Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Accord Healthcare Limited, Sage House, 319 Pinner Road, North Harrow, Middlesex, HA1 4HF, United Kingdom
Vinorelbine must be administered under the supervision of a doctor experienced in the use of chemotherapy.
Vinorelbine must only be administered by the intravenous route.
As the inhibition of the haematopoietic system is the main risk associated with the administration of Vinorelbine solution, close blood monitoring is necessary during treatment (determination of haemoglobin levels and platelet, neutrophil and leukocyte counts, on the first day of each new administration).
The dose-limiting adverse reaction is mainly neutropenia. This effect is not cumulative, having its nadir between 7 and 14 days after administration and is rapidly reversible within 5 to 7 days. If the neutrophil count is below 1500/mm³ and/or the platelet count is below 100000/mm³, treatment should be postponed until the values return to normal.
If the patients present signs or symptoms suggestive of infection, a prompt investigation should be carried out.
Special care is necessary when prescribing this medicinal product to patients with a history of ischaemic heart disease (see section 4.8).
The pharmacokinetics of vinorelbine is not modified in patients who suffer moderate or severe hepatic failure. For adjusting the dose in this specific group of patients, see section 4.2.
As there is a low level of renal clearance, there is no pharmacokinetic basis for reducing the Vinorelbine solution dose in patients with impaired renal function. See section 4.2.
Vinorelbine solution must not be administered simultaneously with radiotherapy when the treatment field includes the liver.
This medicinal product is specifically contraindicated when the yellow fever vaccine is administered. The concomitant use of other live attenuated vaccines is not recommended.
The administration of Vinorelbine solution with potent CYP3A4 inducers requires caution (see section 4.5 – Specific interactions of vinorelbine). The concomitant use of phenytoin (and all other cytotoxic agents) and itraconazole (and all other vinca alkaloids) is not recommended.
All contact with the eyes should be strictly avoided: there is a risk of severe irritation and even corneal ulceration if the medicinal product is sprayed under pressure. Immediate washing of the eye with a 9 mg/ml sodium chloride (0.9%) solution should be undertaken if any contact occurs and an ophthalmologist should be contacted
To reduce the risk of bronchospasm, especially if used concomitant with mitomycin C, appropriate precautionary measures should be considered. Patients treated on an outpatient basis should be informed to contact a physician in case of dyspnoea.
Interstitial pulmonary disease has been reported more frequently in the Japanese population. Therefore, special attention is needed in this specific population.
Due to the increased risk of thromboses in cases of tumours, anticoagulant treatment is frequent. The high intra-individual variability of the ability to coagulate during diseases and the possibility of an interaction between oral anticoagulants and antineoplastic chemotherapy mean that if the patient has to be treated with oral anticoagulants, it will be necessary to increase the frequency of INR (international normalised ratio) monitoring.
Yellow fever vaccine: risk of fatal systemic disease (see section 4.3)
Attenuated live vaccines (for yellow fever, see contraindicated concomitant use): risk of possibly fatal systemic disease. This risk is higher in patients who are already immunosuppressed due to the underlying disease. Whenever possible, the use of inactivated vaccines is recommended (poliomyelitis). See section 4.4.
Phenytoin: risk of exacerbation of seizures as a result of the reduction in the gastrointestinal absorption of phenytoin by the cytotoxic agent or risk of increased toxicity or loss of efficacy of the cytotoxic agent due to increased hepatic metabolism caused by phenytoin.
Ciclosporin, tacrolimus: excessive immunosuppression, with a risk of lymphoproliferation.
Specific interactions of vinca alkaloids:
Itraconazole: increase in the neurotoxicity of vinca alkaloids as a result of a reduction in their hepatic metabolism.
Mitomycin C: increased risk of bronchospasm and dyspnoea. There have been rare reports of interstitial lung disease.
As vinca alkaloids are known substrates of P-glycoprotein and there are no specific studies, precaution is required when Vinorelbine solution is combined with strong modulators of this membrane carrier. Concomitant use with inhibitors (e.g. ritonavir, clarithromycin, ciclosporin, verapamil, quinidine) or inducers (e.g. see list of CYP3A4 inducers) of this transport protein can affect the concentration of vinorelbine.
The combination of Vinorelbine solution with other drugs of known bone marrow toxicity can exacerbate the adverse effects of myelosuppressants.
As CYP 3A4 is particularly involved in the metabolism of Vinorelbine solution, the combination with strong inhibitors of this isoenzyme (for example, ketoconazole, itraconazole, HIV-protease inhibitors, erythromycin, clarithromycin, telithromycin, nefazodone) can increase the serum concentrations of vinorelbine and the combination with potent inducers of this isoenzyme (for example, rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s wort) can reduce the serum concentrations of vinorelbine.
The combination of Vinorelbine solution and cisplatin shows that there is no mutual interaction between the pharmacokinetic parameters during various treatment courses. However, the incidence of granulocytopenia associated with the administration of Vinorelbine solution in combination with cisplatin is higher than that associated with the use of Vinorelbine solution 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 22.5mg/m2 when combined with daily lapatinib 1000mg. This type of combination should be administered with caution.
