side effects of vinorelbine may take some time to occur. Therefore even after you have finished treatment with vinorelbine, you should tell your doctor if you notice anything that is making you feel unwell.

After using DBL™ Vinorelbine Injection Concentrate

Storage

DBL™ Vinorelbine Injection Concentrate will be stored in the pharmacy or on the ward. The injection is kept in the refrigerator where the temperature stays between 2 and 8°C, and is protected from light and freezing.

Product description

What it looks like

DBL™ Vinorelbine Injection Concentrate is a pale yellow, clear fluid for injection in an amber glass vial. It is available in single pack sizes of 10 mg/1mL and 50 mg/5mL.

Ingredients

DBL™ Vinorelbine Injection Concentrate contains 10 mg/mL of vinorelbine (13.85 mg/mL vinorelbine tartrate) as the active ingredient.

It also contains:

  • Water for Injections.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Australian Sponsor:
Hospira Australia Pty Ltd
ABN 58 097 064 330
Level 3
500 Collins Street
Melbourne VIC 3000
Australia

New Zealand Sponsor:
Hospira NZ Limited
58 Richard Pearse Drive
Airport Oaks, Mangere 2022
Auckland
New Zealand

AUST R Number(s):

  • 10 mg/1mL AUST R 97647
  • 50 mg/5mL AUST R 97648

This leaflet was updated in June 2014.

BRAND INFORMATION

Brand name

DBL Vinorelbine Injection Concentrate

Active ingredient

Vinorelbine

Schedule

S4

 

Name of the medicine

Vinorelbine tartrate.

Excipients

Water for injections.

Description

Chemical name: 3',4'-didehydro-4'-deoxy-C'-norvincaleukoblastine (R-(R*,R*)-2,3 dihydroxybutanedioate (1:2)(salt)). Molecular formula: C45H54N4O8.2C4H6O6. MW: 1079.12. CAS: 125317-39-7. Vinorelbine tartrate is a white to yellow or light brown amorphous powder. The aqueous solubility is > 1,000 mg/mL in distilled water. The pH of DBL Vinorelbine Injection Concentrate is approximately 3.0 to 4.0.
Vinorelbine tatrate is a semisynthetic vinca alkaloid with antitumour activity.

Pharmacology

Vinorelbine is a cytostatic 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 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 micromolar 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.

Pharmacokinetics.

Following intravenous (IV) administration of vinorelbine tartrate to patients at 30 mg/m2, concentration in plasma decays in a triphasic manner. The initial rapid decline primarily represents distribution of the drug to peripheral compartments followed by metabolism and excretion of the drug during subsequent phases. 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 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, fluorouracil or doxorubicin.
Penetration of vinorelbine into pulmonary tissue is significant with tissue/ plasma concentration ratios of greater than 300 in a study involving surgical biopsy.
Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in faeces after IV administration to humans. One active metabolite, deacetylvinorelbine, has been detected but not quantified in human plasma. 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 Dosage and Administration).

Clinical Trials

Advanced breast cancer.

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% CI 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 IV 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 eight weeks, respectively. Of those receiving vinorelbine, 13 of 84 (15.5%) patients with measurable disease achieved an objective response compared with four of 46 (8.7%) receiving melphalan. Overall survival was 38 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 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.

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 a 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), 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 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 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.

Indications

DBL Vinorelbine Injection Concentrate 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.

Contraindications

DBL Vinorelbine Injection Concentrate is contraindicated in patients with known hypersensitivity to vinorelbine or other vinca alkaloids; neutrophil counts < 1000 cells/mm3, or severe infection due to neutropenia; severe hepatic insufficiency; pregnancy; lactation.

Precautions

DBL Vinorelbine Injection Concentrate should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents.

Administration.

DBL Vinorelbine Injection Concentrate must only be administered by the IV route. Intrathecal administration of other vinca alkaloids has resulted in death. Improper administration of vinorelbine tartrate may result in extravasation causing local tissue necrosis and/or thrombophlebitis (see Dosage and Administration, Administration precautions).

Myelosuppression.

Patients treated with vinorelbine tartrate should be frequently monitored for myelosuppression both during and after therapy. Neutropenia is dose limiting. Neutrophil nadirs occur between 5 and 10 days after dosing, depending on whether vinorelbine tartrate 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 Injection Concentrate. DBL Vinorelbine Injection Concentrate should not be administered to patients with neutrophil counts < 1000 cells/mm3 (see Contraindications). 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 Dosage and Administration for recommended dose adjustments for neutropenia).
DBL Vinorelbine Injection Concentrate 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 Dosage and Administration).

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 Injection Concentrate.

General.

