Vinorelbine 10 Mg/ Ml Concentrate For Solution For Infusion
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Vinorelbine 10 mg/ ml concentrate for solution for infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml concentrate for solution for infusion contains 10mg vinorelbine base equivalent to 13.85mg vinorelbine tartrate .
Each 5 ml vial contains a total content of 50mg vinorelbine (as tartrate).
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Concentrate for solution for infusion
Vinorelbine 10 mg/ml concentrate for solution for infusion is a clear, colourless to slightly yellow solution.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
• As a single agent or in combination for the first line treatment of stage 3 or 4 non small cell lung cancer.
• Treatment of advanced breast cancer stage 3 and 4 relapsing after or refractory to an anthracycline containing regimen.
Strictly by intravenous injection through an infusion line after appropriate dilution.
The use of intrathecal route is contra-indicated.
Administration should always be followed by a normal saline infusion to flush the vein.
Instructions for use and handling: see section 6.6.
In adults :
Vinorelbine is usually given at 25-30mg/m2 weekly.
Vinorelbine may be administered by slow bolus (5-10 minutes) after dilution in 20-50 ml of sodium chloride 9 mg/ml (0.9%) solution for injection or in 5% glucose solution for injection. Administration should always be followed with at least 250 ml of an isotonic solution to flush the vein.
Advanced 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.
Elderly
See section 5.2: Pharmacokinetic properties.
Impaired hepatic function:
For patients presenting with severe liver impairment (bilirubin > 2xUNL and/or transaminases > 5xUNL), it is suggested that the dose be reduced by 33% and the haematological parameters be closely monitored since the maximum dose which was evaluated in this subset of patients was 20mg/m .
See sections: 4.4: Special warnings and precautions for use
5.2: Pharmacokinetic properties
Impaired renal function:
For patients with impaired kidney function, there is no need to adjust the dosage. See section 4.4: Special warnings and precautions for use.
Paediatric patients
Safety and efficacy in children have not been established and administration is therefore not recommended. See section 5.1: Pharmacodynamic properties Dosage adjustment in specific patient groups: see section 4.4 Special warnings and precautions for use.
- The use of intrathecal route is contra-indicated
- Known hypersensitivity to vinorelbine or other vinca alkaloids, or to any of the excipients
- Pregnancy [see section 4.6]
- Breast-feeding should be discontinued during treatment with vinorelbine [see section 4.6]
- Neutrophil count < 1500/mm3 or severe infection current or recent (within 2 weeks)
- Platelet count below 100,000/mm3
Severe hepatic impairment not related to the tumoral process
- 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 must only be administered by the intravenous route.
Vinorelbine should be administered under the supervision of a physician experienced in the use of chemotherapy.
Close haematological monitoring should be performed during treatment
Determination of haemoglobin level and the leucocyte, neutrophil and platelet counts on the day of each new administration should be undertaken since inhibition of the haematopoietic system is the main risk during treatment with vinorelbine.
The dose limiting adverse reaction is mainly neutropenia. This effect is noncumulative, having its nadir between 7 and 14 days after the 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 100,000/mm3 then the treatment should be delayed until recovery.
If the patient presents signs or symptoms suggestive of infection, a prompt investigation should be carried out.
Special care should be taken when prescribing for patients with history of ischemic heart disease (see section 4.8).
The clinical relevance of impaired drug elimination capacity of the liver has not been characterised. Therefore no exact dose recommendation could be given. However in the pharmacokinetic study the highest administered dose in patients with severe liver
dysfunction was 20 mg/m2 (see section 5.2). For patients with severe hepatic impairment caution is recommended and careful monitoring of haematological parameters is required. Dosage reduction may also be required (see sections 4.2 and 4.3).
As there is a low level of renal excretion there is no pharmacokinetic rationale for reducing Vinorelbine dose in patients with impaired kidney function.
Vinorelbine should not be given concomitantly with radiotherapy if the treatment field includes the liver.
All contact with the eye should be strictly avoided, 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 ophthalmologist.
This product is specifically contra-indicated with yellow fever vaccine and its concomitant use with other live attenuated vaccines is not recommended.
-Strong inhibitors or inducers of CYP3A4 can affect the vinorelbine concentration and caution should therefore be exercised (see section 4.5, interactions specific to vinorelbine), and its combination with phenytoin (like all cytotoxics) and with itraconazole (like all vinca-alkaloids) is not recommended).