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, the product is suspected to cause serious birth effects when administered during pregnancy.
Vinorelbine is contraindicated in pregnancy (see section 4.3). Women should not become pregnant during treatment with vinorelbine.
In case of a 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 should occur during the treatment, the possibility of genetic counselling should be considered.
Women of childbearing potential must be advised to use effective contraception during treatment and three months thereafter
It is unknown whether the product is excreted in human breast milk. The excretion of vinorelbine in milk has not been studied in animal studies. A risk to the suckling cannot be excluded therefore breast feeding must be discontinued before starting treatment with vinorelbine (see section 4.3).
Vinorelbine can have genotoxic effects. Therefore, 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. Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with vinorelbine.
The effects on the ability to drive and use machines have not been studied, but on the basis of its pharmacodynamic profile, vinorelbine does not affect the ability to drive or use machines. Nonetheless, precautions should be taken by patients treated with vinorelbine, bearing in mind some of the undesirable effects of the drug.
The undesirable effects reported with more frequency than isolated cases are listed below according to system organ class and frequency. Frequencies are defined as very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), unknown (cannot be calculated on the basis of the data available), according to the MedDRA frequency convention and classed by system organ class.
The adverse drug reactions reported most frequently are: bone marrow depression with neutropenia, anaemia, neurological diseases, gastrointestinal toxicity accompanied by nausea, vomiting, stomatitis and constipation, transitory increases in liver function test results, alopecia and local phlebitis.
Other adverse reactions were added after post-marketing studies, according to the MedDRA classification and with “unknown” frequency.
Detailed information on undesirable effects: the effects are reported according to the WHO classification (grade 1=G1; grade 2=G2; grade 3=G3; grade 4=G4; grau 1-4= G1-4; grade1-2=G1-2; grade 3-4=G3-4).
Common: bacterial, viral or fungal infections at different sites (respiratory tract, urinary tract, gastrointestinal tract, etc.); mild to moderate and normally reversible with the appropriate treatment.
Uncommon: severe sepsis accompanied by another visceral failure. Septicaemia.
Very rare: sometimes fatal, complicated septicaemia.
Unknown: neutropenic septicaemia.
Very common: bone marrow depression resulting principally in neutropenia (G3: 24.3%; G4: 27.8%) which is reversible within 5 to 7 days and not cumulative over time; anaemia (G3-4: 7.4%)
Common: thrombocytopenia (G3-4: 2.5%), rarely serious.
Unknown: febrile neutropenia.
Unknown: systemic allergic reactions, such as anaphylaxis, anaphylactic shock or anaphylactoid reactions.
Unknown: syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Rare: severe hyponatraemia
Unknown: anorexia
Very common: stomatitis (G 1-4: 15% with Vinorelbine solution as monotherapy); nausea and vomiting (G 3-4: 2.2%); antiemetic therapy can reduce this occurrence; constipation is the principal symptom (G 3-4: 2.7%), which rarely develops into paralytic ileus with Vinorelbine solution as monotherapy and with Vinorelbine solution in conjunction with other chemotherapy agents (G3-4: 4.1%).
Common: diarrhoea, usually mild to moderate.
Rare: paralytic ileus – treatment may be restarted when normal intestinal transit is resumed. Pancreatitis has been reported.
Very common: neurological alterations (G3-4: 2.7%) including loss of deep tendon reflexes. Weakness of the lower limbs has been reported after prolonged chemotherapy.
Uncommon: severe paraesthesia with sensory and motor symptoms.
These effects are usually reversible.
Very common: alopecia, usually mild (G3-4: 4.1% with Vinorelbine solution as isolated chemotherapy agent).
Rare: generalised skin reactions have been reported with Vinorelbine solution.
Unknown: erythema on the hands and feet.
Rare: ischaemic heart disease (angina pectoris, myocardial infarction).
Very rare: tachycardia, palpitations and altered heart rhythm.
Uncommon: hypotension, hypertension, flushing and peripheral coldness.
Rare: severe hypotension, collapse.
Very common: transitory increases in liver function tests (G1-2), without notification of clinical symptoms (AST 27.6% and ALT 29.3%).
Uncommon: dyspnoea and bronchospasm can occur in association with treatment with Vinorelbine solution, as well as with other vinca alkaloids.
Rare: cases of interstitial lung disease have been reported, particularly in patients treated with Vinorelbine solution in combination with mitomycin.
Common: arthralgia, including pain in the jaw; myalgia.
Very common: injection site reactions include erythema, burning sensation, venous discolouration and local phlebitis (G3-4: 3.7% with Vinorelbine solution as isolated chemotherapy agent).
Common: asthenia, fatigue, fever, pain at different sites including chest pain and pain at the site of the tumour have been reported by patients treated with Vinorelbine solution.
Rare: local necrosis has been reported. Correct positioning of the intravenous needle or catheter and a bolus injection followed by flushing of the vein can limit these effects.
Reporting suspected adverse reactions 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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.
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