NAVELBINE 10 mg / ml concentrate for solution for infusion

Vinorelbine 10 mg/ml as vinorelbine tartrate

Each 1ml vial contains 10 mg Vinorelbine as vinorelbine tartrate

Each 4ml vial contains 40 mg Vinorelbine as vinorelbine tartrate

Each 5ml vial contains 50 mg Vinorelbine as vinorelbine tartrate

For a full list of excipients, see section 6.1

Concentrate for solution for infusion.

Navelbine is a clear colourless to pale yellow solution with a pH range from 3.3 to 3.8.

- As a single agent or in combination for the first line treatment of stage 3 or 4 non small cell lung cancer.

- Treatment of advanced breast cancer stage 3 and 4 relapsing after or refractory to an anthracycline containing regimen.

Strictly intravenous administration after appropriate dilution

Intra-thecal administration of Navelbine may be fatal.

Navelbine must only be administered by the intravenous route as an infusion over 6 – 10 minutes.

Instructions for use and handling: see section 6.6.

Administration

- It is recommended to infuse Navelbine over 6 to 10 minutes after dilution in a 50 ml infusion bag with sodium chloride 9 mg/ml (0.9%) solution for injection or in 5% glucose solution for injection.

- Administration should always be followed with at least 250 ml of a normal saline infusion to flush the vein.

- The infusion time of 6 to 10 minutes must be followed as the risk of venous irritation is increased if the infusion exposure time is increased.

- It is vital to ensure that the cannula is accurately placed in the vein before starting to infuse Navelbine. If the drug extravasates into the surrounding tissue during the administration considerable local irritation may occur. In this case, the administration should be stopped, the vein flushed with 0.9 % sodium chloride solution and the remaining dose administered in another vein.

The management of any extravasation should be according to local hospital guidelines and policies.

Advanced non-small cell lung cancer and advanced breast cancer

- In monotherapy the usual dose given is 25-30 mg/m² once weekly.

- In combination chemotherapy the usual dose (25-30 mg/m²) is usually maintained, while the frequency of administration is reduced e.g. day 1 and 5 every 3 weeks or day 1 and 8 every 3 weeks according to treatment protocol.

Administration in the elderly

Clinical experience has not detected any significant differences among elderly patients with regard to the response rate, although greater sensitivity in some of these patients cannot be excluded. Age does not modify the pharmacokinetics of vinorelbine: see section 5.2.

Administration in patients with liver insufficiency

The pharmacokinetics of Navelbine is not modified in patients presenting with moderate or severe liver impairment. Nevertheless as a precautionary measure a reduced dose of 20mg/m² and close monitoring of haematological parameters is recommended in patients with severe liver impairment: see sections: 4.4; 5.2.

Administration in patients with renal insufficiency

Given the minor renal excretion, there is no pharmacokinetic justification for reducing the dose of Navelbine in patients with renal insufficiency: see section 4.4:

Administration in children

Safety and efficacy in children have not been established and administration is therefore not recommended.

- Known hypersensitivity to vinorelbine or other vinca alkaloids, or to any of the excipients.

- Neutrophil count < 1500/mm³ or severe infection current or recent (within 2 weeks)

- Platelet count < 100000/mm³

- In combination with yellow fever vaccine: see section 4.5

- Pregnancy: see section 4.6

- Lactation : see section 4.6

Special warnings

Navelbine should be administered under the supervision of a physician experienced in the use of chemotherapy.

Since inhibition of the hematopoietic system is the main risk associated with Navelbine, close haematological monitoring should be undertaken during treatment (determination of haemoglobin level and the leukocyte, neutrophil and platelet counts on the day of each new administration).

The dose limiting adverse reaction is mainly neutropenia. This effect is non-cumulative, having its nadir between 7 and 14 days after the administration and is rapidly reversible within 5 to 7 days. If the neutrophil count is below 1500/mm³and/or the platelet count is below 100000 /mm³, then the treatment should be delayed until recovery.

If patients present signs or symptoms suggestive of infection, a prompt investigation should be carried out.

Special precautions for use

Special care should be taken when prescribing for patients with history of ischemic heart disease: see section 4.8.

The pharmacokinetics of Navelbine is not modified in patients presenting moderate or severe liver impairment: see section 5.2. For dosage adjustment in this specific patient group, see section 4.2.

