Vinorelbine 10mg/ml concentrate for solution for infusion

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 a full list of excipients, see section 6.1.

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.

Vinorelbine is indicated 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.

For intravenous infusion only.

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

The use of intrathecal route is contra-indicated.

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

Vinorelbine 10mg/ml concentrate for solution for infusion may be administered by slow bolus (5-10 minutes) after dilution in 20-50 ml of normal saline or glucose 50 mg/ml (5%) solution or by a short infusion (20-30 minutes) after dilution in 125 ml of normal saline or glucose 50 mg/ml (5%) solution. Administration should always be followed by a normal saline infusion to flush the vein.

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.

For Adults Only: Safety and efficacy in children have not been determined.

For patients with severely reduced hepatic function caution and careful monitoring of haematological parameters is recommended. The dose may have to be reduced (see sections 4.4 and 5.2).

In patients with reduced kidney function, the dose does not have to be adjusted (see section 5.2).

The use of intrathecal route is contra-indicated

- Hypersensitivity to vinorelbine or other Vinca alkaloids or to any of the excipients.

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

- Platelet count below 100,000/mm³

- Pregnancy

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

- Severe hepatic impairment not related to the tumoral process

- 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.)

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.

-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 and 4.3).

-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.

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 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

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 /…/ 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.

Women of childbearing potential

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

Contraception in males and females

Men being treated with vinorelbine are advised not to father a child during and for up to 6 months (minimum 3 months) following cessation of treatment. Women of childbearing potential must use an effective method of contraception during treatment and up to 3 months after treatment and should inform their doctor if they become pregnant.

Pregnancy

Vinorelbine is suspected to cause serious birth effects when administered during pregnancy (see section 5.3). /…/ is contraindicated in pregnancy (see section 4.3).

In case of vital indication a medical consultation concerning the risk of harmful effects for the child should be performed for the therapy of a pregnant patient. If pregnancy occurs anyhow during treatment, genetic counselling should be offered.

Breastfeeding

It is unknown whether vinorelbine is exreted in human breast milk. The excretion of vinorelbine in milk has not been studien in animal studies. A risk to the suckling can not be excluded therefore bresast feeding must be discontinued before startin 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.

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 patient treated with vinorelbine considering some adverse effects of the drug.

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).

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

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.

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.

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.

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.

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.

Water for injections.

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.

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.

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

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.

The preparation 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 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 (5-10 minutes) after dilution in 20-50 ml of normal saline or glucose 50 mg/ml (5%) solution or by a short infusion (20-30 minutes) after dilution in 125 ml of normal saline or glucose 50 mg/ml (5%) solution. Administration should always be followed by a normal saline infusion to flush the vein.

Vinorelbine 10mg/ml concentrate for solution for infusion should only be given 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.

Actavis Group PTC ehf.,

Reykjavikurvegur 76-78,

220 Hafnarfjordur, Iceland

PL 30306/0189

18/06/2008

27/07/11

(IF APPLICABLE)

(IF APPLICABLE)