Symptoms
Overdosage with Neocitec could produce bone marrow hypoplasia sometimes associated with infection, fever and paralytic ileus.
Emergency procedure
General supportive measures together with blood transfusion, growth factors and broad spectrum antibiotic therapy should be instituted as deemed necessary by the physician.
Antidote
There is no known antidote for overdosage of Neocitec.
- Known hypersensitivity to vinorelbine or other vinca alkaloids, or to any of the excipients.
- Neutrophil count < 1500/mm3 or severe infection current or recent (within 2 weeks)
- Platelet count < 100000/mm3
Neocitec should not be diluted in alkaline solutions (risk of precipitation).
Adverse reactions reported as more than isolated cases are listed below, by system organ class and by the MedRA frequency. Additional Adverse reactions from Post Marketing experience has been added according to the MedDRA classification with the frequency Not known.
| 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 |
| Not known | Post marketing reports |
The most commonly reported adverse drug reactions are bone marrow depression with neutropenia, leucopenia and anaemia, neurologic disorders, gastrointestinal toxicity with nausea, vomiting, stomatitis and constipation, transient elevations of liver function tests, alopecia and local phlebitis.
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).
Infections and infestations
| Common: | Infection bacterial, viral or fungal at different sites mild to moderate and usually reversible with an appropriate treatment. |
| Uncommon: | Septicaemia [very rarely fatal]. |
| Not known: | Neutropenic sepsis. |
Blood and lymphatic system disorders:
| Very Common: | Bone marrow depression resulting mainly in neutropenia (G3: 24.3%; G4: 27.8%) reversible within 5 to 7 days and noncumulative over time. Leucopenia. Anaemia (G3-4: 7.4%). |
| Common: | Thrombocytopenia (G3-4: 2.5%) may occur but are seldom severe. |
| Not known: | Febrile neutropenia. |
Immune system disorders
| Not known: | Systemic allergic reactions as anaphylaxis, anaphylactic shock or anaphylactoïd type reaction. |
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 (G 3-4: 2.7%) 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. | |
Cardiac disorders
| Rare: | Ischemic heart disease: angina pectoris, 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 Neocitec treatment as with other vinca alkaloids. |
| Rare: | Interstitial pneumonopathy has been reported in particular in patients treated with Neocitec in combination with mitomycin. |
Gastrointestinal disorders
| Very Common: | Stomatitis (G1-4: 15%, with Neocitec as single agent). Nausea and vomiting (G 1-2: 30.4% and G 3-4: 2.2%). Anti-emetic therapy may reduce their occurrence. Constipation is the main symptom (G 3-4: 2.7,) which rarely progresses to paralytic ileus with Neocitec as single agent and (G3-4: 4.1%), with the combination of Neocitec and other chemotherapeutic agents. |
| Common: | Diarrhoea usually mild to moderate may occur. |
| Rare: | Paralytic ileus, treatment may be resumed after recovery of normal bowel mobility. Pancreatitis has been reported. |
Hepatobiliary disorders
| Very Common: | Transient elevations of liver function tests (G1-2) without clinical symptoms were reported (SGOT in 27.6% and SGPT in 29.3%). |
Skin and subcutaneous tissue disorders
| Very Common: | Alopecia, usually mild in nature, may occur (G3-4: 4.1% with Neocitec as single chemotherapeutic agent). |
| Rare: | Generalized cutaneous reactions have been reported with Neocitec. |
| Not known: | Erythema on hands and feet. |
Musculoskeletal and connective tissue 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 discoloration and local phlebitis (G 3-4: 3.7% with Neocitec as single chemotherapeutic agent). |
| Common: | Asthenia, fatigue, fever, pain at different sites including chest pain and pain at the tumour site. |
| Rare: | Local necrosis has been observed. Proper positioning of the cannula in the vein before starting to infuse Neocitec followed by liberal flushing of the vein can limit these effects. |
Pre-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity.
Vinorelbine induced chromosome changes but was not mutagenic in Ames test. It is assumed that vinorelbine can cause mutagenic effects (induction of aneuploidy of polyploidy) in man.
In animal reproductive studies, vinorelbine was embryo-feto-lethal and teratogenic.
No haemodynamic effects were found in dogs receiving vinorelbine at maximal tolerated dose; only some minor, non significant disturbances of repolarisation were observed as with other vinca alkaloids tested.
No effect on the cardiovascular system was observed in primates receiving repeated doses of vinorelbine over 39 weeks.
- 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.
Pharmacotherapeutic group: Vinca alkaloids and analogues
ATC Code: L01C A04
Neocitec 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.Neocitec blocks mitosis at G2-M, causing cell death in interphase or at the following mitosis.
Safety and efficacy of Neocitec 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 33.75mg/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..
Pharmacokinetic parameters of vinorelbine were evaluated in blood.
