This information is intended for use by health professionals

1. Name of the medicinal product

Vinorelbine 10mg/ml concentrate for solution for infusion

2. Qualitative and quantitative composition

1 ml concentrate for solution for infusion contains 10mg vinorelbine base equivalent to 13.85mg vinorelbine tartrate.

Each 1 ml vial contains 10 mg vinorelbine (as tartrate).

Each 5 ml vial contains 50 mg vinorelbine (as tartrate).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Concentrate for solution for infusion.

Clear, colourless to slightly yellow solution with a pH of 3.3 to 3.8 and an osmolarity of about 330mOsm/l.

4. Clinical particulars
4.1 Therapeutic indications

Vinorelbine is indicated in adults in the treatment of:

- Non-small cell lung cancer (stage 3 or 4).

- As single agent to patients with metastatic breast cancer (stage 4), where treatment with anthracycline- and taxane containing chemotherapy has failed or is not appropriate.

4.2 Posology and method of administration

Strictly for intravenous administration after appropriate dilution .

Intra-thecal administration is contra-indicated and may be fatal.

For instructions on dilution of the product before administration and other handling, see section 6.6.

Vinorelbine 10mg/ml concentrate for solution for infusion should be given in cooperation with a physician with extensive experience in therapy with cytostatics.

Posology

Non-small cell lung cancer

As a single agent the normal dose is 25-30mg/m², administered once weekly. In polychemotherapy the schedule regimen is a function of the protocol. The normal dose could be used (25-30mg/m²), but the frequency of the administration be reduced to for example day 1 and 5 every third week or day 1 and 8 every third week according to the regimen.

Advanced or metastatic breast cancer

The normal dose is 25-30mg/m², administered once weekly.

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

Special populations

Older people

Clinical experience has not identified relevant 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.

Patients with liver impairment

The pharmacokinetics of vinorelbine 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 patient with severe liver impairment (see sections 4.4 and 5.2).

Patients with renal impairment

Given the minor renal excretion, there is no pharmacokinetic justification for reducing the dose of vinorelbine in patients with renal insufficiency.

Paediatric population

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

Method of administration

For intravenous use only.

For instructions on dilution of the medicinal product before administration, see section 6.6.

Vinorelbine 10mg/ml concentrate for solution for infusion 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 glucose 50 mg/ml (5%) 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 glucose 50 mg/ml (5%) solution for injection. Administration should always be followed with at least 250 ml of sodium chloride 9 mg/ml (0.9%) solution for injection to flush the vein.

4.3 Contraindications

- The use of intrathecal route is contra-indicated

- Hypersensitivity to the active substance or other vinca alkaloids or to any of the excipients listed in section 6.1.

- Neutrophil granulocytes count < 1,500/mm3 or serious, current or recent infection (within 2 weeks).

- Platelet count below 100,000/mm3

- Breast-feeding should be discontinued during treatment with vinorelbine (see section 4.6).

- Women of childbearing potential not using effective contraception (see sections 4.4 and 4.6).

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

4.4 Special warnings and precautions for use

Strictly for intravenous use only. Vinorelbine should be administered under the supervision of a physician experienced in the use of chemotherapy.

Close haematological monitoring should be performed during treatment (determination of haemoglobin level and number of leucocytes, neutrophils and platelets before each new infusion), since inhibition of the haematopoietic system is the main risk during treatment with vinorelbine.

Neutropenia, which is non-cumulative and has its nadir between day 7 and 14 after administration, and is quickly reversible within 5-7 days, is the main dose-limiting adverse reaction. If the number of neutrophil granulocytes is below 1,500/mm3 and/or the platelet count is below 100,000/mm3, the treatment should be postponed until recovery.

If the patient presents 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 caution is advised in patients with a history of ischaemic heart disease (see section 4.8).

The clinical relevance of impaired drug elimination capacity of the liver has not been characterised. Therefore no exact dose recommendation could be given. However in the pharmacokinetic study the highest administered dose in patients with severe liver dysfunction was 20 mg/m² (see section 5.2). For patients with severe hepatic impairment caution is recommended and careful monitoring of haematological parameters is required. Dosage reduction may also be required (see sections 4.2).

Vinorelbine 10mg/ml concentrate for solution for infusion should not be given concomitantly with radiotherapy if the treatment field includes the liver.

Vinorelbine 10mg/ml concentrate for solution for infusion must not get into contact with the eye; risk of severe irritation and even corneal ulceration if the drug is sprayed under pressure. If this occurs, immediately rinse the eye with normal saline solution and contact an ophthalmologist.

