Changes made to Section 7: Updated MAH address. Section 10: Updated revision date.

Changes made to Section 6: Updated MAH and manufacturer's address. Updated revision date.

Section 6. A change in name of the manufacturer; from Pierre Fabre Médicament Production to Fareva Pau 1.

Updated SmPC following aType II C.I.4 worksharing variation; Harmonisation of Section 4.8 of the SmPC of Navelbine Soft Capsules in all European Countries.

Updated PIL following aType II C.I.4 worksharing variation; Harmonisation of Section 4 of the PIL of Navelbine Soft Capsules in all European Countries.

Updated SmPC following the Type II C.I.4 worksharing variation; Harmonisation of section 4.8 of the SmPC of Navelbine Soft Capsules in all European Countries.

Updates to Section 4.8 - Undesirable Effects.

Additions:

Infections and Infestations:

Not known:                 Severe Sepsis sometimes with other organ failure

                                    Septicemia

Blood and lymphatic system disorders:

Not known:                 Thrombocytopenia G3-4

                                    Pancytopenia

Endocrine disorders:

Not known:                 Inappropriate antidiuretic hormone secretion (SIADH)

Metabolism and nutrition disorders:

Very common:            Anorexia G1-2: 34.5%; G3-4: 4.1%

Cardiac disorders:

Uncommon:                Heart failure, Cardiac dysrhythmia

Hepatobiliary disorders:

Not known:                 Transient elevations of liver function tests G1-2

Deletions:

Renal and urinary disorders:

Not known:                 Acute kidney injury

Alterations:

Eye disorders:

Common:                    Visual impairment G1-2: 1.3%

Vascular disorders:

Common:                    Arterial hypertension G1-4: 2.5%; G3-4: 0.3%

            Arterial hypotension G1-4: 2.2%; G3-4: 0.6%

Renal and urinary disorders:

Common:                    Dysuria G1-2: 1.6%

            Other genitourinary symptom G1-2: 1.9%

The Undesirable Effects that were tabulated for the concentrate for infusion presentation have now been summarised as “For the intravenous formulation of Navelbine, the following additional Adverse Drug Reactions were reported: systemic allergic reactions, severe paresthesias, weakness of lower extremities, heart rhythm disorders, flushing, peripheral coldness, collapse, angina pectoris, bronchospasm, interstitial pneumopathy, pancreatitis, palmar-plantar erythrodysesthesia syndrome.”

The Marketing Authorisation (MA) has been transferred to an EU entity as a result of Brexit, see section 7.

The Product Authorisation (PA) number has been updated to reflect the new MA Holder.

The Marketing Authorisation (MA) has been transferred to an EU entity as a result of Brexit, see section 6.

The Product Authorisation (PA) number has been updated to reflect the new MA Holder.

4.2     Posology and method of administration

Posology

Navelbine should be swallowed whole with water without chewing or sucking the capsule. It is recommended to take the capsule with some food.

Administration in patients with liver insufficiency

Navelbine can be administered at the standard dose of 60 mg/m²/week in patients with mild hepatic disorder liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from between 1.5 and to 2.5 x ULN).

In patients with moderate hepatic disorder liver impairment (bilirubin from between 1.5 and to 3 x ULN, independent whatever the levels of ALAT and ASAT level), Navelbine should needs to be administered at a dose of 50 mg/m²/week. The aAdministration of Navelbine in to patients with severe hepatic disorder impairment is contra-indicated not recommended because there is insufficient data in this population in order to determine the pharmacokinetics, efficacy and safety, (see sections 4.3, 4.4, 5.2).

Administration in patients with impaired renal function insufficiency

Given the minor renal excretion, there is no pharmacokinetic justification for reducing the dose of Navelbine in patients with impaired serious renal function insufficiency, (see section 4.4, 5.2).

4.3     Contraindications

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

-        Disease significantly affecting absorption

-        Previous significant surgical resection of stomach or small bowel.

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

-        Platelet count <  100000/mm³

-        Severe hepatic insufficiency

-        Pregnancy: see section 4.6

-        Lactation (see section 4.6)

-        Patients requiring long-term oxygen therapy

-        In combination with yellow fever vaccine (see section 4.5).

4.4     Special warnings and precautions for use

Special precautions for use

Oral Navelbine has been was studied in patients with hepatic disorder liver impairment at the following dosageses:
- 60 mg/m² in 7 patients with mild hepatic disorder liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT between from 1.5 and to 2.5 x ULN);

- 50 mg/m² in 6 patients with moderate hepatic disorder liver impairment (bilirubin between from 1.5 and to 3 x ULN, independent whatever the levels of ALAT and ASAT level).

The safety and pharmacokinetics of vinorelbine were not changed in these patients at the tested doses.

Total clearance of vinorelbine was neither modified between mild and moderate hepatic disorder liver impairment nor was it altered in hepatically impaired patients with hepatic disorder when compared with clearance in patients with normal hepatic liver function.

Oral Navelbine has was not been studied in patients with severe hepatic disorder, impairment therefore it’s the use in these patients is not recommended contra-indicated in these patients: , (see sections 4.2, 4.3, 5.2).

4.5     Interaction with other medicinal products and other forms of interaction

Concomitant use contraindicated

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

Concomitant use not recommended

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.

Concomitant use to take into consideration

An increased incidence of grade 3/4 neutropenia has been suggested when intravenous vinorelbine and lapatinib were associated in one clinical phase I study. In this study, the recommended dose of intravenous form of vinorelbine in a 3-weekly schedule on day 1 and day 8 was 22.5 mg/m² when combined with daily lapatinib 1000 mg. This type of combination should be administered with caution.