Distribution
The steady-state volume of distribution is large, on average 21.2 l.kg-1 (range: 7.5-39.7 l.kg-1), which indicates extensive tissue distribution. Vinorelbine has high affinity for platelets and lymphocytes. Binding to plasma protein is low (13.5%). However, vinorelbine binds strongly to blood cells and especially to platelets. 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
All metabolites of vinorelbine are formed by CYP 3A4 isoform of cytochromes P450, except 4-O-deacetylvinorelbine likely to be formed by carboxylesterases. 4-O-deacetylvinorelbine is the only active metabolite and the main one observed in blood.
Neither sulfate nor glucuronide conjugates are found.
Elimination
The mean terminal half-life of vinorelbine is around 40 hours. Blood clearance is high, approaching hepatic blood flow, and is 0.72 l.h-1.kg-1 on average (range: 0.32 - 1.26 l.h-1.kg-1).
Renal elimination is low (< 20% of the intravenous dose administered) and consists mostly in parent compound. Biliary excretion is the predominant elimination route of unchanged vinorelbine, which is the main recovered compound, and its metabolites.
Special patient groups
Renal impairment
The effects of renal dysfunction on the pharmacokinetics of vinorelbine have not been studied. 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/m².4.
Elderly patients
A study with Neocitec in elderly patients (> 70 years) with NSCLC demonstrated that pharmacokinetics of vinorelbine were not influenced by age.
Pharmacokinetic / pharmacodynamic relationships
A strong relationship has been demonstrated between vinorelbine blood exposure and of leucocytes or PMNs decreases.
Special warnings
Neocitec should be administered under the supervision of a physician experienced in the use of chemotherapy.
Since inhibition of the hematopoietic system is the main risk associated with Neocitec, close haematological monitoring should be undertaken during treatment (determination of haemoglobin level and the leukocyte, neutrophil and platelet counts on the day of each new administration).
The dose limiting adverse reaction is mainly neutropenia. This effect is non-cumulative, 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/mm3and/or the platelet count is below 100000 /mm3, then the treatment should be delayed until recovery.
If patients present signs or symptoms suggestive of infection, a prompt investigation should be carried out.
Special precautions for use
2.Neocitec should not be given concomitantly with radiotherapy if the treatment field includes the liver.
This product is specifically contra-indicated with yellow fever vaccine and its concomitant use with other live attenuated vaccines is not recommended.
(like all cytotoxics) and with itraconazole (like all 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 drug is sprayed under pressure. Immediate washing of the eye with normal saline solution should be undertaken if any contact occurs.
No studies on the effects on the ability to drive and use machines have been performed.
Strictly intravenous administration after appropriate dilution
Intra-thecal administration of Neocitec may be fatal.
Neocitec must only be administered by the intravenous route as an infusion over 6 - 10 minutes.
Administration
- It is recommended to infuse Neocitec over 6 to 10 minutes after dilution in a 50 ml infusion bag with 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 a normal saline infusion to flush the vein.
- The infusion time of 6 to 10 minutes must be followed as the risk of venous irritation is increased if the infusion exposure time is increased.
- It is vital to ensure that the cannula is accurately placed in the vein before starting to infuse Neocitec. If the drug extravasates into the surrounding tissue during the administration considerable local irritation may occur. In this case, the administration should be stopped, the vein flushed with 0.9 % sodium chloride solution and the remaining dose administered in another vein.
The management of any extravasation should be according to local hospital guidelines and policies.
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.
Administration in the elderly
Clinical experience has not detected any significant differences among elderly patients with regard to the response rate, although greater sensitivity in some of these patients cannot be excluded.
Administration in patients with liver insufficiency
The pharmacokinetics of Neocitec is not modified in patients presenting with moderate or severe liver impairment. Nevertheless as a precautionary measure a reduced dose of 20mg/m2 and close monitoring of haematological parameters is recommended in patients with severe liver impairment: see sections: 4.4; 5.2.
Administration in patients with renal insufficiency
:Administration in children
Safety and efficacy in children have not been established and administration is therefore not recommended.
For single use only, discard any unused contents
Handling and Use
The preparation and administration of Neocitec should be carried out by trained staff and as with all cytotoxic agents, precautions should be taken to avoid exposing staff during pregnancy.
Caution should be exercised in handling and preparing the Neocitec solution:
- Suitable eye protection, disposable gloves, face mask and disposable apron should be worn.
- 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 normal saline solution should be undertaken if any contact occurs.
- On completion, any exposed surface should be thoroughly cleaned and hands and face washed.
Preparation of the solution for infusion
Neocitec must be diluted prior to administration in a 50 ml volume of sodium chloride 9 mg/ml (0.9 %) solution for injection or in 5 % glucose solution for injection.
In case of polychemotherapy, Neocitec should not be mixed with other agents.
There is no content / container incompatibility between Neocitec and neutral glass bottle, PVC bag, vinyl acetate bag or infusion set with PVC tubing.
Neocitec must only be administered by the intravenous route as an infusion.
Disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