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

Strong inhibitors or inducers of CYP3A4 can affect the vinorelbine concentration and caution should therefore be exercised (see section 4.5, interactions specific to vinorelbine), and its combination with phenytoin (like all cytotoxics) and with itraconazole (like all vinca-alkaloids) is not recommended.

For information on pregnancy, breast feeding and fertility, please refer to section 4.6.

To avoid the risk of bronchospasm - especially in combination therapy with mitomycin C appropriate prophylaxis may be considered. Outpatients should be informed that in case of dyspnoea a doctor has to be informed.

Because of the low level of renal excretion, there are no pharmacokinetic grounds for reducing the dose in patients with renal impairment, see section 4.2.

4.5 Interaction with other medicinal products and other forms of interaction

Interactions common to all cytotoxics

Due to the increase of thrombotic risk in case of tumoral diseases, the use of anticoagulative treatment is frequent. The high intra-individual variability of the coagulability during diseases, and the eventuality of interaction between oral anticoagulants and anticancer chemotherapy require, if it is decided to treat the patient with oral anticoagulants, to increase frequency of the INR (International Normalised Ratio) monitoring.

Concomitant use contraindicated

Yellow fever vaccine: 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): risk of generalised vaccine disease, possibly fatal. The risk is increased in patients already immunodepressed by their underlying disease. It is recommended to use an inactivated when exists (poliomyelitis) (see section 4.4).

Phenytoin: risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic drug or loss of efficacy of the cytotoxic drug due to increased hepatic metabolism by phenytoin.

Concomitant use to take into consideration

Cyclosporine, tacrolimus: excessive immunodepression with risk of lymphoproliferation

Interactions specific to vinca-alkaloids

Concomitant use not recommended

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

Concomitant use to take into consideration

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

As vinca-alkaloids are known as substrates for P-glycoprotein, and in the absence of specific study, caution should be exercised when combining Vinorelbine 10mg/ml concentrate for solution for infusion with strong modulators of this membrane transporter.

Interactions specific to vinorelbine

The combination of vinorelbine and other drugs with known bone marrow toxicity is likely to increase the myelosuppressive adverse reactions.

CYP3A4 is the main enzyme involved in the metabolism of vinorelbine, and the combination with a drug that induces (such as phenytoin, phenobarbital, rifampicin, carbamazepine, Hypericum perforatum) or inhibits (such as itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin, nefazodone), this iso-enzyme can affect the concentration of vinorelbine (see section 4.4).

The combination vinorelbine-cisplatin (a very common combination) shows no interaction with respect to the pharmacological parameters of vinorelbine. However, a higher incidence of granulocytopenia has been reported in patients receiving combination therapy with vinorelbine and cisplatin than in those receiving vinorelbine alone.

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 Pregnancy and lactation

Pregnancy

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.

Vinorelbine should therefore not be used during pregnancy, unless the indicidual 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.

Women of childbearing potential

Women of child-bearing potential must use effective contraception during treatment and up to 3 months after treatment.

Breastfeeding

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

Fertility

Men being treated with vinorelbine are advised not to father a child during and up to six months (minimum 3 months) following cessation of treatment. Prior to treatment advice should be sought for conserving sperm due to the chance of irreversible infertility as a consequence of treatment with vinorelbine.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

The undesirable effects that have been reported in more than isolated cases are listed below after organ class and frequency. The frequencies are defined using the following convention:

very common (> 1/10); common (> 1/100 and < 1/10); uncommon (> 1/1,000 and < 1/100); rare (> 1/10,000 and < 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.

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.

Detailed adverse reactions information: Reactions were described using the WHO 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 localisation (respiratory, urinary, GI tract) mild to moderate and usually reversible with an appropriate treatment

Uncommon

severe sepsis with other visceral failure, septicaemia

Very rare:

complicated septicaemia and sometimes fatal

Not known:

neutropenic sepsis with potential fatal outcome

Blood and lymphatic system disorders

Very common:

bone marrow depression resulting mainly in neutropenia (G3: 24.3%; G4: 27.8%), reversible within 5-7 days and non-cumulative over time, anaemia (G3-4; 7.4%)

Common:

thrombocytopenia (G3-4: 2.5%) may occur but are seldom severe

Not known:

febrile neutropenia, pancytopenia

Immune system disorders

Not known:

systemic allergic reactions as anaphylaxis, anaphylactic shock or anaphylactoid type reaction

Endocrine disorder

Not known:

inappropriate antidiuretic hormone secretion (SIADH)

Metabolism and nutrition disorders

Rare:

severe hyponatraemia

Not known:

anorexia

Nervous system disorders

Very common:

neurologic disorders (G3-4: 2.7%) including loss of deep tendon reflexes weakness of the lower extremities has been reported after a prolonged chemotherapy

