Навельбин

- 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.

- 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 Навельбин may be fatal.

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

Administration

- It is recommended to infuse Навельбин 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 Навельбин. 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 Навельбин 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.

Posology

- Навельбин is usually given at 25-30 mg/m² once weekly.

In combination with other cytostatic agents the exact dose should be taken from the treatment protocol.

Навельбин may be administered by slow bolus (6-10 minutes) after dilution in 20-50 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection or in 5 % (w/v) glucose solution for injection or by a short infusion (20-30 minutes) after dilution in 125 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection or in 5 % (w/v) glucose solution for injection. Administration should always be followed by a sodium chloride 9 mg/ml (0.9 %) infusion with at least 250 ml to flush the vein.

The maximum tolerated dose per administration: 35.4 mg/m² body surface area

The maximum total dose per administration: 60 mg

Dose modifications

Навельбин metabolism and clearance are mostly hepatic: only 18.5 % is excreted unchanged in the urine. No prospective study relating altered metabolism of the active substance to its pharmacodynamic effects is available in order to establish guidelines for Навельбин dose reduction in patients with impaired liver or kidney function.

Hepatic impairment

The pharmacokinetics of Навельбин is not modified in patients presenting moderate or severe liver impairment.

Nevertheless as a precautionary measure a reduced dose of 20 mg/m² and close monitoring of haematological parameters is recommended in patients with severe liver impairment.

Renal impairment

Given the minor renal excretion, there is no pharmacokinetic rationale for reducing Навельбин dose in patients with impaired kidney function.

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 Навельбин.

Paediatric population

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

Method of administration

Strictly intravenous administration after appropriate dilution.

Intrathecal administration of Навельбин may be fatal.

Precautions to be taken before handling or administering the medicinal product

- 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

- Neutrophil count < 1,500/mm³ or severe current or recent infection (within the last 2 weeks)

- Thrombocyte count below 100,000/mm³

- Severe hepatic impairment not related to the tumoural process

- In combination with yellow fever vaccine

- Pregnancy

- Lactation

Special warnings

Навельбин 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 Навельбин, 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

Навельбин 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.

Special warnings

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

- Навельбин must only be administered by the intravenous route. The use of intrathecal route is contra-indicated. Administration should always be followed by a sodium chloride 9 mg/ml (0.9 %) infusion to flush the vein.

- Навельбин must be administered intravenously with great precision: It is very important to make sure that the cannula has been accurately placed into the vein before starting to infuse Навельбин. If Навельбин extravasates during intravenous administration, this can cause considerable local irritation. In this case, the infusion must be stopped immediately, the vein flushed through with sodium chloride 9 mg/ml (0.9 %) solution and the rest of the dose should be administered in another vein. In the event of extravasation glucosteroids can be given intravenously in order to reduce the risk of phlebitis.

- Treatment should be undertaken with close haematological monitoring (determination of haemoglobin level and number of leukocytes, granulocytes and thrombocytes before each new injection). 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 <1,500/mm³ and/or thrombocyte count is below 100,000/mm³, treatment should be delayed until recovery and the patient should be observed. Administration of the medicinal product is expected to be delayed by 1 week in about 35 % of treatment courses.

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

- Interstitial lung disease has been reported more frequently in the Japanese population. Special attention should be exercised for this specific population.

Special precautions for use

- If there is significant hepatic impairment the dose should be reduced: caution is recommended and careful monitoring of haematological parameters required.

- In case of renal impairment, because of the low level of renal excretion, no dose modification is necessary.

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

- Strong CYP3A4- inhibitors or inducers should be administered with caution because of the risk of affecting the Навельбин concentration.

- This product is generally not recommended in combination with itraconazole (like all vinca-alkaloids) and phenytoin (like all cytotoxics).

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

- To avoid bronchospasm - especially if used concomitantly with mitomycin C-appropriate precautionary measures should be considered. Patients treated on an outpatient basis should be informed that they should contact the physician in case of dyspnoea.