4.6     Fertility, pregnancy and lactation

Pregnancy

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

Navelbine is contra-indicated 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 counseling should be offered.

There are insufficient data available on the use of vinorelbine in pregnant women. Studies in animals have shown embryotoxicity and teratogenicity (see section 5.3). On the basis of the results of animal studies and the pharmacological action of the medicinal product, there is a potential risk of embryonic and foetal abnormalities.

Navelbine should therefore not be used during pregnancy, unless the individual awaited benefit clearly outweighs the potential risks. If pregnancy occurs during treatment, the patient should be informed about the risks for the unborn child and be monitored carefully. The possibility of genetic counselling should be considered.

4.8         Undesirable effects

Undesirable effects reported with Navelbine soft capsule:

Post-marketing experience:

Navelbine soft capsule is used as single agent or in combination with other chemotherapeutic agents or targeted therapy agents such as cisplatin, or capecitabine.  carboplatin, epirubicin, trastuzumab, erlotinib, sorafenib.

The most commonly system organ classes involved during post-marketing experience are: ‘Blood and lymphatic system disorders’, ‘Gastrointestinal disorders’, ‘Infections and infestations’ and ‘General disorders and administration site conditions’. This information is consistent with the pre-marketing experience.

Infections and Infestations

Not known:                  Neutropenic sepsis

                                Complicated septicaemia and sometimes fatal

Cardiac disorders

Uncommon:                 Heart failure and cardiac dysrhythmia

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 preferably through the online reporting option accessible from the IMB homepage. A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’, in addition to the traditional post-paid ‘yellow card’ option.

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

5.2     Pharmacokinetic properties

Renal and liver impairment:

Pharmacokinetics of orally administered vinorelbine were not modified after administration of 60 mg/m² in 7 patients with mild hepatic disorder liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from between 1.5 and to 2.5 x ULN) and of 50 mg/m² in 6 patients with moderate hepatic disorder liver impairment (bilirubin from between 1.5 and to 3 x ULN, independent whatever the levels of ALAT and ASAT level). The safety and pharmacokinetics of vinorelbine were not changed in these patients at the tested doses.

Total clearance of vinorelbine was neither modified between mild and moderate hepatic disorder liver impairment nor was it altered in hepatically impaired patients with hepatic disorder when compared with clearance in patients with normal hepatic liver function.

No data are  is available for patients with severe hepatic disorder, impairment therefore  the use of Navelbine in these patients is not recommended contra-indicated in these patients , (see sections 4.2, 4.3, 4.4).

7.       MARKETING AUTHORISATION HOLDER

PIERRE FABRE Limited

Hyde Abbey House

23 Hyde Street

Winchester Hampshire S023 7DR

United Kingdom

8.       MARKETING AUTHORISATION NUMBER(S)

PA 1287/001/002

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of First Authorisation: 13th April 2006

Date of last renewal: 13th April 2011

10.     DATE OF REVISION OF THE TEXT

01/2014

4.2     Posology and method of administration

Posology

Navelbine should be swallowed whole with water without chewing or sucking the capsule. It is recommended to take the capsule with some food.

Administration in patients with liver insufficiency

Navelbine can be administered at the standard dose of 60 mg/m²/week in patients with mild hepatic disorder liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from between 1.5 and to 2.5 x ULN).

In patients with moderate hepatic disorder liver impairment (bilirubin from between 1.5 and to 3 x ULN, independent whatever the levels of ALAT and ASAT level), Navelbine should needs to be administered at a dose of 50 mg/m²/week. The aAdministration of Navelbine in to patients with severe hepatic disorder impairment is contra-indicated not recommended because there is insufficient data in this population in order to determine the pharmacokinetics, efficacy and safety, (see sections 4.3, 4.4, 5.2).

Administration in patients with impaired renal function insufficiency

Given the minor renal excretion, there is no pharmacokinetic justification for reducing the dose of Navelbine in patients with impaired serious renal function insufficiency, (see section 4.4, 5.2).

4.3     Contraindications

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

-        Disease significantly affecting absorption

-        Previous significant surgical resection of stomach or small bowel.

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

-        Platelet count <  100000/mm³

-        Severe hepatic insufficiency

-        Pregnancy: see section 4.6

-        Lactation (see section 4.6)

-        Patients requiring long-term oxygen therapy

-        In combination with yellow fever vaccine (see section 4.5).

4.4     Special warnings and precautions for use

Special precautions for use

Oral Navelbine has been was studied in patients with hepatic disorder liver impairment at the following dosageses:
- 60 mg/m² in 7 patients with mild hepatic disorder liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT between from 1.5 and to 2.5 x ULN);

- 50 mg/m² in 6 patients with moderate hepatic disorder liver impairment (bilirubin between from 1.5 and to 3 x ULN, independent whatever the levels of ALAT and ASAT level).

The safety and pharmacokinetics of vinorelbine were not changed in these patients at the tested doses.

Total clearance of vinorelbine was neither modified between mild and moderate hepatic disorder liver impairment nor was it altered in hepatically impaired patients with hepatic disorder when compared with clearance in patients with normal hepatic liver function.

Oral Navelbine has was not been studied in patients with severe hepatic disorder, impairment therefore it’s the use in these patients is not recommended contra-indicated in these patients: , (see sections 4.2, 4.3, 5.2).

4.5     Interaction with other medicinal products and other forms of interaction

Concomitant use contraindicated

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

Concomitant use not recommended

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.

Concomitant use to take into consideration

An increased incidence of grade 3/4 neutropenia has been suggested when intravenous vinorelbine and lapatinib were associated in one clinical phase I study. In this study, the recommended dose of intravenous form of vinorelbine in a 3-weekly schedule on day 1 and day 8 was 22.5 mg/m² when combined with daily lapatinib 1000 mg. This type of combination should be administered with caution.