Uncommon:

severe paraesthesias with sensory and motor symptoms are infrequent. These effects are generally reversible

Cardiac disorders

Rare:

ischaemic heart disease (angina pectoris and /or transitory electrocardiogram changes, myocardial infarction, sometimes fatal)

Very rare:

tachycardia, palpitation and heart rhythm disorders

Vascular disorders

Uncommon:

hypotension

hypertension

flushing and peripheral coldness

Rare:

severe hypotension; collapse

Respiratory, thoracic and mediastinal disorders

Uncommon:

dyspnoea and bronchospasm may occur in association with vinorelbine treatment as with other vinca alkaloids

Rare:

interstitial pneumopathy, sometimes fatal has been reported

Gastrointestinal disorders

Very common:

stomatitis (G1-4: 15% with vinorelbine as single agent) nausea and vomiting (G1-2: 30.4% and G3-4: 2.2%).

Antiemetic therapy may reduce their occurrence constipation is the main symptom (G3-4: 2.7%) which rarely progresses to paralytic ileus with vinorelbine as single agent and (G3-4: 4.1%) with the combination of vinorelbine and other chemotherapeutic agents

oesophagitis

Common:

diarrhoea usually mild to moderate may occur

Rare:

paralytic ileus, treatment may be resumed after recovery of normal bowel mobility

pancreatitis

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 vinorelbine as single chemotherapeutic agent).

Rare:

generalized cutaneous reactions have been reported with vinorelbine (as rash, pruritus, urticaria)

Not known:

palmar-plantar erythrodysesthesia syndrome

Musculoskeletal and connective tissue disorders

Common:

myalgia

arthralgia including jaw pain

Renal and urinary disorders

Common:

creatinine increased

General disorders and administration site conditions

Very common:

reactions at the injection site may include erythema, burning pain, vein discolouration and local phlebitis (G3-4: 3.7% with vinorelbine as single chemotherapeutic agent)

Common:

asthenia

fatigue

fever

pain in different locations including chest pain and pain at the tumour site have been experienced by patients receiving vinorelbine therapy.

Rare:

local necrosis has been observed. Proper positioning of the intravenous needle or catheter and bolus injection followed by liberal flushing of the vein can limit these effects

As with other vinca-alkaloids vinorelbine has a moderate vesicant power.

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 website: www.mhra.gov.uk/yellowcard .

4.9 Overdose

Symptoms

Overdosages may produce severe bone marrow depression with fever and infection, paralytic ileus have also been reported. Symptomatic treatment with blood transfusion and broad-spectrum antibiotic therapy is recommended. There is no known specific antidote.

Emergency procedure

As there is no specific antidote for the overdosage of vinorelbine given intravenously, symptomatic measures are necessary in case of an overdosage, 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 minimize 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.

Antidote

There is no known antidote for overusage of vinorelbine.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Vinca alkaloids and analogues, ATC code: L01CA04

Vinorelbine is a cytostatic drug of the Vinca alkaloid family.

Vinorelbine inhibits tubulin polymerisation and binds preferentially to mitotic microtubules, only affecting axonal microtubules at high concentration. The induction of tubulin spiralization is less than that produced by vincristine. Vinorelbine blocks mitosis at G2-M, causing cell death in interphase or at the following mitosis.

Safety and efficacy of vinorelbine 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 33,75 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. (see section 4.2).

5.2 Pharmacokinetic properties

After intravenous administration, the blood concentration-time profile, is characterised by a three exponential elimination curve. The terminal half-life was on average around 40 hours. Clearance in blood is high, close to the hepatic blood flow and was on average 0,72 l/h/kg (interval: 0,32-1,26 l/h/kg), while the volume of distribution at steady-state was large, on average 21,2 l/kg, showing signs of extensive tissue distribution. There is weak binding to plasma proteins (13.5%), but strong binding to blood cells, especially to platelets (78%). The pharmacokinetic properties for intravenously administered vinorelbine have shown to be linear up to the dose level 45 mg/m2.

Vinorelbine is mainly metabolised by CYP3A4 and the main metabolite is 4-O-deacetylvinorelbine.

Renal excretion is low (< 20% of the dose) and consists mainly of the parent compound. Excretion via the biliary route is the most important route of elimination, both for metabolites and unchanged vinorelbine.

The effects of reduced kidney function on the vinorelbine disposition have not been evaluated, but a dose reduction is not necessary due to the low renal excretion.

In patients with liver metastases changes only occurred in the mean clearance of vinorelbine 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 drug elimination capacity of the liver and therefore caution is recommended in patients with severe hepatic impairment and careful monitoring of haematological parameters is required (see sections 4.2 and 4.4).

