Vinorelbine 10 Mg/Ml Concentrate For Solution For Infusion
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Vinorelbine 10 mg/ml Concentrate for Solution for Infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 1 ml concentrate for solution for infusion contains vinorelbine tartrate equivalent to 10 mg vinorelbine
Each 5 ml concentrate for solution for infusion contains vinorelbine tartrate equivalent to 50 mg vinorelbine
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Concentrate for solution for infusion
Clear, colourless or pale yellow solution (pH 3- 4).
The osmolarity is 32 - 38 mOsm.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Vinorelbine is indicated in the treatment of:
• Non-small cell lung cancer (stage 3 or 4).
• As single agent in patients with metastatic breast cancer (stage 4), where treatment with anthracycline- and taxane containing chemotherapy has failed or is not appropriate.
4.2. Posology and method of administration
- Strictly intravenous administration after appropriate dilution.
- Intra-thecal administration of vinorelbine may be fatal.
Vinorelbine should be given in cooperation with a physician with extensive experience in therapy with cytostatics.
For instructions regarding use and handling, see section 6.6.
Administration
- vinorelbine may be administered by slow bolus (6-10 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 with at least 250 ml of a normal saline infusion to flush the vein.
- Non-small cell lung cancer: As a single agent the normal dose is 2530 mg/m2, administered once weekly. In polychemotherapy the schedule regimen are a function of the protocol. The normal dose could be used (25-30 mg/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.
- Metastatic breast cancer: The normal dose is 25-30 mg/m2, administered once weekly.
- The maximum tolerated dose per administration: 35.4 mg/m body surface area.
Administration in children
Safety and efficacy in children have not been determined and administration is therefore not recommended.
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 sections 4.4 and 5.2).
Administration in patients with renal insufficiency
In patients with reduced kidney function, the dose does not have to be adjusted (see section 5.2).
Administration in the elderly
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.
4.3. Contraindications
• Known hypersensitivity to vinorelbine or other vinca alkaloids, or to any of the excipients listed in section 6.1.
• Neutrophil granulocytes <1500/mm or serious, current or recent infection (within 2 weeks).
• Platelet count below 100000/mm3
• Pregnancy (see section 4.6)
• Breast-feeding should be discontinued during treatment with vinorelbine (see section 4.6).
• 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.)
4.4. Special warnings and precautions for use
Special warnings
• Vinorelbine should be administered under the supervision of a physician experienced in the use of chemotherapy.
• Strictly for intravenous use only.
• 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 1500/mm3 and/or the platelet count is below 100000/mm , 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 precautions for use
• Special caution is advised in patients with a history of ischaemic heart disease (see section 4.8).
• The pharmacokinetics of vinorelbine is not modified in patients presenting moderate or severe liver impairment. For dosage adjustment in this specific patient group, see section 4.2.
• Vinorelbine should not be given concomitantly with radiotherapy if the treatment field includes the liver.
• Vinorelbine 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 ophtalmologist.
• Strong inhibitors or inducers of CYP3A4 can affect the vinorelbine concentration and caution should therefore be exercised (see section 4.5).
• This product is specifically contra-indicated with yellow fever vaccine and generally not recommended in combination with live attenuated vaccines, phenytoin and itraconazole (see section 4.5).
• 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.
4.5. Interaction with other medicinal products and other forms of interaction
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).
• Vinorelbine is a substrate for P-glycoprotein and concurrent treatment with other drugs that inhibit (i.e. ritonavir, clarithromycin, cyclosporine, verapamil, quinidine) or induce (see list of CYP 3A4 inducers given above) the same transport protein can affect the concentration of vinorelbine. Caution should be exercised when combining vinorelbine with strong modulators of this membrane transporter.
• 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.
Interactions specific to vinca-alkaloids:
Concomitant administration of vinca alkaloids and mitomycin C may increase the risk of bronchospasm and dyspnoea, in rare cases an interstitial pneumonitis was observed (see also sections 4.4 and 4.8).
Itraconazole: Concomitant use is not recommended due to potential increased neurotoxicity.
Interactions common to all cytotoxics:
Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation treatment is frequent. The high intra-individual variability of the coagulation status during diseases and the possibility of interaction between oral anticoagulants and anticancer chemotherapy require increased frequency of INR (International Normalised Ratio) monitoring, if it is decided to treat the patient with oral anticoagulants.
• Concomitant use contraindicated: Yellow fever vaccine: risk of fatal generalised vaccinale disease (see section 4.3).