4.6     Fertility, pregnancy and lactation

Pregnancy

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

Navelbine is contra-indicated 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 counseling should be offered.

There are insufficient data available on the use of vinorelbine in pregnant women. Studies in animals have shown embryotoxicity and teratogenicity (see section 5.3). On the basis of the results of animal studies and the pharmacological action of the medicinal product, there is a potential risk of embryonic and foetal abnormalities.

Navelbine should therefore not be used during pregnancy, unless the individual awaited benefit clearly outweighs the potential risks. If pregnancy occurs during treatment, the patient should be informed about the risks for the unborn child and be monitored carefully. The possibility of genetic counselling should be considered.

4.8         Undesirable effects

Undesirable effects reported with Navelbine soft capsule:

Post-marketing experience:

Navelbine soft capsule is used as single agent or in combination with other chemotherapeutic agents or targeted therapy agents such as cisplatin, or capecitabine.  carboplatin, epirubicin, trastuzumab, erlotinib, sorafenib.

The most commonly system organ classes involved during post-marketing experience are: ‘Blood and lymphatic system disorders’, ‘Gastrointestinal disorders’, ‘Infections and infestations’ and ‘General disorders and administration site conditions’. This information is consistent with the pre-marketing experience.

Infections and Infestations

Not known:                  Neutropenic sepsis

                                Complicated septicaemia and sometimes fatal

Cardiac disorders

Uncommon:                 Heart failure and cardiac dysrhythmia

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 preferably through the online reporting option accessible from the IMB homepage. A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’, in addition to the traditional post-paid ‘yellow card’ option.

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

5.2     Pharmacokinetic properties

Renal and liver impairment:

Pharmacokinetics of orally administered vinorelbine were not modified after administration of 60 mg/m² in 7 patients with mild hepatic disorder liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from between 1.5 and to 2.5 x ULN) and of 50 mg/m² in 6 patients with moderate hepatic disorder liver impairment (bilirubin from between 1.5 and to 3 x ULN, independent whatever the levels of ALAT and ASAT level). The safety and pharmacokinetics of vinorelbine were not changed in these patients at the tested doses.

Total clearance of vinorelbine was neither modified between mild and moderate hepatic disorder liver impairment nor was it altered in hepatically impaired patients with hepatic disorder when compared with clearance in patients with normal hepatic liver function.

No data are  is available for patients with severe hepatic disorder, impairment therefore  the use of Navelbine in these patients is not recommended contra-indicated in these patients , (see sections 4.2, 4.3, 4.4).

7.       MARKETING AUTHORISATION HOLDER

PIERRE FABRE Limited

Hyde Abbey House

23 Hyde Street

Winchester Hampshire S023 7DR

United Kingdom

8.       MARKETING AUTHORISATION NUMBER(S)

PA 1287/001/002

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of First Authorisation: 13th April 2006

Date of last renewal: 13th April 2011

10.     DATE OF REVISION OF THE TEXT

01/2014

SUMMARY OF CHANGES

(All changes in blue)

4.2       Posology and method of administration

Dose modification

If the neutrophil count is below 1500 /mm³ and/or the platelet count is between 75000 and 100000/mm³, then the treatment should be delayed until recovery.

Administration

Navelbine must be given strictly by the oral route.

Navelbine must be swallowed whole with water, without chewing, sucking or dissolving the capsule.

It is recommended to administer the capsule with some food.

Specific instructions must be observed for handling of Navelbine: see section 6.6

Administration in children

Safety and efficacy in children have not been established administration is therefore not recommended. Please see section 5.1.

Navelbine is not recommended for use in children due to a lack of data on safety and

efficacy. Administration is therefore not recommended: see section 5.1

Administration in patients with renal function insufficiency

Given the minor renal excretion, there is no pharmacokinetic justification for reducing the dose of Navelbine in patients with impaired serious renal function insufficiency: see sections 4.4, 5.2.

Administration

Navelbine is to be administered orally.
Navelbine must be swallowed whole with water, without chewing, sucking or dissolving the capsule.
It is recommended to administer the capsule with some food.

Specific instructions must be observed for administration of Navelbine: see section 6.6

4.3       Contraindications

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

-          Disease significantly affecting absorption

-          Previous significant surgical resection of stomach or small bowel.

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

-          Platelets < 75000mm³  < 100000mm³

-          Severe hepatic insufficiency not related to the tumoural process.

-          Pregnancy: see section 4.6

-          Lactation: see section 4.6

-          Patients requiring long-term oxygen therapy

-          Patients with rare hereditary problems of fructose intolerance should not take this medicine

-          In combination with yellow fever vaccine: see section 4.5

4.4       Special warnings and precautions for use

Special warnings

In the case of vomiting within a few hours after drug intake, do not readminister. never repeat the administration of this dose. Supportive treatment (such as 5HT₃ antagonists (e.g. ondansetron, granisetron) may reduce the occurrence of this: see section 4.5.

Dosing should be determined by haematological status

·      If the neutrophil count is below 1500 /mm³ and/or the platelet count is below between 75000 and 100000/mm³, then the treatment should be delayed until recovery.

4.5              Interaction with other medicinal products and other forms of interaction

Concomitant use to take into consideration

Mitomycin C: as with all vinca-alkaloids, increased risk of bronchospasm and dyspnoea are increased, in rare case an interstitial pneumonitis was observed. 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 as 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.

No clinically significant pharmacokinetic interaction was observed when combining Navelbine with several other chemotherapeutic agents (paclitaxel, docetaxel, capecitabine and oral cyclophosphamide).