As there is a low level of renal excretion there is no pharmacokinetic rationale for reducing the dose of Navelbine in patients with impaired kidney function: see sections 4.2, 5.2.

Navelbine should not be given concomitantly with radiotherapy if the treatment field includes the liver.

This product is specifically contra-indicated with yellow fever vaccine and its concomitant use with other live attenuated vaccines is not recommended.

Caution must be exercised when combining Navelbine and strong inhibitors or inducers of CYP3A4: see section 4.5, and its combination with phenytoin (like all cytotoxics) and with itraconazole (like all vinca alkaloids) is not recommended.

All contact with the eyes should be strictly avoided. There is a risk of severe irritation and even corneal ulceration if the drug is sprayed under pressure. Immediate washing of the eye with normal saline solution should be undertaken if any contact occurs.

Concomitant use contraindicated

Yellow fever vaccine: as with all cytotoxics, risk of fatal generalised vaccine disease: see section 4.3.

Live attenuated vaccines: (for yellow fever vaccine, see concomitant use contraindicated) as with all cytotoxics, risk of generalised vaccine disease, possibly fatal. This risk is increased in patients already immunodepressed by their underlying disease. It is recommended to use an inactivated vaccine when one exists (e.g. poliomyelitis): see section 4.4.

Phenytoin: as with all cytotoxics, risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic drug or risk of toxicity enhancement or loss of efficacy of the cytotoxic drug due to increased hepatic metabolism by phenytoin.

Itraconazole: as with all vinca-alkaloids, increased neurotoxicity of vinca-alkaloids due to the decrease of their hepatic metabolism.

Concomitant use to take into consideration

Cisplatin: There is no mutual pharmacokinetic interaction when combining Navelbine with cisplatin over several cycles of treatment. However, the incidence of granulocytopenia associated with Navelbine use in combination with cisplatin is higher than associated with Navelbine single agent.

Mitomycin C: risk of bronchospam and dyspnoea are increased, in rare case an interstitial pneumonitis was observed.

Ciclosporin,tacrolimus:excessive immunodepression with risk of lymphoproliferation.

As vinca alkaloids are known substrates for P_glycoprotein, and in the absence of specific study, caution should be exercised when combining Navelbine with strong modulators of this membrane transporter.

The combination of Navelbine with other drugs with known bone marrow toxicity is likely to exacerbate the myelosuppressive adverse effects.

As CYP3A4 is mainly involved in the metabolism of vinorelbine, combination with strong inhibitors of this isoenzyme (e.g. azole antifungals such as ketoconazole and itraconazole) could increase blood concentrations of vinorelbine and combination with strong inducers of this isoenzyme (e.g. rifampicin, phenytoin) could decrease blood concentrations of vinorelbine.

Anticoagulant treatment: as with all cytotoxics, the frequency of INR (International Normalised Ratio) monitoring should be increased due to the potential interaction with oral anticoagulants and increased variability of coagulation in patients with cancer.

Pregnancy:

Navelbine is suspected to cause serious birth effects when administered during pregnancy: see section 5.3.

Navelbine is contraindicated in pregnancy: see section 4.3.

In case of a vital indication for treatment with Navelbine during pregnancy a medical consultation concerning the risk of harmful effects for the child should be conducted. If pregnancy occurs during treatment genetic counselling should be offered.

Women of child-bearing potential

Women of child-bearing potential have to use effective contraception during treatment and up to 3 months after treatment: see section 4.3.

Lactation:

It is unknown whether Navelbine is excreted in human breast milk. The excretion of Navelbine in milk has not been studied in animal studies. A risk to the suckling child can not be excluded therefore breast feeding must be discontinued before starting treatment with Navelbine: see section 4.3.

Fertility:

Men being treated with Navelbine are advised not to father a child during and minimally up to 3 months after treatment: see section 4.3. Prior to treatment advice should be sought for conserving sperm due to the chance of irreversible infertility as a consequence of treatment with vinorelbine.

No studies on the effects on the ability to drive and use machines have been performed.

On the basis of the vinorelbine pharmacodynamic profile, Navelbine is unlikely to impair the ability to drive or operate machinery. However, caution is necessary in patients treated with Navelbine considering some side effects of the drug: see section 4.8.

Adverse reactions reported as more than isolated cases are listed below, by system organ class and by the MedRA frequency. Additional Adverse reactions from Post Marketing experience has been added according to the MedDRA classification with the frequency Not known.