-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, see section 4.2.
4.5 Interaction with other medicinal products and other forms of interaction
Interactions common to all cytotoxics
Due 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 contraindicated
Yellow fever vaccine: risk of fatal generalised vaccine disease (see section 4.3).
Concomitant use not recommended
Live 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 risk of toxicity enhancement or loss of efficacy of the cytotoxic drug due to increased hepatic metabolism by phenytoin.
Concomitant use to take into consideration
Cyclosporine, tacrolimus: excessive immunodepression with risk of lymphoproliferation
Interactions specific to vinca-alkaloids
Concomitant use not recommended
Itraconazole: increased neurotoxicity of vinca-alkaloids due to the decrease of their hepatic metabolism.
Concomitant use to take into consideration
Mitomycin 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 /... / with strong modulators of this membrane transporter.
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).
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.
Pregnancy
Vinorelbine is suspected to cause serious birth defects when administered during pregnancy: see section 5.3.
- Vinorelbine is contraindicated in pregnancy: see section 4.3 contraindications.
In case of 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 occurs anyhow during treatment, genetic counselling should be offered.
Women of childbearing potential
Women of child-bearing potential have to use effective contraception during treatment and up to 3 months after treatment: see section 4.3 contraindications.
Breast feeding
- It is unknown whether Vinorelbine is excreted in human breast milk.
- The excretion of Vinorelbine in milk has not been studied in animal studies.
- A risk to the suckling child cannot be excluded therefore breast feeding must be discontinued before starting treatment with Vinorelbine: see section 4.3 contraindications.
Fertility
Men 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.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
On the basis of the vinorelbine pharmacodynamic profile, Vinorelbine is unlikely to impair the ability to drive or operate machinery. However, caution is necessary in patients treated with Vinorelbine considering some side effects of the drug [see section 4.8].
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, <1/10); uncommon ( ^ 1/1,000, <1/100); rare ( ^ 1/10,000, <1/1,000); very rare ( <1/10,000) according to the MedDRA frequency convention and system organ classification.
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 reversible within 5 to 7 days and noncumulative over time.
- Anaemia.
Common :
- Thrombocytopenia may occur but are seldom severe.
Not Known: febrile neutropenia
Immune system disorders
Not known:
- Systemic allergic reactions reported as anaphylactic shock, anaphylaxis and anaphylactoid type reactions.
Endocrine disorders
Not known:
- Inappropriate antidiuretic hormone secretion. (SIADH)
Metabolism and nutrition disorders
Rare:
- Severe hyponatraemia. Not known: anorexia
Nervous system disorders Very Common:
- Neurologic disorders including loss of deep tendon reflexes.
- Weakness of the lower extremities has been reported after a prolonged chemotherapy.
Uncommon:
- Severe paresthesias with sensory and motor symptoms are infrequent. These effects are generally reversible upon discontinuation of treatment.
Very rare: Guillain-Barre syndrome
Cardiac disorders
Rare:
- Ischemic heart disease: (angina pectoris and /or transitory electrocardiogram changes, myocardial infarction.)
Very rare:
- Tachycardia, palpitation and heart rhythm disorders.
Vascular disorders
Uncommon:
- Hypotension.
- Hypertension.
- Flushing and peripheral coldness.
Rare:
- Severe hypotension.
- Collapse.
Respiratory system, thoracic and mediastinal disorders Uncommon:
- Dyspnoea and bronchospasm may occur in association with Vinorelbine treatment as with other vinca alkaloids.
Rare:
- Interstitial pneumonopathy has been reported in particular in patients treated with Vinorelbine in combination with mitomycin.
Gastrointestinal disorders
Very Common:
- Stomatitis.
- Nausea and vomiting.
- Antiemetic therapy may reduce their occurrence constipation is the main symptom which rarely progresses to paralytic ileus with vinorelbine as single agent and 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.
Hepatobiliary disorders Very common:
- Transient elevations of liver function tests without clinical symptoms were reported.
Skin and subcutaneous tissue disorders
Very Common:
- Alopecia, usually mild in nature, may occur.
Rare:
- Generalized cutaneous reactions (as rash, pruritus, urticaria) -Not known erythema on hands and feet
Musculoskeletal, connective tissue and bone disorders Common:
- Arthralgia including jaw pain and myalgia.