Anti-emetic drugs such as 5HT₃ antagonists (e.g. ondansetron, granisetron) do not modify the pharmacokinetics of Navelbine soft capsules (see section 4.4).

4.6              Fertility, pregnancy and lactation

Fertility

Men and women being treated with Navelbine are advised not to father conceive a child during and up to 3 months after treatment: see section 4.3.

Prior 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

The reactions were described using the NCI common toxicity criteria

For greater clarity, the effects specific to Navelbine concentrate for solution for infusion are presented separately at the end of this section in accordance with the company core reference data.

Undesirable effects reported with Navelbine soft capsule:

Post-marketing experience:

Navelbine soft capsule is used as single agent or in combination with other chemotherapeutic agents or targeted therapy agents such as cisplatin, capecitabine, carboplatin, epirubicin, trastuzumab, erlotinib, sorafenib.

The most commonly system organ classes involved during post-marketing experience are: ‘Blood and lymphatic system disorders’, ‘Gastrointestinal disorders’, ‘Infections and infestations’ and ‘General disorders and administration site conditions’. This information is consistent with the pre-marketing experience.

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.

A close monitoring of hepatic function is recommended.

5.         PHARMACOLOGICAL PROPERTIES

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. The toxicity profile Toxicities were was similar to that those reported in adult patients. (see section 4.2).

SUMMARY OF CHANGES

(All changes in blue)

4.2       Posology and method of administration

Dose modification

If the neutrophil count is below 1500 /mm³ and/or the platelet count is between 75000 and 100000/mm³, then the treatment should be delayed until recovery.

Administration

Navelbine must be given strictly by the oral route.

Navelbine must be swallowed whole with water, without chewing, sucking or dissolving the capsule.

It is recommended to administer the capsule with some food.

Specific instructions must be observed for handling of Navelbine: see section 6.6

Administration in children

Safety and efficacy in children have not been established administration is therefore not recommended. Please see section 5.1.

Navelbine is not recommended for use in children due to a lack of data on safety and

efficacy. Administration is therefore not recommended: see section 5.1

Administration in patients with renal function insufficiency

Given the minor renal excretion, there is no pharmacokinetic justification for reducing the dose of Navelbine in patients with impaired serious renal function insufficiency: see sections 4.4, 5.2.

Administration

Navelbine is to be administered orally.
Navelbine must be swallowed whole with water, without chewing, sucking or dissolving the capsule.
It is recommended to administer the capsule with some food.

Specific instructions must be observed for administration of Navelbine: see section 6.6

4.3       Contraindications

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

-          Disease significantly affecting absorption

-          Previous significant surgical resection of stomach or small bowel.

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

-          Platelets < 75000mm³  < 100000mm³

-          Severe hepatic insufficiency not related to the tumoural process.

-          Pregnancy: see section 4.6

-          Lactation: see section 4.6

-          Patients requiring long-term oxygen therapy

-          Patients with rare hereditary problems of fructose intolerance should not take this medicine

-          In combination with yellow fever vaccine: see section 4.5

4.4       Special warnings and precautions for use

Special warnings

In the case of vomiting within a few hours after drug intake, do not readminister. never repeat the administration of this dose. Supportive treatment (such as 5HT₃ antagonists (e.g. ondansetron, granisetron) may reduce the occurrence of this: see section 4.5.

Dosing should be determined by haematological status

·      If the neutrophil count is below 1500 /mm³ and/or the platelet count is below between 75000 and 100000/mm³, then the treatment should be delayed until recovery.

4.5              Interaction with other medicinal products and other forms of interaction

Concomitant use to take into consideration

Mitomycin C: as with all vinca-alkaloids, increased risk of bronchospasm and dyspnoea are increased, in rare case an interstitial pneumonitis was observed. 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 as 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.

No clinically significant pharmacokinetic interaction was observed when combining Navelbine with several other chemotherapeutic agents (paclitaxel, docetaxel, capecitabine and oral cyclophosphamide).

Anti-emetic drugs such as 5HT₃ antagonists (e.g. ondansetron, granisetron) do not modify the pharmacokinetics of Navelbine soft capsules (see section 4.4).

4.6              Fertility, pregnancy and lactation

Fertility

Men and women being treated with Navelbine are advised not to father conceive a child during and up to 3 months after treatment: see section 4.3.

Prior 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

The reactions were described using the NCI common toxicity criteria

For greater clarity, the effects specific to Navelbine concentrate for solution for infusion are presented separately at the end of this section in accordance with the company core reference data.

Undesirable effects reported with Navelbine soft capsule:

Post-marketing experience:

Navelbine soft capsule is used as single agent or in combination with other chemotherapeutic agents or targeted therapy agents such as cisplatin, capecitabine, carboplatin, epirubicin, trastuzumab, erlotinib, sorafenib.

The most commonly system organ classes involved during post-marketing experience are: ‘Blood and lymphatic system disorders’, ‘Gastrointestinal disorders’, ‘Infections and infestations’ and ‘General disorders and administration site conditions’. This information is consistent with the pre-marketing experience.

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.

A close monitoring of hepatic function is recommended.

5.         PHARMACOLOGICAL PROPERTIES

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. The toxicity profile Toxicities were was similar to that those reported in adult patients. (see section 4.2).

The highlighted text is new in this version of the SmPC:

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Excipients: Each 30mg capsule contains:-

Ethanol anhydrous                   7.50 mg

Sorbitol                                               15.96 mg

4.4       Special warnings and precautions for use

This medicinal product contains small amounts of ethanol (alcohol), less than 100mg per dose.

5.3       Preclinical safety data

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 man.

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

6.1       List of excipients

Edible printing ink:

Carminic acid E120

Sodium hydroxide

Aluminium chloride hexahydrate

Hypromellose

Propylene glycol

Isopropyl alcohol

Purified water.

