Vinorelbin “Ebewe” 10 mg/ml

/ Novartis

Strictly intravenous administration after appropriate dilution. Intra-thecal administration of vinorelbine may be fatal.
It is recommended to infuse vinorelbine over 6-10 minutes after dilution in 20-50 ml of sodium chloride 9 mg/ml (0.9%) solution for injection or in glucose solution for injection 5%.
Administration should always be followed with at least 250 ml of an isotonic solution infusion to flush the vein.
Non-small cell lung cancer and advanced breast cancer: In monotherapy the usual dose given is 25-30 mg/m² once weekly. In combination chemotherapy the usual dose (25-30 mg/m²) is usually maintained, while the frequency of administration is reduced e.g. day 1 and 5 every 3 weeks or day 1 and 8 every 3 weeks according to treatment protocol.
Hormone-resistant prostate cancer: The usual dose given is 30 mg/m2 on days 1 and 8 every 3 weeks with low doses of corticosteroids everyday (i.e. hydrocortisone 40 mg/day).
Administration in patients with liver insufficiency: 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 prescribing information for full details.

For the treatment of non small cell lung cancer.
For the treatment of advanced breast cancer.
Hormone-refractory prostate cancer, especially in combination with low dose oral corticoid
therapy or Estramustin.

Hypersensitivity to vinorelbine or other vinca alkaloids, or to any of the excipients
Women of child-bearing potential who are not using reliable contraceptive measures
Breastfeeding
Severe infections (acute or within the last 14 days)
Neutropenia (< 1500/mm3 ) or thrombocytopenia (< 100,000/mm3 )
Combination with yellow fever vaccine

Warnings
For intravenous use only. As bone marrow depression is the main risk associated with the administration of Vinorelbin, close haematological monitoring necessary during treatment (determination of haemoglobin level and number of leucocytes, neutrophils and thrombocytes before each new administration). The dose-limiting toxic effect is usually neutropenia. This effect is non-cumulative but is most pronounced between days 7 and 14 after administration, and is quickly reversible within 5-7 days. If the number of neutrophil granulocytes is below 1500/mm3 and/or the platelet count is below 100000/mm3, the treatment should be postponed until recovery (neutrophil count >1,500/mm3 and platelet count >100,000/mm3). If the patient presents signs or symptoms suggestive of infection, a prompt investigation should be carried out.
If radiotherapy of the bone marrow–rich regions (pelvis, spine, or long bones) is performed at the same time as vinorelbine administration, increased myelotoxicity is to be expected. This risk appears to rise as larger proportions of active bone marrow (≥25%) receive moderate to high radiation doses ≥40Gy, or when notable portions of pelvic bone marrow (≥45%) receive lower dose levels (e.g., 20Gy). The same applies to previous radiotherapy (<3 weeks) of the regions mentioned, as marrow recovery is incomplete and susceptibility to vinorelbine induced myelosuppression remains elevated. Injection site necrosis. This effect can be limited by precise positioning of the injection needle and good flushing of the vein. Occasionally, it may be necessary to insert a central venous access.><3 weeks) of the regions mentioned, as marrow recovery is incomplete and susceptibility to vinorelbine induced myelosuppression remains elevated. Injection site necrosis. This effect can be limited by precise positioning of the injection needle and good flushing of the vein. Occasionally, it may be necessary to insert a central venous access.
Precautions for use
Particular caution is required in patients with a history of ischaemic heart disease.
To avoid the risk of bronchospasm and dyspnoea, appropriate prophylaxis should be considered, especially in combination treatment with mitomycin C. Patients undergoing treatment with vinorelbine require immediate medical attention if they have difficulty breathing.
This medical product should not be given concomitantly with radiotherapy if the treatment field includes the liver.
This product is specifically contraindicated for simultaneous use with yellow fever vaccine. Concomitant use with live attenuated vaccines is not recommended. Caution should be exercised when combining vinorelbine with strong inhibitors or inducers of CYP3A4. Its combination with phenytoin (like all cytostatics) and with itraconazole (like all vinca alkaloids) is not recommended.
Vinorelbin must not get into contact with the eye; there is a risk of severe irritation and even corneal ulceration if the drug is sprayed under pressure. If this occurs, the eye should be rinsed immediately with physiological saline solution (0.9% NaCl solution) and an ophthalmologist should be contacted.
Neurological investigations (including EMG if necessary) should be carried out during ongoing treatment with Vinorelbin or in patients with increased risk. Treatment can be continued after normalisation of intestinal activity following the occurrence of paralytic ileus. Antiemetic therapy is recommended due to the very frequent occurrence of nausea and vomiting. Pulmonary toxicity, including dyspnoea, severe acute bronchospasm, interstitial lung disease (including interstitial pneumonitis), and acute respiratory distress syndrome (ARDS), has been reported with vinorelbine, predominantly with the intravenous formulation. The median time to onset of ARDS after vinorelbine administration was one week (range 3 to 8 days). The infusion must be immediately interrupted in patients who develop unclear dyspnoea or have any evidence of pulmonary toxicity. Interstitial lung disease has been reported more frequently in the Japanese population. Special attention should be exercised for this specific population.
See prescribing information for full details.