- It is recommended that special caution should be shown towards patients with ischaemic heart disease in the medical history.

- All contact with the eyes should be strictly avoided: risk of severe irritation and even corneal ulceration if the medicinal product is sprayed under pressure. Immediate liberal washing of the eye with sodium chloride 9 mg/ml (0.9 %) solution should be undertaken if any contact occurs.

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

No studies of the effects on the ability to drive and use machines have been performed but on the basis of the pharmacodynamic profile Навельбин has no or negligible influence on the ability to drive and use machines. However, caution is necessary in patients treated with Навельбин considering some adverse effects of the medicinal product.

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

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

In combined chemotherapy of Навельбин with other antineoplastic medicinal products it has to be considered, that the listed undesirable effects can occur more frequently and more severe than those undesirable effects observed during and after monotherapy. Moreover, the additional specific undesirable effects of the other medicinal products have to be considered.

Adverse reactions reported as more than isolated cases are listed below, by system organ class and by frequency. Frequencies are defined as:

Very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000).

Additional adverse reactions from post marketing experience have been added according to the MedDRA classification with the frequency Not known (cannot be estimated from the available data).

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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Symptoms

Overdosage with Навельбин 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 Навельбин.

Cases of accidental acute overdose have been reported in humans: Such cases can result in bone marrow hypoplasia and are sometimes associated with infection, fever and paralytic ileus. Supporting treatment such as blood transfusion, growth factors or broad-spectrum antibiotic treatment is normally initiated at the doctor's discretion. There is no known antidote.

As there is no specific antidote for the overdose of Навельбин given intravenously, symptomatic measures are necessary in case of an overdose, e.g.:

- Continuous control of vital signs and careful monitoring of the patient.

- Daily control of blood count to observe the need of blood transfusions, of growth factors and to detect the need of intensive care and to minimise the risk of infections.

- Measures for prevention or for therapy of paralytic ileus

- Control of circulation system and of liver function

- Broad spectrum antibiotic therapy may be necessary in case of complications due to infections. In case of a paralytic ileus, decompression by a probe may be necessary.

Pharmacotherapeutic group: Vinca alkaloids and analogues

ATC Code: L01C A04

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

Safety and efficacy of Навельбин 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..

Pharmacotherapeutic group: Antineoplastic and immunmodulating agents, vinca alkaloids

ATC code: L 01 CA 04

Навельбин is an antineoplastic active substance of the vinca alkaloid family, but in contrast to all other vinca alkaloids the catharanthine portion of Навельбин has undergone a structural modification. On the molecular level it affects the dynamic equilibrium of tubulin in the microtubular system of the cell.

Mechanism of action

Навельбин inhibits tubulin polymerisation and binds preferentially to mitotic microtubules, only affecting axonal microtubules at high concentrations. Spiralisation of the tubulin is induced to a lesser degree than with vincristine. Навельбин blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.

Paediatric population

The safety and efficacy of Навельбин in paediatric patients have not been established. Clinical data from two single arm Phase II studies using intravenous Навельбин 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 33.75 mg/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 Навельбин 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.

Distribution

The active ingredient is widely distributed in the body with a volume of distribution ranging from 25.4-40.1 l/kg. Penetration of Навельбин into pulmonary tissue is significant with tissue/plasma concentration ratios of greater than 300 in a study involving surgical biopsy. There is moderate binding to plasma proteins (13.5 %) but strong binding to platelets (78 %). Linear pharmacokinetics has been shown for intravenously administered Навельбин up to a dose of 45 mg/m².

Biotransformation

Навельбин is primarily metabolised by CYP3A4 of cytochrome P450. All metabolites have been identified and none are active with the exception of 4-O-deacetylНавельбин, which is the principal metabolite in the blood.