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of First Authorisation: 13th April 2006

Date of last renewal: 13 April 2011

10.              DATE OF REVISION OF THE TEXT

May 2011

The highlighted text is new in this version of the SmPC:

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Excipients: Each 30mg capsule contains:-

Ethanol anhydrous                   7.50 mg

Sorbitol                                               15.96 mg

4.4       Special warnings and precautions for use

This medicinal product contains small amounts of ethanol (alcohol), less than 100mg per dose.

5.3       Preclinical safety data

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 man.

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

6.1       List of excipients

Edible printing ink:

Carminic acid E120

Sodium hydroxide

Aluminium chloride hexahydrate

Hypromellose

Propylene glycol

Isopropyl alcohol

Purified water.

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of First Authorisation: 13th April 2006

Date of last renewal: 13 April 2011

10.              DATE OF REVISION OF THE TEXT

May 2011

Sections with changes are provided below, with the specific changes in blue.

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Each soft capsule contains xx mg vinorelbine (as tartrate).

For a full list of excipients, see section 6.1

4.2       Posology and method of administration

For oral use only.

Navelbine^Ò soft capsules should be swallowed whole with water without chewing or sucking the capsule. It is recommended to take the capsule with some food.

In adult patients

As a single agent, the recommended regimen is:

First three administrations

60mg/m² of body surface area, administered once weekly.

Subsequent administrations

Beyond the third administration, it is recommended to increase the dose of Navelbine^Ò soft capsules to 80mg/m² once weekly except in those patients whose neutrophil count dropped once below 500/mm³ or more than once between 500 and 1000/mm³ during the first three administrations at 60mg/m².

Dose modification

For any administration planned to be given at 80mg/m², if the neutrophil count is below 500/ mm³  more than once between 500 and 1000/mm³, the administration should be delayed until recovery and the dose reduced from 80 to 60mg/m² per week during the 3 following administrations.

For combination regimens, the dose and schedule will be adapted to the treatment protocol.

Capsules of different strengths (20, 30, 40, 80 mg) are available in order to choose the adequate combination for the right dosage.

As there is a low level of renal excretion there is no pharmacokinetic rationale for reducing Navelbine^® soft capsules dose in patients with impaired kidney function.

Administration in the elderly

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

Administration in children

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

Administration in patients with liver insufficiency

Navelbine can be administered at the standard dose of 60 mg/m²/week in patients with mild liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN). In patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT), Navelbine should be administered at a dose of 50 mg/m²/week. The administration of Navelbine in patients with severe hepatic impairment is contra-indicated: see sections 4.3, 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 serious renal insufficiency: see sections 4.4, 5.2.

Administration

Navelbine is to be administered orally.
Navelbine must be swallowed whole with water, without chewing, sucking or dissolving the capsule.
It is recommended to administer the capsule with some food.

Specific instructions must be observed for administration of Navelbine: see section 6.6.

Dosage adjustment in specific patient groups: refer to paragraph 4.4. : Special warnings and precautions for use.

Instructions for use / handling :

To open the “peel-push” blister:

1.    Cut the blister along the black dotted line

2.    Peel the soft plastic foil off

3.    Push the capsule through the aluminium foil

4.3       Contraindications

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

-          Disease significantly affecting absorption

-          Previous significant surgical resection of stomach or small bowel.

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

-          Platelets < 75000mm³

-          Severe hepatic insufficiency not related to the tumoural process.

-          Poor performance status ( Karnofsky performance <70%)

-          Pregnancy: see section 4.6

-          Lactation: see section 4.6

-          Patients requiring long-term oxygen

-          Patients with rare hereditary problems of fructose intolerance

-          In combination with yellow fever vaccine: see section 4.5

4.4       Special warnings and precautions for use

Special warnings

It is recommended that Navelbine^â soft capsules should be prescribed by a physician who is experienced in the use of chemotherapy with facilities for monitoring cytotoxic drugs.

If the patient chews or sucks the capsule by error, as the liquid content is an irritant. Proceed to mouth rinses with water or preferably a normal saline solution.

In the case of vomiting within a few hours after drug intake, never repeat the administration of this dose. Supportive treatment (such as metoclopramide 5HT₃ antagonists (e.g. ondansetron, granisetron) may reduce the occurrence of this.

Navelbine soft capsule is associated with a higher incidence of nausea/vomiting than the intravenous formulation. Primary prophylaxis with antiemetics and administration of the capsules with some food is recommended as this has also been shown to reduce the incidence of nausea and vomiting: see section 4.2.

Patients receiving concomitant morphine or opioid analgesics, laxatives and careful monitoring of bowel mobility are recommended.  Prescription of laxatives may be appropriate in patients with prior history of constipation

·      For dose escalation from 60 to 80 mg/m² per week, after the third administration:  please refer to paragraph see section 4.2. : Posology and method of administration

·      For the administrations given at 80mg/m², if the neutrophil count is below 500/mm³ or more than once between 500 and 1000 /mm³, the administration should not only be delayed but also reduced to 60mg/m² per week. It is possible to reescalate the dose from 60 to 80 mg/m² per week: : refer to paragraph see section 4.2. : Posology and method of administration.

During clinical trials where treatments were initiated at 80 mg/m², a few patients developed excessive neutropenic complications including those with a poor performance status. Therefore it is recommended that the starting dose should be 60 mg/m² escalating to 80 mg/m² if the dose is tolerated as described in paragraph section 4.2 :Posology and method of administration.

Because of the presence of sorbitol, patients with rare hereditary problems of fructose intolerance should not take this medicine.