The most commonly reported adverse drug reactions are bone marrow depression with neutropenia, leucopenia and anaemia, neurologic disorders, gastrointestinal toxicity with nausea, vomiting, stomatitis and constipation, transient elevations of liver function tests, alopecia and local phlebitis.

Detailed Adverse reactions information:

Reactions were described using the W.H.O classification (grade 1=G1; grade 2=G2; grade 3=G3; grade 4=G4; grade 1-4=G1-4; grade 1-2=G1-2; grade 3-4=G3-4).

Infections and infestations

Blood and lymphatic system disorders:

Immune system disorders

Endocrine disorders

Metabolism and nutrition disorders

Nervous system disorders

Cardiac disorders

Vascular disorders

Respiratory system, thoracic and mediastinal disorders

Gastrointestinal disorders

Hepatobiliary disorders

Skin and subcutaneous tissue disorders

Musculoskeletal and connective tissue disorders

General disorders and administration site conditions

Symptoms

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

Emergency procedure

General supportive measures together with blood transfusion, growth factors and broad spectrum antibiotic therapy should be instituted as deemed necessary by the physician.

Antidote

There is no known antidote for overdosage of Navelbine.

Pharmacotherapeutic group: Vinca alkaloïds and analogues

ATC Code: L01C A04

Navelbine is an antineoplastic drug of the vinca alkaloid family but unlike all the other vinca alkaloids, the catharantine moiety of vinorelbine has been structurally modified. At the molecular level, it acts on the dynamic equilibrium of tubulin in the microtubular apparatus of the cell. It inhibits tubulin polymerization and binds preferentially to mitotic microtubules, affecting axonal microtubules at high concentrations only. The induction of tubulin spiralization is less than that produced by vincristine.

Navelbine-blocks mitosis at G2-M, causing cell death in interphase or at the following mitosis.

Safety and efficacy of Navelbine in paediatric patients have not been established.

Clinical data from two single arm Phase II studies using intravenous vinorelbine in 33 and 46 paediatric patients with recurrent solid tumours, including rhabdomyosarcoma, other soft tissue sarcoma, Ewing sarcoma, liposarcoma, synovial sarcoma, fibrosarcoma, central nervous system cancer, osteosarcoma, neuroblastoma at doses of 30 to 33.75mg/m² D1 and D8 every 3 weeks or once weekly for 6 weeks every 8 weeks, showed no meaningful clinical activity. The toxicity profile was similar to that reported in adult patients.(see section 4.2).

Pharmacokinetic parameters of vinorelbine were evaluated in blood.

Distribution

The steady-state volume of distribution is large, on average 21.2 l.kg^-1 (range: 7.5-39.7 l.kg^-1), which indicates extensive tissue distribution. Vinorelbine has high affinity for platelets and lymphocytes. Binding to plasma protein is low (13.5%). However, vinorelbine binds strongly to blood cells and especially to platelets. 78% of the total blood-bound vinorelbine was associated with platelets and 4.8% of the total blood-bound vinorelbine was associated with lymphocytes.There is significant uptake of vinorelbine in the lungs, as assessed by surgical lung biopsies, which showed concentrations up to 300-fold higher than in serum. Vinorelbine is not found in the central nervous system.

Biotransformation

All metabolites of vinorelbine are formed by CYP 3A4 isoform of cytochromes P450, except 4-O-deacetylvinorelbine likely to be formed by carboxylesterases. 4-O-deacetylvinorelbine is the only active metabolite and the main one observed in blood.

Neither sulfate nor glucuronide conjugates are found.

Elimination

The mean terminal half-life of vinorelbine is around 40 hours. Blood clearance is high, approaching hepatic blood flow, and is 0.72 l.h^-1.kg^-1 on average (range: 0.32 – 1.26 l.h^-1.kg^-1).

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

Special patient groups

Renal impairment

The effects of renal dysfunction on the pharmacokinetics of vinorelbine have not been studied. However, dose reduction in case of reduced renal function is not indicated due to the low renal elimination.

Liver impairment

A first study has reported the effects of liver impairment on vinorelbine pharmacokinetics. This study was performed in patients with liver metastases due to breast cancer, and concluded that a change in mean clearance of vinorelbine was only observed when more than 75% of the liver is involved.

