1. Name Of The Medicinal Product
Vinorelbine 10 mg/ml Concentrate for solution for infusion
2. Qualitative And Quantitative Composition
Vinorelbine (as tartrate) 10 mg/ml
Each 1 ml vial contains a total content of vinorelbine (as tartrate) of 10 mg
Each 5 ml vial contains a total content of vinorelbine (as tartrate) of 50 mg
For excipients, see section 6.1.
3. Pharmaceutical Form
Concentrate for solution for infusion
Clear, colourless to pale 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.
4.2 Posology And Method Of Administration
Vinorelbine must be administered under the supervision of a doctor experienced in the use of chemotherapy.
Strictly by intravenous injection through an infusion line.
The use of intrathecal route is contra-indicated.
In adults:
• Vinorelbine is usually given at 25-30 mg/m2 weekly.
Vinorelbine may be administered by slow bolus (5-10 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 by a normal saline infusion to flush the vein.
Dose modifications:
Vinorelbine metabolism and clearance are mostly hepatic: only 18.5% is excreted unchanged in the urine. No prospective study relating altered metabolism of the active substance to its pharmacodynamic effects is available in order to establish guidelines for vinorelbine dose reduction in patients with impaired liver or kidney function.
Hepatic Impairment
In breast cancer-patients, vinorelbine clearance is not altered in the presence of moderate liver metastases (i.e. 75% of liver volume replaced by the tumour). In these patients, there is no pharmacokinetic rationale for reducing vinorelbine doses.
In patients with massive liver metastases (i.e.>75% of liver volume replaced by the tumour), the real impact of impaired drug elimination capacity of the liver has not been characterised. In these patients, it is empirically suggested that the dose be reduced by 1/3 and the haematological toxicity closely followed-up.
Renal impairment
There is no pharmacokinetic rationale for reducing vinorelbine dose in patients with impaired kidney function.
The dose limiting toxicity of vinorelbine is mainly neutropenia. This usually occurs between day 8 and day 12 after administration of the medicinal product, is short-lived, and is not cumulative. If the neutrophil count is <2000/mm³ and/or platelet number is <75000/mm³, then the treatment should be delayed until recovery. Administration of the medicinal product is expected to be delayed by 1 week in about 35% of treatment courses.
The maximum tolerated dose per administration: 35.4 mg/m² body surface area
The maximum total dose per administration: 60 mg
The safety and efficacy in children and adolescents have not been demonstrated.
4.3 Contraindications
- Hypersensitivity to vinorelbine or other vinca alkaloids
- Neutrophil count <2000/mm³ or severe current or recent infection (within the last 2 weeks)
- Platelet count less than 75.000/mm³
- Severe hepatic impairment not related to the tumoural process
- In combination with yellow fever vaccine
- Pregnancy (see section 4.6)
- Lactation (see section 4.6)
4.4 Special Warnings And Precautions For Use
- Vinorelbine must only be administered by the intravenous route. The use of intrathecal route is contra-indicated. Administration should always be followed by a normal saline infusion to flush the vein.
- Vinorelbine must be administered intravenously with great precision: It is very important to make sure that the cannula has been accurately placed into the vein before starting to infuse vinorelbine. If vinorelbine extravasates during intravenous administration, this can cause considerable local irritation. In this case, the infusion must be stopped immediately, the vein flushed through with physiological saline solution and the rest of the dose should be administered in another vein. In the event of extravasation glucosteroids can be given intravenously in order to reduce the risk of phlebitis.
- Treatment should be undertaken with close haematological monitoring (determination of haemoglobin level and number of leukocytes, granulocytes and platelets before each new injection). If the neutrophil count is <2000/mm³ and/or thrombocyte count is below 75000/mm³, treatment should be delayed until recovery and the patient should be observed (see section 4.2).
- If the patients present signs or symptoms suggestive of infection, a prompt investigation should be carried out.
