Pierre Fabre Limited

5.1. Pharmacodynamic properties

Safety and efficacy of Navelbine in paediatric patients have not been established. Clinical data from two a single-arm Phase II studies using intravenous vinorelbine in 33 and 46 paediatric patients with recurrent solid tumours, including rhabdomyosarcoma, other soft tissue sarcoma /undiffentiated sarcoma, Ewing sarcoma, liposarcoma, synovial sarcoma, fibrosarcoma, central nervous system cancer, osteosarcoma, neuroblastoma, and CNS tumours, at doses of 30 to 33.75mg/m2 D1 and D8 every 3 weeks or once weekly for 6 weeks every 8 weeks, similar to those used in adults, showed no meaningful clinical activity. Toxicities were similar to those reported in adult patients: The toxicity profile was similar to that reported in adult patients. (see section 4.2).

4.2. Posology and method of administration

Administration in children:

Safety and efficacy in children have not been established Navelbine is not recommended for use in children due to a lack of data on safety and efficacy. and administration is therefore not recommended. : see section 5.1

5.3       Preclinical safety data

            Mutagenic and carcinogenic potential

The interaction of  NAVELBINE with the spindle apparatus during mitosis can cause an incorrect distribution of chromosomes. In animal studies NAVELBINE induced aneuploidy and polyploidy. It is therefore to be assumed that NAVELBINE can also cause mutagenic effects (induction of aneuploidy) in man.

The carcinogenicity studies, in which NAVELBINE was administered only once every two weeks in order to avoid the toxic effects of the drug, are negative.

            Reproductive toxicity

Changes from Dec-09 to Feb-11 (in blue):

4.2.      Posology and method of administration

FOR INTRAVENOUS USE ONLY AFTER APPROPRIATE DILUTION.

Strictly intravenous administration after appropriate dilution

The use of i Intra-thecal route is contra-indicated administration of Navelbine may be fatal: see section 4.4

NavelbineAVELBINE must only be administered by the intravenous route as an

infusion over 6 5 – 10 minutes.

Instructions for use and handling: see section 6.6.

Administration

-          It is recommended to infuse NavelbineAVELBINEover 6 5 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.

-          The infusion time of 6 5 to 10 minutes must be followed as the risk of venous irritation is increased if the infusion exposure time is increased.

In adults:

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

Administration in patients with liver insufficiency

For patients presenting with severe liver impairment (bilirubin > 2xUNL and/or transaminases > 5xUNL), it is suggested that the dose be reduced by 33% and the haematological parameters closely monitored since the maximum dose which was evaluated in this subset of patients was 20 mg/m² : see sections: 4.4; : 5.2.

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.

4.3.      Contraindications

-          Platelet count <  100000  75000/mm³

4.4.      Special warnings and precautions for use

Special warnings

Navelbine must only be administered by the intravenous route as an infusion over 5 – 10 minutes.

The use of intra-thecal route is contra-indicated administration of Navelbine may be fatal.

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

The risk of venous irritation is increased if the infusion exposure time exceeds the recommendedation time of 5 to 10 minutes.

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 75,000/mm³, then the treatment should be delayed until recovery.

Mitomycin C: risk of bronchospam and dyspnoea are increased, in rare case an interstitial pneumonitis was observed . as with all vinca-alkaloids, increased risk of pulmonary toxicity. Caution is advised when using vinorelbine and mitomycin C simultaneously.

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.

4.6.      Fertility, pregnancy and lactation

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.

4.8.      Undesirable effects

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

Common:        Infection bacterial, viral or fungal at different sites mild to moderate and usually reversible with an appropriate treatment.

Uncommon:    Septicaemia [very rarely fatal].

Not known:     Neutropenic sepsis, sometimes fatal

Blood and lymphatic system disorders:

Very Common: Bone marrow depression resulting mainly in neutropenia (G3: 24.3%;  

                              G4: 27.8%) reversible within 5 to 7 days and noncumulative over time.

                         Leucopenia

                                        Anaemia (G3-4: 7.4%)

Common :       Thrombocytopenia (G3-4: 2.5%) may occur but are seldom severe.

Nervous system disorders

Very Common:  Neurologic disorders (G 3-4: 2.7%) including loss of deep tendon reflexes.

   Weakness of the lower extremities has been reported after a prolonged        

     chemotherapy.

Uncommon:       Severe paresthesias with sensory and motor symptoms are infrequent.

.           These effects are generally reversible. upon discontinuation of treatment.

Respiratory system, thoracic and mediastinal disorders

Uncommon:    Dyspnoea and bronchospasm may occur in association with Navelbine

  treatment as with other vinca alkaloids.

Rare:                Interstitial pneumonopathy ies has have been reported in particular in  

                           patients treated with  Navelbine in combination with mitomycin.

Gastrointestinal disorders

Very Common:  Stomatitis (G1-4: 15%, with Navelbine as single agent)

   Nausea and vomiting (G 1-2: 30.4% and G 3-4: 2.2%). Anti-emetic therapy 

                 may reduce their occurence

    Constipation is the main symptom (G 3-4: 2.7) which rarely progresses to    

     paralytic ileus with Navelbine as single agent and (G3-4: 4.1%), with the

     combination of Navelbine and other chemotherapeutic agents.

Common:          Diarrhoea usually mild to moderate may occur.

.

Rare:               Paralytic ileus, treatment may be resumed after recovery of normal bowel                                              

                            mobility.

 Pancreatitis has been reported

Hepatobiliary disorders

Very common  Transient elevations of liver function tests (G1-2) without clinical symptoms                                      

  were reported  (SGOT in 27.6% and SGPT in 29.3%).

