Vinorelbin Ebewe

Vinorelbin Ebewe

vinorelbine tartrate

Manufacturer:

Sandoz

Distributor:

Zuellig
Full Prescribing Info
Contents
Vinorelbine tartrate.
Description
Vinorelbine 10mg/ml (as tartrate).
1 ml concentrate for solution for infusion contains 10 mg Vinorelbine (as tartrate).
5 ml concentrate for solution for infusion contains 50 mg Vinorelbine (as tartrate).
Excipients/Inactive Ingredients: Water for injections, nitrogen.
Action
Pharmacotherapeutic Group: Antineoplastic medicines (vinca alkaloids). ATC Code: L01CA04.
Pharmacology: Pharmacodynamics: Vinorelbin Ebewe 10 mg/ml - concentrate for solution for infusion is a cytostatic medicine of the vinca alkaloid family.
Vinorelbine inhibits tubulin polymerization and binds preferentially to mitotic microtubules, only affecting axonal microtubules at high concentrations. The induction of tubulin spiralization by vinorelbine is less than that produced by vincristine. Vinorelbine blocks mitosis in the G2-M phase, causing cell death in the interphase and at the following mitosis.
Pharmacokinetics: The blood concentration profile over time following intravenous administration is characterized by a three exponential elimination curve. The terminal half-life is 40 hours on average. Clearance in the blood is high, close to the hepatic blood flow and averages 0.72 l/h/kg (interval: 0.32-1.26 l/h/kg), with a volume of distribution equal to 21.2 l/kg on average in the steady state and signs of extensive tissue distribution.
There is moderate binding to plasma proteins (13.5%) but strong binding to blood cells and especially platelets (78%).
The pharmacokinetic properties after intravenous administration of Vinorelbine are linear up to a dose of 45 mg/m2.
Vinorelbine is primarily metabolized via CYP3A4 with 4-O-deacetyl vinorelbine as primary metabolite.
Renal excretion is low (<20% of the dose) and primarily comprises the parent compound.
Excretion by the biliary route is the most important channel for elimination of both the metabolites and the unmodified Vinorelbine.
The effects of impaired renal function on the distribution of Vinorelbine have not been investigated, but a reduction in dose is not required on account of the low renal excretion.
In patients with liver metastases, mean Vinorelbine clearance only changed if more that 75% of the liver was affected. In the case of six cancer patients with moderate hepatic dysfunction (bilirubin ≤2x upper limit of normal and aminotransferase ≤5x ULN) who were treated with up to 25mg/m2, and in eight other cancer patients with severe hepatic dysfunction (bilirubin >2x upper limit of normal and aminotransferase >5x ULN) who were treated with up to 20mg/m2, the mean total clearance in both groups was similar to that of patients with normal liver function. These data may not be representative for patients with reduced elimination. For this reason, care must be taken in the cases of patients with severe hepatic dysfunction, with close monitoring of the blood counts (see Dosage & Administration and Precautions).
A close relationship has been proved between presence in the blood and the reduction in the leucocytes or polynuclear leucocytes.
Toxicology: Preclinical safety data: Mutagenic and carcinogenic potential: In animal studies, Vinorelbine induced aneuploidy and polyploidy. It must therefore be assumed that Vinorelbine can also cause genotoxic effects in man (induction of aneuploidy and polyploidy). Studies investigating the carcinogenic potential in mice and rats were negative, but they only investigated low doses.
Reproductive toxicity studies: Animal studies showed effects on reproduction, in sub-therapeutic doses. They showed embryo- and feto-toxicity, as well as intra-uterine growth retardation and late ossification.
Teratogenicity (vertebral fusion, missing ribs) was observed following toxic doses for the mother. Spermatogenesis and secretion from the prostate gland and seminal vesicles were also reduced, but fertility in rats was not reduced.
Safety pharmacology: Studies carried out on pharmacological safety in dogs and monkeys did not show any undersirable effects on the cardiovascular system.
Indications/Uses
Non-small-cell lung cancer (NSCLC).
Metastatic breast cancer.
Dosage/Direction for Use
For intravenous administration only.
The use of the intrathecal route is strictly contraindicated.
Vinorelbin Ebewe 10 mg/ml - concentrate for solution for infusion may only be administered intravenously. Before application it is essential to ensure that the intravenous needle is correctly positioned in the vein. Leakage of vinorelbine into the surrounding tissue during administration may cause considerable irritation.
If extravasation occurs, the infusion must be discontinued immediately, and any remaining portion of the dose is to be introduced into another vein.
For instructions on handling and administration, see Cautions for Usage.