Precautions for use

Special care should be taken when prescribing for patients with:

-           History of ischemic  heart disease: see section 4.8.

-           Poor performance status

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.

Oral Navelbine was studied in patients with liver impairment at the following doses:
- 60 mg/m² in 7  patients with mild liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN);

- 50 mg/m² in 6 patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT).

Total clearance of vinorelbine was neither modified between mild and moderate liver impairment nor was it altered in hepatically impaired patients when compared with clearance in patients with normal liver function..

Oral Navelbine was not studied in patients with severe hepatic impairment, therefore its use is contra-indicated in these patients: see sections 4.2, 4.3, 5.2.

In case of ³ grade 3 peripheral neuropathy or ³ grade 3 abnormality of liver function tests (increase in AST/ALT and/or bilirubin) administration of Navelbine^® should be delayed until recovery

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

Patients receiving concomitant morphine or morphino-mimetics, laxatives and careful monitoring of bowel mobility are recommended.

Navelbine^® soft capsules is associated with a higher incidence of nausea/vomiting than the i.v formulation. A primary prophylaxis with anti-emetics is recommended.

4.5              Interaction with other medicinal products and other forms of interaction

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

Concomitant use contraindicated

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

Concomitant use not recommended

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: as with all vinca-alkaloids, increased risk of pulmonary toxicity Caution is advised when using vinorelbine and mitomycin C simultaneously.

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

As CYP 3A4 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. might modify the pharmacokinetics of  vinorelbine. Strong inhibitors of CYP 3A4 affect vinorelbine pharmacokinetics resulting in increased blood exposure and therefore should be discontinued or closely monitored

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.

Food interaction: a simultaneous food intake Food does not modify the pharmacokinetics of vinorelbine.

4.6              Fertility, pregnancy and lactation

Pregnancy

In animal studies Navelbine was embryo and fetotoxic and teratogenic  is suspected to cause serious birth effects when administered during pregnancy: see section 5.3.

Therefore, Navelbine should not be used during pregnancy

Navelbine is contra-indicated in pregnancy: see section 4.3.

If pregnancy occurs during treatment, genetic counselling should be offered.

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 must use effective contraception during treatment and up to 3 months after treatment: see section 4.3. .

Lactation

It is not unknown whether Navelbine^Òvinorelbine passes into is excreted in human breast milk.

The excretion of vinorelbine in milk has not been studied in animal studies.

A risk to the suckling child cannot be excluded therefore breast feeding must be discontinued prior  before starting treatment with Navelbine soft capsules: see section 4.3.

Fertility

Men and women being treated with Navelbine are advised not to father conceive a child during and up to 3 months after treatment: see section 4.3.

4.7       Effects on ability to drive and use machines

Navelbine^Ò soft capsules are unlikely to impair the ability of patients to drive or to operate machinery. However, patients should be advised that their ability to drive or operate machinery may be affected.

No studies on the effects on the ability to drive and use machines have been performed but on the basis of the pharmacodynamic profile vinorelbine does not affect the ability to drive and use machines. However, caution is necessary in patients treated with vinorelbine considering some adverse effects of the drug: see section 4.8.

4.8       Undesirable effects

The overall reported frequency of undesirable effects was determined from clinical studies in 316 patients (132 patients with non small cell lung cancer and 184 patients with breast cancer) who received the recommended regimen of Navelbine^â soft capsules (first three administrations at 60mg/m²/week followed by 80mg/m²/week).

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

Additional Adverse reactions from Post Marketing experience has been added according to the MedDRA classification with the frequency Not known.

Frequencies are defined as: very common (³ 1/10), common (>1/100, < 1/10), uncommon (> 1/1,000, £ 1/100), rare (>1/10, 000, £ 1/1,000), very rare (£ 1/10,000) according to the MedDRA frequency convention and system organ classification .

These reactions were described using the NCI common toxicity criteria (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)

See Appendix 1 – Section 4.8 “Undesirable Effects Tabulated Presentation”

For greater clarity, the effects specific to Navelbine concentrate for solution for infusion are presented separately in accordance with the company core reference data.

Undesirable effects reported with Navelbine soft capsule:

Pre-marketing experience:

The most commonly reported adverse drug reactions are bone marrow depression with neutropenia, leucopenia, anaemia and thrombocytopenia, gastrointestinal toxicity with nausea, vomiting, diarrohea, stomatitis and constipation. Fatigue and fever were also reported very commonly.

Infections and Infestations

Very common: Bacterial, viral or fungal infections without neutropenia at different sites.  (respiratory, GI, urinary tracts…) G1-4: 12.7%; G3-4: 4.4%, mild to moderate and usually reversible with an appropriate treatment.

Common:

- Bacterial, viral or fungal infections resulting from bone marrow depression and/or immune system compromise (neutropenic infections) are usually reversible with an appropriate treatment.

- Neutropenic infection

- Neutropenic sepsis

Uncommon : severe sepsis with other visceral failure and septicaemia were reported with Navelbine^â, concentrate for solution for infusion.

Very rare : complicated septicaemia and sometimes fatal septicaemia were reported with Navelbine^â, concentrate for solution for infusion.

Blood and lymphatic system disorders

Very common: Bone marrow depression resulting mainly in neutropenia G1-4: 71.5 %; G3: 21.8 %; G 4: 25.9 %, is reversible and is the dose limiting toxicity. The incidence per patient of grade 3-4 neutropenia lasting at least 7 days was 30.3% for Navelbine^® soft capsules (59.5% for Navelbine^® concentrate for solution for infusion) in accordance with the pivotal study conducted in NSCLC indication

Infections resulting from bone marrow depression and/or immune system compromise including bacterial, viral, fungal etiologies at different sites such as respiratory, gastrointestinal, urinary tracts G1-4: 3.5%, were usually mild to moderate and reversible with an appropriate treatment.