A phase I pharmacokinetic dose-adjusted study was conducted in cancer patients with liver dysfunction: 6 patients with moderate dysfunction (Bilirubin < 2 x UNL and Transaminases < 5 x UNL) treated up to 25 mg/m² and 8 patients with severe dysfunction (Bilirubin> 2 x UNL and/or Transaminases>5 x UNL) treated up to 20 mg/m². Mean total clearance in these two subsets of patients was similar to that in patients with normal hepatic function. Therefore, the pharmacokinetics of vinorelbine is not modified in patients presenting moderate or severe liver impairment. Nevertheless, as a precautionary measure a reduced dose of 20mg/m² and close monitoring of haematological parameters is recommended in patient with severe liver impairment: see sections 4.2 and 4.4.

Elderly patients

A study with Navelbine in elderly patients ( 70 years) with NSCLC demonstrated that pharmacokinetics of vinorelbine were not influenced by age. However, since elderly patients are frail, caution should be exercised when increasing the dose of Navelbine: see section 4.2

Pharmacokinetic / pharmacodynamic relationships

A strong relationship has been demonstrated between vinorelbine blood exposure and of leucocytes or PMNs decreases.

Pre-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity.

Vinorelbine induced chromosome changes but was not mutagenic in Ames test. It is assumed that vinorelbine can cause mutagenic effects (induction of aneuploidy of polyploidy) in man.

In animal reproductive studies, vinorelbine was embryo-feto-lethal and teratogenic.

No haemodynamic effects were found in dogs receiving vinorelbine at maximal tolerated dose; only some minor, non significant disturbances of repolarisation were observed as with other vinca alkaloids tested.

No effect on the cardiovascular system was observed in primates receiving repeated doses of vinorelbine over 39 weeks.

Navelbine should not be diluted in alkaline solutions (risk of precipitation).

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Vial before opening:

3 years.

After dilution:

After diluting Navelbine in sodium chloride 9 mg/ml (0.9%) solution for injection or in glucose solution for injection 5%, chemical and physical in-use stability has been demonstrated for 8 days at room temperature (20°C ± 5°C) or in the refrigerator (2°C - 8°C) protected from light, in neutral glass bottle, PVC and vinyl acetate bags.

From a microbiological point of view, the product should be used immediately. If not used immediately, in use storage times and conditions prior to use are under the responsibility of the user and would normally not be longer than 24 hours at 2° - 8°C, unless preparation has taken place in controlled and validated aseptic conditions.

Store in a refrigerator at 2° C - 8° C

Do not freeze

Store in the original container in order to protect from light.

Diluted solution: see section 6.3.

The drug is distributed in clear glass vials (type I) of appropriated volume closed by a butyl or chlorobutyl stopper. The stopper is covered with a crimped-on aluminium cap equipped with a polypropylene seal.

Vials of 1, 4 and 5 ml.

Boxes containing 10 vials for each strength:

10 mg / 1 ml

40 mg / 4 ml

50 mg / 5 ml

Not all pack sizes may be marketed

For single use only, discard any unused contents

Handling and Use

The preparation and administration of Navelbine should be carried out by trained staff and as with all cytotoxic agents, precautions should be taken to avoid exposing staff during pregnancy.

Caution should be exercised in handling and preparing the Navelbine solution:

- Suitable eye protection, disposable gloves, face mask and disposable apron should be

- worn.

- Eventual spillage or leakage should be mopped up wearing protective gloves.

- All contact with the eye should be strictly avoided: risk of severe irritation and even

- corneal ulceration if the drug is sprayed under pressure. Immediate liberal washing

- of the eye with normal saline solution should be undertaken if any contact occurs.

- On completion, any exposed surface should be thoroughly cleaned and hands and face washed.

Preparation of the solution for infusion

Navelbine must be diluted prior to administration in a 50 ml volume of sodium chloride 9 mg/ml (0.9 %) solution for injection or in 5 % glucose solution for injection.

In case of polychemotherapy, Navelbine should not be mixed with other agents

There is no content / container incompatibility between Navelbine and neutral glass bottle, PVC bag, vinyl acetate bag or infusion set with PVC tubing.

Navelbine must only be administered by the intravenous route as an infusion.

For further instructions on administration: see section 4.2.

Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

PIERRE FABRE Ltd

Hyde Abbey House

23 Hyde Street

Winchester

Hampshire SO23 7DR

UNITED KINGDOM

PL 00603/0028

Date of First Authorisation 10 May 1996

Date of last renewal: 10 May 2002

28/07/2011