Vinorel

Vinorelbine 10mg/ml concentrate for solution for infusion

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 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.

Strictly for intravenous administration after appropriate dilution.

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.

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.

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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.

- 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.

- Women of childbearing potential not using effective contraception.

- In combination with yellow fever vaccine

To avoid the risk of bronchospasm - especially in combination therapy with mitomycin C appropriate prophylaxis may be considered.

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.

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.

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.

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.

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..

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.

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.

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 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).

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 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.

Actavis Group PTC ehf.,

Reykjavikurvegur 76-78,

220 Hafnarfjordur, Iceland

PL 30306/0189

18/06/2008

17/04/14