Very common: Bone marrow depression resulting mainly in neutropenia, Neurologic disorders including loss of deep tendon reflexes, Weakness of the lower extremities after prolonged use, Oesophagitis, Stomatitis, Temporary increase in liver enzymes, Alopecia, Vein irritation, reactions at the injection site such us erythema, burning pain, discolouration of the vein, local phlebitis.
Common: Viral, bacterial, or fungal infections at different localization (respiratory, urinary, GI tract), Allergic reactions (skin reactions, respiratory reactions), Severe paraesthesia with sensory and motor symptoms, Diarrhoea, Generalised skin reactions such as rash, pruritus, urticaria, Myalgia, arthralgia (including jaw pain), Increase in creatinine, Asthenia, Fatigue, Fever, Pain in different locations including chest pain and tumour pain.
See prescribing information for full details.

Interactions that can occur with all cytotoxic medicinal products
Due to the increase of thrombotic risk in patients with cancer, the use of anticoagulant therapy is frequently necessary. The high intra-individual variability of coagulability during the course of disease and the eventuality of interaction between oral anticoagulants and anticancer chemotherapy requires to increase the frequency of the INR (International Normalised Ratio) monitoring if the patient is treated with oral anticoagulants.
Concomitant uses contraindicated: The concomitant use of yellow fever vaccine is contraindicated due to the risk of fatal vaccinalinduced disease.
Concomitant uses not recommended:
Live attenuated vaccines: The simultaneous use of live attenuated vaccines is not recommended (for yellow fever vaccine, see concomitant use contraindicated), as there is a risk of a potentially fatal vaccine-induced disease. This risk is increased in patients who are already immunosuppressed by their underlying disease. In this case, it is recommended to use an inactivated vaccine (e.g. poliomyelitis)
Phenytoin: There is the risk of a renewed worsening of seizures resulting from a decreased concentration of phenytoin, as the absorption of phenytoin is reduced by the cytotoxic medicinal product. There is also a risk of loss of efficacy of the cytostatic medicinal product, vinorelbine, as hepatic metabolism is increased by phenytoin.
Concomitant uses to be carefully considered: Simultaneous use of cyclosporine and tacrolimus must be carefully considered, as there may be excessive immunosuppression with the risk of lymphoproliferation.
Interactions that can occur specifically to with vinca alkaloids
Concomitant use not recommended:
Itraconazole: Concomitant use is not recommended, as the neurotoxicity of vinca alkaloids increases due to their slower hepatic metabolism.
Concomitant use to be carefully considered:
Mitomycin C: The concomitant of mitomycin C must be carefully considered, as there is an increased risk of dyspnoea and bronchospasms. In rare case an interstitial pneumonitis was observed.
Vinca alkaloids are substrates for P-glycoprotein. Although no specific studies are available, caution should be exercised when combining vinorelbine with strong modulators of this membrane transporter (e.g. ritonavir, clarithromycin, ciclosporine, verapamil, quinidine or, among others, CYP3A4 inducers).
Interactions that can occur specifically with to vinorelbine:
* If vinorelbine is combined with other substances with known bone marrow toxicity, an increase in the myelosuppressive effect must be expected.
* CYP3A4 is the main enzyme involved in the metabolism of vinorelbine, and the combination with an agentthat induces this isoenzyme (such as phenytoin, phenobarbital, rifampicin, carbamazepine, Hypericum perforatum) or inhibits (such as itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin, nefazodone), can decrease or increase the concentration of vinorelbine in the blood.
* The combination of vinorelbine and cisplatin over several cycles of treatment shows no pharmacokinetic interactions. However, a higher incidence of granulocytopenia has been reported in patients receiving combination therapy with vinorelbine and cisplatin than in those receiving vinorelbine alone.
* In a clinical phase I study with intravenous vinorelbine in combination with lapatinib, an increased incidence of grade 3/4 neutropenia was observed. In this study, the recommended dose of the intravenous form of vinorelbine in a 3-week-schedule was 22.5 mg/m2 on day 1 and day 8 when combined with 1000 mg of lapatinib daily. This type of combination should be administered with caution.
See prescribing information for full details.  

Fertility: Men being treated with vinorelbine are advised not to father children during treatment and for 4 months after the end of therapy. Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with vinorelbine.
Pregnancy: There are insufficient data from the use of vinorelbine in pregnant women. Vinorelbine should not be used during pregnancy, unless the individually expected benefits clearly outweigh the possible 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 also considered.
Contraception for men and women: Due to the genotoxic potential of vinorelbine (see section 5.3), women of child-bearing potential should use effective methods of contraception during treatment with vinorelbine and for 7 months after the end of therapy. Men should use effective contraception during treatment and for 4 months after the end of therapy. Vinorelbine is genotoxic, so genetic counselling is also recommended if the patient wishes to have children after treatment.
Lactation: It is not known whether vinorelbine is excreted in human milk. The passage of vinorelbine into breast milk has not been studied in animal studies. Since a risk to the infant cannot be excluded, the infant must be weaned before starting treatment.       

Overdosage can cause severe bone marrow depression with fever and infections. Paralytic ileus has also been reported. As there is no specific antidote for an overdose with vinorelbine, symptomatic measures are necessary in the event of an overdose. These measures include: – continuous monitoring of vital signs and particularly careful monitoring of the patient – daily blood count in order to recognise the need for transfusions, for the administration of growth factors or for intensive medical care in good time, and to be able to assess the risk of infection – measures to prevent paralytic ileus – monitoring of the circulatory system and liver function. Infection-related complications can be treated with broad-spectrum antibiotics; paralytic ileus, with decompression via a tube.