• Concomitant use not recommended: Live attenuated vaccines (except yellow fever): risk of systemic, possibly fatal, disease. The risk is increased in subjects who are already immunosuppressed by their underlying disease. Use an inactivated vaccine where it exists (poliomyelitis) (see section 4.4).
• Concomitant use of phenytoin and vinorelbine is not recommended.
The risk of exacerbation of convulsions may result from vinorelbine induced decrease in gastro-intestinal phenytoin absorption. Also, increased toxicity due to metabolites and/ or reduced efficacy of vinorelbine may result from phenytoin induced increase of hepatic metabolisation of vinorelbine.
• Concomitant use to take into consideration
Ciclosporine, Tacrolimus: Excessive immunosuppression with risk of lymphoproliferation is to be taken into consideration.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are insufficient data from the use of vinorelbine in pregnant women. In animal reproductive studies vinorelbine was embryo- and feto-lethal and teratogenic (see section 5.3). During pregnancy this product should not be used (see section 4.3). Fertile women should use effective methods of contraception during treatment with vinorelbine and should inform their doctor if they become pregnant. 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.
Breast-feeding
It is not known whether vinorelbine passes into the breast milk. The excretion of vinorelbine in milk has not been studied in animal studies. Breast-feeding must be discontinued before treatment with vinorelbine is commenced.
Fertility:
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.
4.7. Effects on ability to drive and use machines
No studies of the effects on the ability to drive and use machines have been performed, but 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.
4.8 Undesirable effects
Adverse reactions reported as more than isolated cases are listed below, by system organ class and by frequency. Frequencies are defined as: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000), according to the MedDRA frequency convention and system organ classification.
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.
Additional Adverse reactions from Post Marketing experience has been added according to the MedDRA classification with the frequency Not known
Detailed adverse reactions information:
Reactions were described using the W.H.O 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).
|
System Organ Class |
Very common > 1/10 |
Common > 1/100 to < 1/10 |
Uncommon > 1/1,000 to < 1/100 |
Rare > 1/10,000 to < 1/1,000 |
Very rare < 1/10,000 |
Not known (frequency cannot be estimated from available data) |
|
Infections and infestations |
Infection bacterial, viral or fungal at different localization (respiratory , urinary, GI tract) mild to moderate and usually reversible with an appropriate treatment |
Severe sepsis with other visceral failure, Septicaemia |
Complicated septicaemia and sometimes fatal |
Neutropenic sepsis | ||
|
Blood and lymphatic system disorders |
Bone marrow depression resulting mainly in neutropenia (G3: 24.3%; G4: 27.8%), reversible within 5 to 7 days and noncumulative over time, Anaemia (G3-4: 7.4%) |
Thrombocy topenia (G3-4: 2.5%) may occur but are seldom severe |
Febrile neutropenia | |||
|
Immune system disorders |
Systemic allergic reactions as anaphylaxis, anaphylactic shock or |
|
System Organ Class |
Very common > 1/10 |
Common > 1/100 to < 1/10 |
Uncommon > 1/1,000 to < 1/100 |
Rare > 1/10,000 to < 1/1,000 |
Very rare < 1/10,000 |
Not known (frequency cannot be estimated from available data) |
|
anaphylactoid type reaction | ||||||
|
Endocrine disorders |
Inappropriate antidiuretic hormone secretion (SIADH) | |||||
|
Metabolism and nutrition disorders |
Severe hyponatraemi a |
Anorexia | ||||
|
Nervous system disorders |
Neurologic disorders (G 3-4: 2.7%) including loss of deep tendon reflexes, Weakness of the lower extremities has been reported after a prolonged chemotherapy * |
Severe paresthesias with sensory and motor symptoms are infrequent* | ||||
|
Cardiac disorders |
Ischemic heart disease (angina pectoris, myocardial infarction) |
Tachycardia, palpitation and heart rhythm disorders | ||||
|
Vascular disorders |
Hypotension, hypertension, flushing and peripheral coldness |
Severe hypotension, collapse | ||||
|
Respiratory system, thoracic and mediastinal disorders |
Dyspnoea and bronchospasm may occur in association with vinorelbine treatment as |
Interstitial pneumopathy has been reported in particular in patients treated with |
|
System Organ Class |
Very common > 1/10 |
Common > 1/100 to < 1/10 |
Uncommon > 1/1,000 to < 1/100 |
Rare > 1/10,000 to < 1/1,000 |
Very rare < 1/10,000 |
Not known (frequency cannot be estimated from available data) |
|
with other vinca alkaloids |
vinorelbine in combination with mitomycin | |||||
|
Gastro intestinal disorders |
