- vinorelbine tartrate
POM: Prescription only medicine
This information is intended for use by health professionals
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.
Non-small cell lung cancerAs 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 cancerThe 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 peopleClinical 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 impairmentThe 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 impairmentGiven the minor renal excretion, there is no pharmacokinetic justification for reducing the dose of vinorelbine in patients with renal insufficiency.
Paediatric populationSafety 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.
Interactions common to all cytotoxicsDue 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 contraindicatedYellow fever vaccine: risk of fatal generalised vaccine disease (see section 4.3).
Concomitant use not recommendedLive 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 considerationCyclosporine, tacrolimus: excessive immunodepression with risk of lymphoproliferation
Interactions specific to vinca-alkaloids
Concomitant use not recommendedItraconazole: increased neurotoxicity of vinca-alkaloids due to the decrease of their hepatic metabolism.
Concomitant use to take into considerationMitomycin 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 vinorelbineThe 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.
PregnancyThere 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 potentialWomen of child-bearing potential must use effective contraception during treatment and up to 3 months after treatment.
BreastfeedingIt 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).
FertilityMen 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.
|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|
|Not known:||inappropriate antidiuretic hormone secretion (SIADH)|
|Metabolism and nutrition disorders|
|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|
|Rare:||ischaemic heart disease (angina pectoris and /or transitory electrocardiogram changes, myocardial infarction, sometimes fatal)|
|Very rare:||tachycardia, palpitation and heart rhythm 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|
|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|
|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:||myalgiaarthralgia including jaw pain|
|Renal and urinary disorders|
|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|
SymptomsOverdosages 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 procedureAs 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.
AntidoteThere is no known antidote for overusage of vinorelbine.
Mutagenic and carcinogenic potentialIn 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 studiesIn 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 pharmacologySafety pharmacology studies performed in the dog and in the monkey did not reveal any adverse effect on the cardio-vascular system.
As packaged for sale3 years.
After openingThe content of the vial should be used immediately after the first breakage of vial.
Shelf-life after dilutionThe 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 saleStore 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
Pack-sizes:1 x 1 ml vial10 x 1 ml vial1 x 5 ml vial10 x 5 ml vialNot all pack sizes may be marketed.