- If there is significant hepatic impairment the dose should be reduced: caution is recommended and careful monitoring of haematological parameters required (see section 4.2).
- In case of renal impairment, because of the low level of renal excretion, no dose modification is necessary (see section 4.2 and 5.2).
- Vinorelbine should not be given concomitantly with radiotherapy if the treatment field includes the liver.
- This product is generally not recommended in combination with live attenuated vaccines.
- All contact with the eyes should be strictly avoided: risk of severe irritation and even corneal ulceration if the medicinal product is sprayed under pressure. Immediate liberal washing of the eye with normal saline solution should be undertaken if any contact occurs.
- Vinorelbine can have genotoxic effects. Therefore, men being treated with vinorelbine are advised not to father a child during and up to six months after treatment. Women of childbearing potential must use an effective method of contraception during treatment and three months thereafter.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The combination of vinorelbine and cisplatin (a very common combination) does not affect the pharmacokinetic parameters. However, there is an increased incidence of granulocytopenia in the combination of vinorelbine and cisplatin than in vinorelbine as monotherapy.
As the metabolism of vinorelbine mainly involves CYP3A4, combinations with inductors (e.g. phenytoin, rifampicin) or inhibitors of this enzyme (e.g. itraconazole, ketoconazole) can modify the pharmacokinetics of vinorelbine.
Concomitant use of vinca alkaloids and mitomycin C increases the risk of bronchospasm and dyspnoea. In rare cases, particularly in combination with mitomycin, an interstitial pneumonitis has been observed.
Vinorelbine is a P-glycoprotein substrate and concomitant use with inhibitors or inducers of this transport protein can affect the concentration of vinorelbine.
4.6 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. Women should not become pregnant during treatment with vinorelbine. This product should not be used during pregnancy. 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 and should inform their doctor if they become pregnant.
- Lactation
There are no data on the excretion of vinorelbine into breast milk. Breast-feeding must therefore be discontinued before treatment with this medicinal product.
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.
4.8 Undesirable Effects
Bone marrow toxicity and gastrointestinal symptoms are the most frequent and relevant undesirable effects of vinorelbine in monotherapy and combined therapy.
In combined chemotherapy of vinorelbine with other antineoplastic medicinal products it has to be considered, that the listed undesirable effect can occur more frequently and more severe than those undesirable effects observed during and after monotherapy. Moreover, the additional specific undesirable effects of the other medicinal products have to be considered.
Frequencies
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), including isolated reports
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Grades (G) of toxicity according to WHO classification
Infections and infestations
- Infections can develop commonly, mainly due to bone marrow suppression.
Blood and lymphatic system disorders
- The limiting toxicity is bone marrow depression which is manifested, in particular, as neutropenia (G1: 9.7%; G2: 15.2%; G3: 24.3%, G4: 27.8%), which is reversible within 5-7 days and non-cumulative; the neutrophil count is usually at its lowest 7-14 days after administration.
- Febrile neutropenia and neutropenic sepsis which in some cases (1.2%) had a fatal outcome can occur.
- Anaemia (G1-2: 61.2%; G3-4: 7.4% in monotherapy) and thrombocytopenia (G1-2: 5.1%; G3-4: 2.5% in monotherapy) can occur but are rarely severe.
Immune system disorders
- Allergic reactions (skin reactions, respiratory reactions) are common.
Metabolism and nutrition disorders
- Rare cases of severe hyponatraemia and in very rare cases SIADH-syndrome (syndrome of inappropriate antidiuretic hormone secretion) have been reported.
Nervous system disorders
Peripheral nervous system
Neurological conditions will normally be restricted to loss of deep tendon reflexes.
Development of severe paraesthesias, neurosensory and neuromotor disorders can occur (G1: 17.2%, G2: 3.6%, G3: 2.6%, G4: 0.1%). Very rarely Guillain-Barré syndrome.
Weakness of the lower extremities has been reported after long-term treatment. These symptoms are generally reversible.