General disorders and administration site conditions:
Very Common: Reactions at the injection site may include erythema, burning pain, vein discolouration and local phlebitis.
Common:
-Asthenia, fever, pain at different locations including chest pain and pain at the tumour site.
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.
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 at:www.mhra.gov.uk/yellowcard.
Overdose
4.9
Accidental overdosages have been reported in humans : they may produce a period of bone marrow aplasia sometimes associated with infection, fever, paralytic ileus. General supportive measures together with blood transfusion and broad spectrum antibiotic therapy should be instituted as deemed necessary by the physician.
There is no known antidote for 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
ATC Code: L01C A04 (Vinca alkaloids and analogues)
Vinorelbine is an antineoplastic drug of the vinca alkaloid family but unlike all the other vinca alkaloids, the catharantine moiety of vinorelbine has been structurally modified. At the molecular level, it acts on the dynamic equilibrium of tubulin in the microtubular apparatus of the cell. It inhibits tubulin polymerization and binds preferentially to mitotic microtubules, affecting axonal microtubules at high concentrations only. 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. (see section 4.2)
5.2 Pharmacokinetic properties
Pharmacokinetic parameters of vinorelbine were evaluated in blood.
Distribution
The steady-state volume of distribution is large, on average 21.2 l/h/kg (range: 7.5-39.7 l/h/kg ), which indicates extensive tissue distribution.
Vinorelbine has high affinity for platelets and lymphocytes. Binding to plasma protein is low (13.5% of the total blood-bound vinorelbine). 78% of the total blood-bound vinorelbine was associated with platelets and 4.8% of the total blood-bound vinorelbine was associated with lymphocytes.
There is significant uptake of vinorelbine in the lungs, as assessed by surgical lung biopsies, which showed concentrations up to 300-fold higher than in serum. Vinorelbine is not found in the central nervous system.
Biotransformation
Vinorelbine is principally metabolised by cytochrome P450 3A4. All metabolites have been identified and none is active, except 4-O-deacetyl vinorelbine, which is the main metabolite in blood. No sulphonic or glucuronic conjugates are found.
Elimination
The mean terminal half-life of vinorelbine is around 40hours. Blood clearance is high, approaching hepatic blood flow, and is 0.72 l/h/kg on average (range: 0.32 - 1.26 l/h/kg).
Renal elimination is low ( < 20% of the intravenous dose administered) and consists mostly of the in parent compound. Biliary excretion is the predominant elimination route of unchanged vinorelbine, which is the main recovered compound, and its metabolite 4-O-deacetyl vinorelbine.
Special patient groups
Renal impairment
The effects of renal dysfunction on vinorelbine disposition have not been assessed. However, dose reduction in case of reduced renal function is not indicated due to the low renal elimination.
Liver impairment
A first study has reported the effects of liver impairment on vinorelbine pharmacokinetics. This study was performed in patients with liver metastases due to breast cancer, and concluded that a change in mean clearance of vinorelbine was only observed when more than 75% of the liver is involved.
A phase I pharmacokinetic dose-adjusted study was conducted in cancer patients with liver dysfunction : 6 patients with moderate dysfunction (Bilirubin < 2 x UNL and Transaminases < 5 x UNL) treated up to 25 mg/m2 and 8 patients with severe dysfunction (Bilirubin > 2 x UNL and/or Transaminases > 5 x UNL) treated up to 20 mg/m2. Mean total clearance in these two subsets of patients was similar to that in patients with normal hepatic function. Therefore, the pharmacokinetics of vinorelbine are not modified in patients presenting with moderate or severe liver impairment. Nevertheless, in a conservative approach it is suggested that the dose be reduced by 33% and the haematological parameters closely monitored in patients with severe liver impairment since the maximum dose which was given in this subset of patients was 20 mg/m2.
Elderly patients
Study on oral vinorelbine in elderly patients ( ^ 70 years) with NSCLC demonstrated there is no influence of the age on vinorelbine pharmacokinetics and that no dose reduction is required.
PK-PD relation
A strong relationship has been demonstrated between vinorelbine blood exposure and of leucocytes or PMNs decreases.
5.3 Preclinical safety data
• Mutagenic and carcinogenic potential
The interaction of vinorelbine with the spindle apparatus during mitosis can cause an incorrect distribution of chromosomes. In animal studies vinorelbine induced aneuploidy and polyploidy. It is therefore to be assumed that vinorelbine can also cause mutagenic effects (induction of aneuploidy) in man.