Skin and subcutaneous tissue disorders

Very common:   Alopecia, usually mild in nature, may occur  (G3-4: 4.1% with Navelbine

                               as single chemotherapeutic agent).

            Rare:                  Generalized cutaneous reactions have been reported with Navelbine.

Not known:        - Erythema on hands and feet

General disorders and administration site conditions

Very common:  Reactions at the injection site may include erythema, burning pain,

                                         vein discoloration and local phlebitis (G 3-4: 3.7% with Navelbine as single

                                        chemotherapeutic agent).

Common:        Asthenia, fatigue, fever, pain at different sites including chest pain and pain       

                          at the tumour site.

4.9       Overdose

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.

5.2.      Pharmacokinetic properties

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. in a conservative approach it is suggested that the dose be reduced by 33% and the haematological parameters closely monitored in patient with severe liver impairment since the maximum dose which was given in this subset of patients was 20 mg/m².

          5.3.      Preclinical Safety Data

            Mutagenic and carcinogenic potential

The interaction of  NAVELBINE with the spindle apparatus during mitosis can cause an incorrect distribution of chromosomes. In animal studies NAVELBINE induced aneuploidy and polyploidy. It is therefore to be assumed that NAVELBINE can also cause mutagenic effects (induction of aneuploidy) in man.

The carcinogenicity studies, in which NAVELBINE was administered only once every two weeks in order to avoid the toxic effects of the drug, are negative.

            Reproductive toxicity

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

The NOEL in the rat was 0.26 mg/kg every 3 days.

Following peri/postnatal administration in the rat at doses of 1.0 mg/kg every 3 days i.v., retarded weight gain was found in the offspring up to the 7th week of life.

            Safety pharmacology

Bibliographic review concerning the tolerance of vinca alkaloids on the cardiovascular system shows the occurence of some cardiac events (such as angina, myocardial infarction), but the incidence of these is low.

Haemodynamic and electrocardiographic studies on animals have been carried out by Pierre Fabre Médicament Laboratories; no haemodynamic effects have been found using a maximal tolerated dose in dogs, however only some non significant disturbances of repolarization were found for all vinca alkaloids tested. No effect on the cardiovascular system has been detected using repeated doses (study 39 weeks) of NAVELBINE on primates.

Vinorelbine induced chromosome damages but was not mutagenic in Ames test.

It is assumed that vinorelbine can cause mutagenic effects (induction aneuploidy and polyploidy) in humans..

In animal reproductive studies, vinorelbine was embryo-foeto-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.

          6.6.      Instructions for Use, Handling and Disposal

For single use only, discard any unused contents

The intra-thecal route is contraindicated: see sections 4.2 and 4.4

Changes from v8 (Jun-09) to v9 (Dec-09):
Section 4.8:

The table of adverse reactions at the end of section 4.8 has been removed. 

Also, the following changes have been made:

See table of adverse reactions

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.

Infections and infestations

Common: Infection bacterial, viral or fungal at different sites.

Uncommon: Septicaemia [very rarely fatal].

Not known: Neutropenic sepsis, sometimes fatal

Blood and lymphatic system disorders:

Very Common: Bone marrow depression resulting mainly in neutropenia reversible within 5 to 7 days and noncumulative over time.

-          Leucopenia

-          Anaemia

Common: Thrombocytopenia.

Not known: Febrile neutropenia

Section 3: pH range added

Section 4.2: The following information has been added:

·         NAVELBINE must only be administered by the intravenous route as an infusion over 5 – 10 minutes.

·         The infusion time of 5 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.

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: 

Section 4.3: The following information has been added:

·         Platelet count <  75000/mm3

·         In combination with yellow fever vaccine: see section 4.5

Section 4.4: The following information has been added:

·         NAVELBINE must only be administered by the intravenous route as an infusion over 5 – 10 minutes.

·         The risk of venous irritation is increased if the infusion exposure time exceeds the recommendation time of 5 to 10 minutes.

Precautions for use

·         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.

Section 4.5: Rewritten

Section 4.6: The following information has been added:

·         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.

“Breast feeding” changed to “lactation”

Section 4.8: The following information has been added:

·         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, anaemia, neurologic disorders, gastrointestinal toxicity with nausea, vomiting, stomatitis and constipation, Transient elevations of liver function tests, alopecia and local phlebitis.

Adverse reactions added:

Febrile neutropenia and anorexia

Section 5.2: The following information has been added:

·         Biotransformation: All metabolites of vinorelbine are formed by CYP 3A4 isoform of cytochromes P450

·         Elderly patients: However, since elderly patients are frail, caution should be exercised when increasing the dose of Navelbine

Section 2 - change of table to following text:

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

Section 3 - addition of following text:

NAVELBINE  is a clear colourless to pale yellow solution

Section 6.2 - Addition of following text and removal of information on dilution:

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

Section 6.3 - Additional information regarding after dilution:

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 (20⁰C ± 5⁰C) or in the refrigerator (2⁰C - 8⁰C) 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.

Section 6.4 - Additional information regarding freezing:

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.

Section 6.5 - Additional information on glass vials and outers:

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

Section 6.6 - Complete section re-written
                

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.

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.

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

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

It is recommended to infuse Navelbine over 5 -10 minutes after dilution in 20-50 ml of sodium chloride 9 mg/ml (0.9%) solution for injection or in glucose solution for injection 5%. After administration the vein should be thoroughly flushed with at least 250 ml of saline solution.

Navelbine 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 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 normal saline and the remaining dose administered in another vein.

Disposal

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

Section 10 - New revision date

16 January 2008