Leucopenia

Anaemia G1-4: 67.4 %; G3-4: 3.8 %, was usually mild to moderate.

Thrombocytopenia G1-2: 10.8 %, might occur but was seldom severe.

Common:

G4 Neutropenia associated with fever over 38 °C including febrile neutropenia was reported in 2.8 % patients.

·  Immune system disorders

Rare: Systemic allergic reactions were reported as anaphylactic shock, anaphylaxis and anaphylactoid type reactions with Navelbine® concentrate for solution for infusion.

Metabolism and nutrition disorders

Uncommon: severe hyponatraemia reported in post-marketing clinical experience. Hyperglycaemia was observed in one patient.

Not known: Severe hyponatraemia

Psychiatric disorders

Common: Insomnia G1-2: 2.8%

Nervous system disorders

Very common:  Neurosensory disorders G1-2: 11.1% were generally limited to loss of tendon reflexes and infrequently severe.

Common : Neuromotor disorders G1-4 : 9.2% ;G3-4 : 1.3%.

Headache G1-4: 4.1%, G3-4: 0.6%.

Dizziness G1-4: 6%; G3-4: 0.6%.

Taste disorders G1-2:3.8%.

Other neurological disorders G1-4: 2.2%; G3-4: 0.3%

Uncommon: Seizure

Ataxia grade 3, partially reversible

Cerebrovascular ischemia

Eye disorders

Common: Visual disorders G1-2: 1.3%

Cardiac disorders

Uncommon: Heart failure and cardiac dysrhythmia

Not known: Ischemic heart disease (angina pectoris, myocardial infarction)

Rare: ischemic heart disease (angina pectoris, myocardial infarction) were reported with Navelbine^â, concentrate for solution for infusion.

Vascular disorders

Common: Hypertension G1-4: 2.5%; G3-4: 0.3%; hypotension G1-4: 2.2%; G3-4: 0.6%

Uncommon: Hypotension, hypertension, flushing and peripheral coldness were reported with Navelbine^® concentrate for solution for infusion.

Rare: Severe hypotension, collapse were reported with Navelbine^® concentrate for solution for infusion.

Respiratory system, thoracic and mediastinal disorders

Common: Dyspnoea G1-4: 2.8%; G3-4: 0.3%, Cough: G1-2: 2.8%

Uncommon: Dyspnoea and bronchospasm may occur in association with Navelbine^® concentrate for solution for infusion treatment as with other vinca alkaloids.

Pulmonary embolism (rarely fatal) was reported. In one patient the event was fatal.

Pulmonary haemorrhage (rarely fatal) were observed and resulted in death in one patient.

Rare: Interstitial pneumopathies were reported in particular in patients treated with Navelbine^® concentrate for solution for infusion in combination with mitomycin.

Not known: Respiratory distress

Gastrointestinal  disorders

Very Common: Nausea G1-4: 74.7% ; G3-4: 7.3%;

Vomiting G1-4: 54.7%; G 3-4: 6.3%; supportive treatment (such as oral setrons or metoclopramide) may reduce the occurrence of nausea and vomiting.

Diarrhoea G1-4: 49.7 %; G3-4: 5.7%;

Anorexia  G 1-4 : 38.6%; G 3-4: 4.1%.

Stomatitis G1-4: 10.4 %; G3-4: 0.9%, is usually mild to moderate.

Abdominal pain : G1-4: 14.2%

Constipation G1-4: 15.2 %  19%; G3-4: 0.9% was reported.

Prescription of laxatives  may be appropriate in patients with prior  history of constipation and /or who received concomitant treatment with morphine or morphine-mimetics.

Gastric disorders: G1-4: 11.7%

Common :  Oesophagitis G1-3 : 3.8% ; G3 : 0.3%

                    Dysphagia: G1-2: 2.3%

Uncommon : paralytic ileus G3-4 : 0.9% was reported One episode was fatal. [rarely fatal] – treatment may be resumed after recovery of normal bowel mobility.

Gastro-intestinal bleeding was reported in one patient.

Rare: Pancreatitis were reported with Navelbine^®, concentrate for solution for infusion.

Not known: Gastro-intestinal bleeding

Hepatobiliary disorders

Very common: transient elevation of liver functions tests (G1-2) without clinical symptoms were reported with Navelbine^â, concentrate for solution for infusion

Common: Hepatic disorders: G1-2: 1.3%

Skin and subcutaneous tissue disorders

Very common: Alopecia G1-2 : 29.4%  usually mild in nature may occur. may appear progressively with an extended course of treatment and is was usually mild in nature.

Common: Skin reactions G1-2: 5.7%

Rare: Generalized cutaneous reactions were reported with Navelbine^® concentrate for solution for infusion.

Musculoskeletal and connective tissue disorders

Common: Arthralgia including  jaw pain, myalgia G1-4 : 7%; G3-4: 0.3% were reported .

Renal and urinary disorders

Common: Dysuria G1-2: 1.6%

Other genitourinary disorders G1-2: 1.9%

General disorders and administration site conditions

Very common: Fatigue , Malaise G1-4: 36.7%; G3-4: 8.5% ;

Fever G1-4 : 13.0%; G3-4: 12.1%

Common: Pain including pain at the tumour site G1-4 : 3.8%; G3-4: 0.6%. , Chills: G1-2: 3.8%

Investigations

Very common: Weight loss G1-4: 25%,G3-4: 0.3%

Common: Weight gain G1-2: 1.3%

Undesirable effects with Navelbine concentrate for infusion:

Some undesirable effects were observed with Navelbine, concentrate for infusion during pre- and post-marketing experience which were not reported with Navelbine soft capsule.