The carcinogenicity studies, in which vinorelbine was administered only once every two weeks in order to avoid the toxic effects of the drug, are negative.
• Reproductive toxicity
In animal reproductive studies vinorelbine was embryo- and feto-lethal and teratogenic.
The NOEL in the rat was 0.26 mg/kg every 3 days.
Following peri/postnatal administration in the rat at doses of 1.0 mg/kg every 3 days i.v., retarded weight gain was found in the offspring up to the 7th week of life.
• Safety pharmacology
Bibliographic review concerning the tolerance of vinca alkaloids on the cardiovascular system shows the occurrence of some cardiac events (such as angina, myocardial infarction), but the incidence of these is low.
Haemodynamic and electrocardiographic studies on animals have shown that no haemodynamic effects have been found using a maximal tolerated dose in dogs, however only some non significant disturbances of repolarization were found for all vinca alkaloids tested. No effect on the cardiovascular system has been detected using repeated doses (study 39 weeks) of vinorelbine on primates.
6.1 List of excipients
Water for Injections.
6.2 Incompatibilities
- Vinorelbine solution (10mg/ml) may be diluted in a solution for infusion of normal saline or 5% dextrose.
- The volume of dilution depends on the mode of administration :
Bolus = 20-50 ml
Infusion = 125 ml
• Vinorelbine 10 mg/ml concentrate for solution for infusion should not be diluted in alkaline solutions (risk of precipitate)
• In case of polychemotherapy, Vinorelbine 10 mg/ml concentrate for solution for infusion should not be mixed with other agents.
• Vinorelbine 10 mg/ml concentrate for solution for infusion is not absorbed to or affected by either PVC or clear neutral glass.
6.3 Shelf life
As packaged for sale 30 months.
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 (see section 6.6) has been demonstrated for 24 hours at 2-8°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.”
6.4 Special precautions for storage
As packaged for sale
Store 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 conditions of the diluted medicinal product, see section 6.3
6.5 Nature and contents of container
Type I glass vials with bromobutyl rubber stoppers containing 10 mg vinorelbine in 1 ml solution or 50 mg vinorelbine in 5 ml solution. The vials are available individually packaged in a carton folding box.
6.6 Special precautions for disposal
Vinorelbine 10 mg/ml concentrate for solution for infusion has a more or less yellow colouration which does not affect the quality of the product.
Handling guidelines: the preparation and administration of Vinorelbine 10 mg/ml concentrate for solution for infusion should be carried out only by trained staff and as with all cytotoxic agents, precautions should be taken to avoid exposing staff during pregnancy.
Preparation of solution for administration should be carried out in a designated handling area and working over a washable tray or disposable plastic-backed absorbent paper.
Suitable eye protection, disposable gloves, face mask and disposable apron should be worn.
Syringes and infusion sets should be assembled carefully to avoid leakage (use of Luer lock fittings is recommended).
Eventual spillage or leakage should be mopped up wearing protective gloves.
All contact with the eye should be strictly avoided : risk of severe irritation and even corneal ulceration if the drug is sprayed under pressure. Immediate liberal washing of the eye with 0.9% Sodium Chloride solution should be undertaken if any contact occurs.
On completion, any exposed surface should be thoroughly cleaned and hands and face washed.
Vinorelbine 10 mg/ml concentrate for solution for infusion may be administered by slow bolus (5-10 minutes) after dilution in 20-50 ml of 0.9% Sodium Chloride solution or by a short infusion (20-30 minutes) after dilution
in 125 ml of 0.9% Sodium Chloride solution. Administration should always be followed by a 0.9% Sodium Chloride infusion to flush the vein.
Vinorelbine 10 mg/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 starting to infuse the solution.
If the drug extravasates during intravenous administration, a substantial local reaction may occur. In this case, the injection should be stopped and the rest of the dose should be administered in another vein.
Disposal guidelines: all sharps should be placed in an appropriate container and all other disposable items and cleaning materials in a sealed plastic bag which should be incinerated with other clinical waste.
Waste material may be disposed of by incineration.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Ennogen Pharma Limited Unit G4,
Riverside Industrial Estate,
Riverside Way,
Dartford DA1 5BS UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 40147/0087
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 16/09/2008
10 DATE OF REVISION OF THE TEXT
22/11/2013