Elimination

After intravenous bolus injection or infusion in patients, the plasma concentration of Навельбин is characterised by a three exponential elimination curve. The terminal elimination phase reflects a long half-life greater than 40 hours. Total clearance of Навельбин is high (0.97-1.26 l/h/kg).

Renal elimination is low (< 20 % of the dose). Small concentrations of deacetyl Навельбин have been recovered in humans, but Навельбин is principally detected as the unchanged compound in urine. Elimination of the active substance is mainly via the bile duct and consists of the metabolites and mainly of unchanged Навельбин.

The effect of kidney dysfunction on the disposition of Навельбин has not been studied, but dose reduction is not indicated because of the low degree of renal excretion. In patients with liver metastases changes only occurred in the mean clearance of Навельбин when over 75 % of the liver was affected. In 6 cancer patients with moderate liver dysfunction (bilirubin ≤ 2 x ULN and aminotransferases ≤ 5 x ULN) treated with up to 25 mg/m² and 8 cancer patients with severe liver dysfunction (bilirubin > 2 x ULN and/or aminotransferases > 5 x ULN) treated with up to 20 mg/m², mean total clearance in the two groups were similar to that in patients with normal liver function. These data may however not be representative for patients with reduced capacity to eliminate the active substance via the liver and therefore caution is recommended in patients with severe hepatic impairment and careful monitoring of haematological parameters required.

Elderly

A study, conducted by the innovator, with Навельбин in elderly patients (> 70 years) with NSCLC demonstrated that pharmacokinetics of Навельбин were not influenced by age. However, since elderly patients are frail, caution should be exercised when increasing the dose of Навельбин.

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.

The limiting toxicity in animals is bone marrow depression. In animal studies, Навельбин induced aneuploidy and polyploidy.

It can be assumed that Навельбин can also cause genotoxic effects in humans (induction of aneuploidy and polyploidy).

The results of studies for carcinogenic potential in mice and rats were negative but only low doses have been tested.

In animal reproductive studies, effects were observed at subtherapeutic doses. Embryo- and fetotoxicity were seen, such as intra-uterine growth retardation and delayed ossification. Teratogenicity (fusion of the vertebrae, missing ribs) was observed at maternally toxic doses. In addition, spermatogenesis and secretion of prostate and seminal vesicles were reduced, but fertility in rats was not diminished.

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

- Навельбин 10 mg/ml concentrate for solution for infusion should not be diluted with alkaline solutions (risk for precipitation).

For single use only, discard any unused contents

Handling and Use

The preparation and administration of Навельбин 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 Навельбин 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

Навельбин 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, Навельбин should not be mixed with other agents.

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

Навельбин 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.

The preparation and administration of Навельбин should be carried out only by trained personnel. Suitable protective goggles, disposable gloves, face mask and disposable clothing must be worn. Spills and leakages must be wiped up.

Any contact with the eyes must be strictly avoided. If the solution does come into contact with the eyes they must be rinsed immediately with plenty of sodium chloride 9 mg/ml (0.9 %) solution.

After preparation, any exposed surface must be thoroughly cleaned and hands and face washed.

There is no incompatibility between the contents and container for Навельбин 10 mg/ml concentrate for solution for infusion and a neutral glass bottle, PVC bag, vinylacetate bag or infusion set with PVC tubes.

It is recommended to administer Навельбин as an infusion over the course of 6-10 minutes after dilution in 20-50 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection or in 5 % (w/v) glucose solution for injection or by a short infusion (20-30 minutes) after dilution in 125 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection or in 5 % (w/v) glucose solution for injection. After administration the vein must be flushed through thoroughly with at least 250 ml sodium chloride 9 mg/ml (0.9 %) solution.

Навельбин must be given strictly intravenously: it is very important to make sure that the cannula is accurately placed in the vein before starting to infuse Навельбин. If the medicinal product 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 sodium chloride 9 mg/ml (0.9 %) solution and the remaining dose administered in another vein.

In case of extravasations, to reduce the risk of phlebitis IV glucocorticoids could be administered immediately.

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