Most drug related adverse events of vinorelbine tartrate are reversible. If severe adverse events occur, vinorelbine tartrate should be reduced in dosage or discontinued and appropriate corrective measures taken. Reinstitution of therapy with vinorelbine tartrate should be carried out with caution and alertness as to possible recurrence of toxicity.
Patients presenting with ischaemic cardiac disease should be carefully monitored (see Adverse Effects).
Acute shortness of breath and severe bronchospasm have been reported infrequently following the administration of vinorelbine tartrate 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 vinorelbine tartrate. Severe irritation of the eye has been reported with accidental exposure to another vinca alkaloid and even corneal ulceration if the drug is sprayed under pressure. If exposure occurs, the eye should immediately be thoroughly flushed with water.
There is no evidence that the toxicity of vinorelbine tartrate 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 tartrate. Because clinical experience in patients with liver disease is limited, caution should be exercised when administering Vinorelbine Injection Concentrate to patients with hepatic injury or impairment (see Dosage and Administration). Administration to patients with severe hepatic insufficiency is contraindicated.
DBL Vinorelbine Injection Concentrate should not be given concomitantly with radiotherapy if the treatment field includes the liver.
Because of the low level of renal excretion, no dose modification is necessary in patients with renal impairment.

Carcinogenicity/ mutagenicity.

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 studies in mice and rats showed no tumourigenic 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.

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 to 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 three day intervals) were lower than the human dose.

Use in pregnancy.

(Category D)
Vinorelbine tartrate 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 tartrate is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be informed of the potential hazard to the foetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with vinorelbine tartrate (see Contraindications).

Use in lactation.

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 for serious adverse reactions in nursing infants from vinorelbine tartrate, it is recommended that breastfeeding be discontinued in women who are receiving therapy with vinorelbine tartrate (see Contraindications).

Use in paediatrics.

Safety and effectiveness have not been established.

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.

Interactions

Acute pulmonary reactions have been reported with vinorelbine tartrate and other vinca alkaloids used in conjunction with mitomycin. DBL Vinorelbine Injection Concentrate 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 tartrate and cisplatin is significantly higher than with single agent vinorelbine tartrate.
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 four consecutive days or 15 mg/m2/day for five consecutive days) but combination treatment with sodium valproate did not cause any increase in anticonvulsant activity.
Based on the available limited information, it is possible that interactions may occur with other drugs which are metabolised via the cytochrome CYP3A4.

Adverse Effects

Haematological.

Neutropenia is the major dose limiting toxicity with vinorelbine tartrate. Neutropenia (grade 3: 25.2%, grade 4: 28.4%) is rapidly reversible (7 to 14 days) and noncumulative. It is maximal between 5 and 10 days after administration, depending on whether vinorelbine tartrate is used as single agent or in combination. Further treatment may be given after recovery of the neutrophil count. Anaemia (grade 3 to 4: 8%) and thrombocytopenia (grade 3 to 4: 2.3%) can also occur. Dose adjustments are required for haematologic toxicity and hepatic insufficiency (see Dosage and Administration).

Neurological.

Mild to moderate peripheral neuropathy manifested by paraesthesia and loss of deep tendon reflexes (grade 3: 2.5%, grade 4:0.2%) and hyperaesthesia have been reported. After prolonged treatment weakness of the lower extremities has also been reported. The effects are dose dependent but usually reversible when treatment is discontinued.

Autonomic neuropathy.

The main symptom is intestinal paresis causing constipation, which rarely progresses to paralytic ileus (grade 3: 2%, grade 4: 0.6%). Treatment may be resumed after recovery of normal bowel mobility.

Gastrointestinal.

Constipation (see above).
Mild to moderate nausea occurred in 25.5% of patients treated with vinorelbine tartrate. Severe nausea and vomiting (grade 3: 2%, grade 4: 0.3%) occurred less frequently. Due to the low incidence of severe nausea and vomiting with single agent vinorelbine tartrate, the use of serotonin antagonists is generally not required.
Stomatitis and diarrhoea, usually mild to moderate, may occur.
Pancreatitis has been reported very rarely.

Dermatological.

Alopecia is mild and may appear progressively with extended courses of treatment.
Rarely vinorelbine tartrate may produce generalised cutaneous reactions.
Like other anticancer vinca alkaloids, vinorelbine tartrate 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.

Hepatic.

Transient elevations of liver enzymes were reported without clinical symptoms.

Respiratory.

Shortness of breath was reported in 3% of patients. Vinorelbine tartrate, like other vinca alkaloids, may produce bronchospasm. Rare cases of interstitial pneumopathy have been reported, in particular in patients treated with vinorelbine tartrate in combination with mitomycin.

Cardiovascular.

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. A few cases of myocardial infarction, angina pectoris and/or transient ECG changes have been reported (see Precautions).
Rare cases of severe hyponatraemia have been reported. In very rare cases, cardiac failure and pulmonary oedema have been reported during treatment with vinorelbine tartrate, however a causal relationship has not been established.

Other.

Fatigue occurred in 27% of patients. It was usually mild or moderate but tended to increase with cumulative dosing. Other reported toxicities occurring in less than 5% of patients include jaw pain, myalgia, arthralgia, pain at the tumour site and rash. Chest pain of noncardiac origin has also been reported. Haemorrhagic cystitis and the syndrome of inappropriate ADH secretion were each reported in < 1% of patients.
(See Table 1.)