Autonomic nervous system
The main symptom is constipation due to intestinal paresis (G1: 16.9%; G2: 4.9%; G3: 2%; G4: 0.7%), but it rarely progresses to paralytic ileus (see also “Gastrointestinal disorders”). The incidence of such reactions can increase when vinorelbine is combined with other chemotherapy.
Cardiac disorders
- Ischaemic heart disease (angina pectoris and/or transitory electrocardiogram modifications, myocardial infarction) has been reported in rare cases.
Respiratory system, thoracic and mediastinal disorders
- As with other vinca alkaloids, vinorelbine can cause dyspnoea and bronchospasm. Rare cases of interstitial lung disease have been reported, especially in patients treated with vinorelbine in combination with mitomycin.
Gastrointestinal disorders
- Very commonly nausea and vomiting is observed (G1: 19.9%; G2: 8.3%). Severe nausea and vomiting can occur commonly (G3: 1.9%; G4: 0.3%). The incidence of nausea and vomiting can increase when vinorelbine is combined with other chemotherapy. Antiemetic treatment can reduce the frequency.
- Constipation and paralytic ileus (see also “Autonomous nervous system”). The treatment can be resumed after recovery of normal intestinal function.
- Stomatitis as well as diarrhoea (G1: 7.6%; G2: 3.6%; G3: 0.7%; G4: 0.1%) and oesophagitis can occur. Severe diarrhoea is uncommon.
- Anorexia is observed very commonly (G1-2: 14%; G3: 1%).
- Rare cases of pancreatitis have been reported.
Hepatobiliary disorders
Temporary elevation of liver parameters without clinical symptoms has been reported: total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase.
Skin and subcutaneous tissue disorders
Mild alopecia may commonly occur which progresses if the treatment is continued (G1-2: 21%; G3-4: 4.1% in monotherapy). Commonly vinorelbine can cause skin reactions and in rare cases generalised skin reactions.
Musculoskeletal and connective tissue disorders
Arthralgia including jaw pain and myalgia have been reported in patients being treated with vinorelbine.
Renal and urinary disorders
Increased blood creatinine was observed commonly.
General disorders and administration site conditions
Patients being treated with vinorelbine can have fatigue, asthenia, fever and pain in different locations such as chest pain and pain in the tumor.
Reactions at the injection site can include erythema, smarting pains, discoloration of the vein and local phlebitis (G1: 12.3%; G2: 8.2%, G3: 3.6%; G4: 0.1% in monotherapy). As other vinca alkaloids vinorelbine has vesicant power. In rare cases local necrosis due to extravasation has been observed. This undesirable effect can be limited by correct positioning of the intravenous cannula or catheter and bolus injection, followed by liberal flushing of the vein.
4.9 Overdose
Cases of accidental acute overdose have been reported in humans: Such cases can result in bone marrow hypoplasia and are sometimes associated with infection, fever and paralytic ileus. Supporting treatment such as blood transfusion or broad-spectrum antibiotic treatment is normally initiated at the doctor's discretion. There is no known 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. In case of a paralytic ileus, decompression by a probe may be necessary.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Antineoplastic and immunmodulating agents, vinca alkaloids
ATC code: L 01 CA 04
Vinorelbine is an antineoplastic active substance of the vinca alkaloid family, but in contrast to all other vinca alkaloids the catharanthine portion of vinorelbine has undergone a structural modification. On the molecular level it affects the dynamic equilibrium of tubulin in the microtubular system of the cell.
Vinorelbine inhibits tubulin polymerisation and binds preferentially to mitotic microtubules, only affecting axonal microtubules at high concentrations. Spiralisation of the tubulin is induced to a lesser degree than with vincristine. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.
5.2 Pharmacokinetic Properties
After intravenous bolus injection or infusion in patients, the plasma concentration of vinorelbine is characterised by a three exponential elimination curve. The terminal elimination phase reflects a long half-life greater than 40 hours. Total clearance of vinorelbine is high (0.97-1.26 l/h/kg).