In order to provide the complete information and to further the safety of use of Navelbine soft capsule, these effects are presented below:

Infections and Infestations

Uncommon : Septicaemia [rarely fatal]

Immune system disorders

Not known: Systemic allergic reactions as anaphylaxis, anaphylactic shock or anaphylactoid type reactions

Endocrine disorders

Not known: Inappropriate antidiuretic hormone secretion (SIADH)

Vascular disorders

Rare: Severe hypotension, collapse

Uncommon: Flushing, peripheral coldness

Respiratory system, thoracic and mediastinal disorders

Rare: Interstitial pneumonopathy has been reported in particular in patients treated with Navelbine concentrate for solution for infusion in combination with mitomycin C.

Uncommon: Bronchospasm may occur as with other vinca alkaloids.

Gastrointestinal disorders

Rare: Pancreatitis

4.9      Overdose

Human experience Symptoms

No case of overdosage with Navelbine^â soft capsules has been reported, however Overdosage with Navelbine soft capsules will result in could produce bone marrow hypoplasia suppression sometimes associated with infection, fever, and paralytic ileus and hepatic disorders.

.

·       Management of overdose in man 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.

Management of paralytic ileus requires digestive aspiration and monitoring of bowel motility.

Antidote

There is no known antidote for overdosage of Navelbine.

5.         PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group : Vinca alkaloïds and analogues, ATC code : L01C A04.

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Vinca alkaloïds and analogues

ATC Code: L01C A04

Safety and efficacy of Navelbine in paediatric patients have not been established. Clinical data from a single-arm study in 46 paediatric patients with recurrent solid tumours, including rhabdomyosarcoma/undiffentiated sarcoma, neuroblastoma, and CNS tumours, at doses similar to those used in adults, showed no meaningful clinical activity. Toxicities were similar to those reported in adult patients: see section 4.2.

5.2       Pharmacokinetic properties

Absorption

After oral administration, vinorelbine is rapidly absorbed and the T_max is reached between 1.5 to 3 h with a blood concentration peak (C_max) of approximately 130 ng/ml after a dose of 80 mg/m². The absolute bioavailability is 40% and the simultaneous intake of food does not modify the exposure to vinorelbine.

Oral vinorelbine 60 and 80 mg/m² leads to comparable blood exposure comparable to that  achieved with intravenous vinorelbine at 25 and 30 mg/m² , respectively. of the iv form  .

Interindividual variability of the exposure is similar after administration by intravenous iv and oral routes.

Distribution

Metabolism Biotransformation

Vinorelbine is principally metabolised by CYP 3A4 isoform of cytochromes P450. All metabolites have been identified, and none is active except 4-O-deacetyl vinorelbine, which is the main metabolite in blood.

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.

No sulfo or glucurono conjugates are found. Neither sulfate nor glucuronide conjugates are found.

Elimination

Renal elimination is low (< 5% of the dose administered) and consists mostly in parent compound. Biliary excretion is the predominant elimination route of both metabolites and unchanged vinorelbine, which is the main recovered compound.unchanged vinorelbine, which is the main recovered compound, and its metabolites.

Special patient groups

Renal and liver impairment :

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

Impact of liver dysfunction on pharmacokinetics of vinorelbine has not been evaluated with the oral form. No significant impact was observed with IV vinorelbine.

Pharmacokinetics of orally administered vinorelbine were not modified after administration of 60 mg/m² in 7 patients with mild liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN) and of 50 mg/m² in 6 patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT).

No data is available for patients with severe liver impairment, therefore Navelbine is contra-indicated in these patients: see sections 4.2; 4.3.; 4.4.

Elderly patients

Study on oral vinorelbine in elderly patients (³ 70 years) with NSCLC demonstrated there is no influence of the age on vinorelbine pharmacokinetics and that no dose reduction is required.

A study with oral vinorelbine in elderly patients (³ 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 soft capsule: see section 4.2.

PK-PD relation Pharmacokinetics/Pharmacodynamic relationships

A strong relationship has been demonstrated between blood exposure and depletion of leucocyte or PMNs.

5.3       Preclinical safety data

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 man.

In animal reproductive studies vinorelbine Navelbine^® was embryo-foeto-lethal and teratogenic. 

6.6       Instructions for use and handling

For safety reason any unused capsule must be returned to the doctor or pha.rmacy for destruction according to local standard procedures for cytotoxics

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

Instructions for use/handling

To open the packaging :

1.   Cut the blister along the black dotted line

2.      Peel the soft plastic foil off

3.      Push the capsule through the aluminium foil

Sections with changes are provided below, with the specific changes in blue.

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Each soft capsule contains xx mg vinorelbine (as tartrate).

For a full list of excipients, see section 6.1

4.2       Posology and method of administration

For oral use only.

Navelbine^Ò soft capsules should be swallowed whole with water without chewing or sucking the capsule. It is recommended to take the capsule with some food.

In adult patients

As a single agent, the recommended regimen is:

First three administrations

60mg/m² of body surface area, administered once weekly.

Subsequent administrations

Beyond the third administration, it is recommended to increase the dose of Navelbine^Ò soft capsules to 80mg/m² once weekly except in those patients whose neutrophil count dropped once below 500/mm³ or more than once between 500 and 1000/mm³ during the first three administrations at 60mg/m².

Dose modification

For any administration planned to be given at 80mg/m², if the neutrophil count is below 500/ mm³  more than once between 500 and 1000/mm³, the administration should be delayed until recovery and the dose reduced from 80 to 60mg/m² per week during the 3 following administrations.

For combination regimens, the dose and schedule will be adapted to the treatment protocol.