Stomatitis (G1-4: 15% with vinorelbine as single agent), Nausea and vomiting (G 1-2: 30.4% and G 3-4: 2.2%). Antiemetic therapy may reduce their occurrence, Constipation is the main symptom (G 3-4: 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 chemotherape utic agents |
Diarrhoea usually mild to moderate may occur |
Paralytic ileus, treatment may be resumed after recovery of normal bowel mobility, Pancreatitis has been reported | |||
|
Hepato biliary disorders |
Transient elevations of liver function tests (G 1-2) without clinical symptoms were reported |
|
System Organ Class |
Very common > 1/10 |
Common > 1/100 to < 1/10 |
Uncommon > 1/1,000 to < 1/100 |
Rare > 1/10,000 to < 1/1,000 |
Very rare < 1/10,000 |
Not known (frequency cannot be estimated from available data) |
|
(SGOT in 27.6% and SGPT in 29.3%) | ||||||
|
Skin and subcutaneous tissue disorders |
Alopecia, usually mild in nature, may occur (G3-4: 4.1% with vinorelbine as single chemotherape utic agent) |
Generalized cutaneous reactions have been reported with vinorelbine |
Erythema on hands and feet | |||
|
Musculoskeletal and connective tissue disorders |
Arthralgia including jaw pain and myalgia | |||||
|
General disorders and administration site conditions |
Reactions at the injection site may include erythema, burning pain, vein discoloration and local phlebitis (G 34: 3.7% with vinorelbine as single chemotherape utic agent) |
Asthenia, fatigue, fever, pain at different locations including chest pain and pain at the tumour site have been experienced by patients receiving vinorelbine therapy |
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 |
* These effects are generally reversible.
4.9. Overdose
Overdosages may produce severe bone marrow depression with fever and infection, paralytic ileus have also been reported. Symptomatic treatment with blood transfusion, growth factors 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents (vinca alkaloids), 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.
5.2 Pharmacokinetic properties
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.
5.3 Preclinical safety data
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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Water for injections.
6.2 Incompatibilities
• Vinorelbine should not be diluted in alkaline solutions (risk of precipitation)
• Vinorelbine must not be mixed with other medicinal products except those mentioned in section 6.6.
Shelf life
6.3
10 mg/ ml: 36 months 50 mg/ 5 ml: 36 months
In-use shelf life:
After dilution in 0.9 % NaCl or 5 % glucose solution, chemical and physical in-use stability has been demonstrated at concentrations of 0.43 mg/ml and 2.68 mg/ml for 48 hours at 2 to 8 °C protected from light. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsability of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless reconstitution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2 - 8°C). Do not freeze. Store the vial in the outer carton in order to protect from light.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
Clear, colourless glass vials (type I) with fluoropolymer coated rubber stoppers and aluminium crimp caps.
Pack sizes: 1x1 ml vial, 5x1 ml vials, 10x1 ml vials, 1x5 ml vial, 5x5 ml vials and 10x5 ml vials.
Not all pack sizes may be marketed.
6.6. Special precautions for disposal and handling
Only trained staff should carry out the preparation and administration of vinorelbine. Precautions should be taken into account to avoid exposing staff during pregnancy.
Suitable safety equipment, eye protection, disposable gloves, facemask and disposable apron should be worn. Syringes and infusion sets should be assembled carefully to avoid leakage (use of Luer lock fittings is recommended). Excreta and vomit must be handled with care.
Spills and leakages must be wiped up. All contact with the eye must be strictly avoided. Immediate washing of the eye with normal saline solution should be undertaken if any contact occurs. On completion, any exposed surface should be thoroughly cleaned and hands and face washed. There is no incompatibility between vinorelbine and clear glass vials, PVC or vinyl acetate bags, or infusion sets with PVC tubing. Vinorelbine may be administered by slow bolus (6-10 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 with at least 250 ml of a normal saline infusion to flush the vein.
Vinorelbine 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 infiltrates the surrounding tissue during intravenous administration, a substantial irritation may occur. In this case, the injection should be stopped, the vein flushed with normal 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.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Sandoz Limited Frimley Business Park,
Frimley,
Camberley,
Surrey,
GU16 7SR.
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 04416/0807
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
30/12/2009
10 DATE OF REVISION OF THE TEXT
29/03/2012