The active ingredient is widely distributed in the body with a volume of distribution ranging from 25.4-40.1 l/kg. Penetration of vinorelbine into pulmonary tissue is significant with tissue/plasma concentration ratios of greater than 300 in a study involving surgical biopsy. There is moderate binding to plasma proteins (13.5 %) but strong binding to platelets (78%). Linear pharmacokinetics have been shown for intravenously administered vinorelbine up to a dose of 45 mg/m².
Vinorelbine is primarily metabolised by CYP3A4 of cytochrome P450. All metabolites have been identified and none are active with the exception of 4-O-deacetylvinorelbine, which is the principal metabolite in the blood.
Renal elimination is low (<20% of the dose). Small concentrations of deacetyl vinorelbine have been recovered in humans, but vinorelbine is principally detected as the unchanged compound in urine. Elimination of the active substance is mainly via the bile duct and consists of the metabolites and mainly of unchanged vinorelbine.
The effect of kidney dysfunction on the disposition of vinorelbine has not been studied, but dose reduction is not indicated because of the low degree of 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
5.3 Preclinical Safety Data
The limiting toxicity in animals is bone marrow depression. In animal studies, vinorelbine induced aneuploidy and polyploidy.
It can be assumed that vinorelbine can also cause genotoxic effects in humans (induction of aneuploidy and polyploidy).
The results of studies for carcinogenic potential in mice and rats were negative but only low doses have been tested.
In animal reproductive studies, effects were observed at subtherapeutic dosages. Embryo- and fetotoxicity were seen, such as intra-uterine growth retardation and delayed ossification. Teratogenicity (fusion of the vertebrae, missing ribs) was observed at maternally toxic doses. In addition, spermatogenesis and secretion of prostate and seminal vesicles were reduced, but fertility in rats was not diminished.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Water for injections.
6.2 Incompatibilities
- Vinorelbine 10 mg/ml concentrate for solution for infusion should not be diluted with alkaline solutions (risk for precipitation).
- This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf Life
In unopened packaging: 36 months.
After dilution:
Chemical and physical in use stability has been demonstrated for 24 hours at 2-8°C and at 25°C.
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 responsibility of the user and would not normally be longer than 24 hours at 2-8°C, unless opening and dilution has taken place in controlled and validated aseptic conditions.
6.4 Special Precautions For Storage
Store in a refrigerator (2ºC - 8ºC).
Store in the original package in order to protect from light.
Do not freeze.
6.5 Nature And Contents Of Container
Glass vial type I with fluoropolymer-coated bromobutyl rubber stoppers and aluminium cap.
Pack sizes: 1 ml or 5 ml concentrate in packs of 1 or 10 vials. Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
The preparation and administration of vinorelbine should be carried out only by trained personnel. Suitable protective goggles, disposable gloves and disposable clothing must be worn. Spills and leakages must be wiped up.
Any contact with the eyes must be strictly avoided. If the solution does come into contact with the eyes they must be rinsed immediately with plenty of physiological saline.
After preparation, any exposed surface must be thoroughly cleaned and hands and face washed.
There is no incompatibility between the contents and container for Vinorelbine 10 mg/ml Concentrate for solution for infusion and a neutral glass bottle, PVC bag, vinylacetate bag or infusion set with PVC tubes.
It is recommended to administer vinorelbine as an infusion over the course of 5-10 minutes after dilution in 20-50 ml physiological 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. After administration the vein must be flushed through thoroughly with at least 250 ml isotonic solution.
Unused medicinal product and waste must be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
m e d a c
Gesellschaft für klinische
Spezialpräparate mbH
Fehlandtstraße 3
D-20354 Hamburg
Germany
Telefon: +49 4103 8006 0
Fax: +49 4103 8006 100
8. Marketing Authorisation Number(S)
11587/0036
9. Date Of First Authorisation/Renewal Of The Authorisation
20/07/2006
10. Date Of Revision Of The Text
01/08/2006
