Navildez

- 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 Navildez may be fatal.

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

Administration

- It is recommended to infuse Navildez 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 Navildez. 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.

Administration in patients with liver insufficiency

The pharmacokinetics of Navildez 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

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

Special warnings

Navildez 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 Navildez, 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

Navildez 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.

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.

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

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 Navildez 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 Navildez.

Pharmacotherapeutic group: Vinca alkaloids and analogues

ATC Code: L01C A04

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

Safety and efficacy of Navildez 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..

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/m².4.

Elderly patients

A study with Navildez in elderly patients (> 70 years) with NSCLC demonstrated that pharmacokinetics of vinorelbine were not influenced by age.

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.

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

For single use only, discard any unused contents

Handling and Use

The preparation and administration of Navildez 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 Navildez 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

Navildez 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, Navildez should not be mixed with other agents.

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

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

Disposal

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