A strong relationship between the exposure of blood and reduction in leucocytes or polynuclear leucocytes has been demonstrated.

5.3 Preclinical safety data

Mutagenic and carcinogenic potential

In animal studies vinorelbine induced aneuploidy and polyploidy. It can be assumed that vinorelbine can also cause genotoxic effects in humans (aneuploidy and polyploidy). The results for carcinogenic potential in the mouse and rat were negative but only low doses have been tested.

Reproductive toxicity studies

In animal reproductive studies, effects were observed at subtherapeutic dosages. Embryo- and foetotoxicity were seen, such as intra-uterine growth retardation and delayed ossification.

Teratogenicity (fusion of the vertebrae, missing ribs) was observed at maternal toxic doses. In addition, spermatogenesis and secretion of prostate and seminal vesicles were reduced, but fertility in rats was not diminished.

Safety pharmacology

Safety pharmacology studies performed in the dog and in the monkey did not reveal any adverse effect on the cardio-vascular system.

6. Pharmaceutical particulars
6.1 List of excipients

Water for injections.

6.2 Incompatibilities

Vinorelbine 10mg/ml concentrate for solution for infusion should not be diluted in alkaline solutions (risk of precipitation).

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

As packaged for sale

3 years.

After opening

The content of the vial should be used immediately after the first breakage of vial.

Shelf-life after dilution

The physicochemical and microbiological stability of the drug product after dilution in the recommended solutions for infusion (see section 6.6) has been demonstrated for 24 hours at 2-8°C and 25°C.

From a microbiological point of view the product should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

As packaged for sale

Store in a refrigerator (2°C - 8°C). Keep the vial in the outer carton in order to protect from light.

Do not freeze.

For storage condition of the diluted medicinal product, see section 6.3

6.5 Nature and contents of container

1ml vial: Colourless glass vial (type I) with bromobutyl rubber stopper and metallic cap with polypropylene disk. Vial will be packed with or without a protective plastic overwrap.

5ml vial: Colourless glass vial (type I) with bromobutyl rubber stopper and metallic cap with polypropylene disk. Vial will be packed with or without a protective plastic overwrap.

Pack-sizes:

1 x 1 ml vial

10 x 1 ml vial

1 x 5 ml vial

10 x 5 ml vial

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The preparation and administration of injectable solutions of cytotoxic agents must be carried out by trained specialist personnel with knowledge of the medicines used, in conditions that guarantee the protection of the environment and, in particular, the protection of the personnel handling the medicines. It requires a preparation area reserved for this purpose. It is forbidden to smoke, eat or drink in this area.

Personnel must be provided with appropriate handling materials, notably long sleeved gowns, protection masks, caps, protective goggles, sterile single-use gloves, protective covers for the work area and collection bags for waste.

Syringes and infusion sets should be assembled carefully to avoid leakage (use of Luer lock fittings is recommended).

Spills and leakages must be wiped up.

Precautions should be taken to avoid exposing staff during pregnancy.

All contact with eyes must be strictly avoided. Immediate liberal washing of the eye with normal saline solution should be undertaken if any contact occurs. In case of irritation an ophthalmologist should be contacted.

In case of skin contact, the affected area should be thoroughly washed with water.

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

There is no incompatibility between Vinorelbine 10mg/ml concentrate for solution for infusion and glass vials, PVC bag, polyethylene vial or polypropylene syringe.

Vinorelbine 10mg/ml concentrate for solution for infusion 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 glucose 50 mg/ml (5%) 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 glucose 50 mg/ml (5%) solution for injection. Administration should always be followed by at least 250ml of sodium chloride 9 mg/ml (0.9%) solution for injection to flush the vein.

Vinorelbine 10mg/ml concentrate for solution for infusion must be given strictly intravenously. It is very important to make sure that the cannula is accurately placed in the vein before the injection is commenced. If Vinorelbine 10mg/ml concentrate for solution for infusion infiltrates the surrounding tissue during intravenous administration, a substantial irritation may occur. In this case, the injection should be stopped, the vein flushed with saline solution and the rest of the dose should be administered in another vein. In the event of extravasation, glucocorticoids could be given intravenously to reduce the risk of phlebitis.

Excreta and vomit must be handled with care.

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

7. Marketing authorisation holder

Actavis Group PTC ehf.,

Reykjavikurvegur 76-78,

220 Hafnarfjordur, Iceland

8. Marketing authorisation number(s)

PL 30306/0189

9. Date of first authorisation/renewal of the authorisation

18/06/2008

10. Date of revision of the text

17/04/14

11 Dosimetry

IF APPLICABLE

12 Instructions for preparation of radiopharmaceuticals

IF APPLICABLE