Dosage and Administration

Adults.

Single agent treatment is usually given at 25 to 30 mg/m2 weekly.
In combination chemotherapy the dose may be the same and the frequency of administration reduced, i.e. day one and eight or day one and five every three weeks.
DBL Vinorelbine Injection Concentrate should be administered either by slow bolus over six to ten 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.

Dose modifications for haematological toxicity.

Neutrophil counts should be ≥ 1000 cells/mm3 prior to the administration of Vinorelbine Injection Concentrate. Adjustments in the dosage of DBL Vinorelbine Injection Concentrate should be based on neutrophil counts obtained on the day of treatment (see Table 2).

Note.

For patients who, during treatment with Vinorelbine Injection Concentrate, have experienced fever and/or sepsis while neutropenic or had two consecutive weekly doses withheld due to neutropenia, subsequent doses of DBL Vinorelbine Injection Concentrate should be 22.5 mg/m2 for neutrophils ≥ 1500 cells/mm3 and 11.25 mg/m2 for neutrophils 1000 to 1499 cells/mm3.

Dose modifications for hepatic insufficiency.

DBL Vinorelbine Injection Concentrate should be administered with caution to patients with hepatic insufficiency. In patients who develop hyperbilirubinaemia during treatment with Vinorelbine Injection Concentrate, the dose should be adjusted on the basis of total bilirubin, as a measure of hepatic function (see Table 3).
For patients with both haematological toxicity and hepatic insufficiency, the lower of the doses from Tables 2 and 3 should be administered.

Administration precautions.

Caution.

DBL Vinorelbine Injection Concentrate must be only administered IV through an infusion line. It is extremely important that the IV needle or catheter be properly positioned before any vinorelbine tartrate is injected. Leakage into surrounding tissue during IV administration of DBL Vinorelbine Injection Concentrate 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 Injection Concentrate, institutional guidelines may be used.
DBL Vinorelbine Injection Concentrate is a clear, colourless to pale yellow solution. Parenteral drug products should be visually inspected for particulate matter and discolouration prior to administration whenever solution and container permit. If particulate matter is seen, DBL Vinorelbine Injection Concentrate should not be administered.

Preparation for administration.

DBL Vinorelbine Injection Concentrate must be diluted in either a syringe or IV bag using one of the recommended solutions. The volume of dilution depends on the mode of administration: bolus injection: 50 mL; infusion: 125 mL.
Administration of DBL Vinorelbine Injection Concentrate must be followed with at least 250 mL of one of the solutions.

Syringe.

The calculated dose of DBL Vinorelbine Injection Concentrate 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, Sodium Chloride 0.9% Injection USP.

IV bag.

The calculated dose of DBL Vinorelbine Injection Concentrate 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, Lactated Ringer's Injection USP and Compound Sodium Lactate Intravenous Infusion BP.
DBL Vinorelbine Injection Concentrate should not be diluted in alkaline solutions due to the risk of precipitation.
DBL Vinorelbine Injection Concentrate should not be mixed with other agents. DBL Vinorelbine Injection Concentrate is not absorbed to or affected by either PVC or clear neutral glass.
As with all parenteral drug products, IV 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.
Diluted DBL Vinorelbine Injection Concentrate is chemically stable for up to 24 hours under normal room light when stored in polypropylene syringes or polyvinyl chloride bags at 5°C to 30°C.
However, to reduce microbiological hazard, the diluted solution should preferably be used immediately and any residue remaining discarded. If the diluted product cannot be used immediately or as soon as practicable after preparation, store between 2°C to 8°C for not more than 24 hours.

Pharmaceutical precautions.

The following protective recommendations are given due to the toxic nature of this substance.
Personnel should be trained in good technique for handling.
Pregnant staff should be excluded from working with this drug.
Personnel handling Vinorelbine Injection Concentrate should wear protective clothing:. goggles, gowns and disposable gloves and masks.
A designated area should be defined for reconstitution (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 disposal bags 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 the eyes, whereas water or soap and water, or sodium bicarbonate solution may be used on the skin; medical attention should be sought.

Overdosage

Symptoms.

The primary anticipated complications of overdosage would consist of bone marrow suppression and peripheral neurotoxicity.

Treatment.

There is no known antidote for overdoses of Vinorelbine Injection Concentrate. If overdosage occurs, general supportive measures together with appropriate blood transfusions and antibiotics should be instituted as deemed necessary by the physician.
In case of overdose, immediately contact the Poisons Information Centre for advice. (In Australia, call 131 126.)

Presentation

Concentrate (clear colourless to pale yellow solution), vinorelbine 10 mg/mL (≡ vinorelbine tartrate 13.85 mg): 10 mg/1 mL (in a 2 mL single use clear glass vial); 50 mg/5 mL (in a 5 mL single use clear glass vial): 1's.

Storage

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

Poison Schedule

S4.