Vinorelbine may be administered either by slow bolus (5-10 minutes) after dilution with 20-50 ml of physiological saline solution or 50mg/ml (5%) glucose solution or by short-term infusion (20-30 minutes) after dilution with 125 ml of physiological saline solution or 50mg/ml (5%) glucose solution. Administration should always be followed by thorough flushing of the vein with physiological saline solution.
Non-small-cell lung cancer (NSCLC): The normal dose for monotherapy is 25-30 mg/m2 per week. The normal dose of 25-30 mg/m2 can be retained for poly-chemotherapy while simultaneously reducing the frequency of administration to Days 1 and 5 every three weeks, for example, or Days 1 and 8 every three weeks, in accordance with the chemotherapy regimen used.
Advanced or metastasized breast cancer: The normal dose is 25-30 mg/m2 once per week.
The maximum tolerable single dose is 35.4 mg/m2 body surface area.
Children and adolescents: Safety and efficacy in paediatric patients have not been investigated.
Hepatic dysfunction: Caution must be exercised in the case of patients with severely restricted hepatic function, with close monitoring of the haematological parameters. The dose must be reduced accordingly. (See Precautions and Pharmacology: Pharmacokinetics under Actions.)
Renal insufficiency: It is not necessary to adjust the dose for patients with impaired renal function. (See Pharmacology: Pharmacokinetics under Actions.)
Overdosage
Overdoses can lead to severe bone marrow aplasia with fever and infections; paralytic ileus has also been reported. Symptomatic treatment with blood transfusions and broad-spectrum antibiotics is recommended. There is no known specific antidote.
Since there is no specific antidote for intravenously administrated Vinorelbine, symptomatic measures must be taken in the event of an overdose, such as: Continuous monitoring of vital functions and close observation of the patient.
Daily blood counts to establish the need for blood transfusions and/or growth factors, as well as to establish the need for intensive medical care and reduce the risk of infection.
Prophylactic or curative treatment of paralytic ileus.
Monitoring of the cardiovascular system and liver function.
Treatment with broad-spectrum antibiotics may become necessary in the event of infectious complications.
Contraindications
Known hypersensitivity to Vinorelbine or other vinca alkaloids.
Neutrophil granulocytes <1500/mm3 or severe existing or past infection (within the last 2 weeks).
Thrombocyte value below 75000/mm3.
Pregnancy (the risk to embryo and feotal development must be weighed up against the potential benefit of the treatment for the mother).
Breast-feeding must be interrupted during treatment with Vinorelbine (see Use in Pregnancy & Lactation).
Severe hepatic dysfunction unrelated to the cancer.
Women of childbearing potential who do not use effective contraception (see Precautions and Use in Pregnancy & Lactation).
In combination with yellow fever vaccination (see Interactions).
Special Precautions
Vinorelbin Ebewe 10 mg/ml - concentrate for solution for infusion is exclusively for intravenous administration.
Treatment should be undertaken with close haematological monitoring (determination of haemoglobin level and number of leucocytes, neutrophils and thrombocytes prior to each fresh infusion), as inhibition of the haematopoietic system constitutes the main risk during treatment with Vinorelbine.
Non-cumulative neutropenia with nadir between days 7 and 14 following administration and rapid reversibility within 5-7 days is the most important dose-limiting side effect. Treatment should be delayed to allow the bone marrow to recover if neutrophil granulocyte value drops below 1500/mm3 and/or the thrombocyte value drops below 75000/mm3.
Immediate examination is indicated if the patient shows any signs or symptoms of an infection.
Particular care must be exercised in the case of patients with a history of coronary heart disease.
The Clinical relevance of reduced elimination of medicinal products by the liver has not been investigated. It is therefore not possible to give any precise recommendation on dosage. However, the maximum dose given in pharmacokinetic studies of patients with severe hepatic dysfunction was 20 mg/m2 (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). Caution must be exercised in the case of patients with severe hepatic dysfunction, with close monitoring of the haematological parameters.
Vinorelbin Ebewe 10 mg/ml - concentrate for solution for infusion should not be given simultaneously with radiotherapy if the liver is included in the treatment field.
Vinorelbin Ebewe 10 mg/ml - concentrate for solution for infusion must not be allowed to come into contact with the eye; it may cause severe irritation and can even promote corneal ulceration when sprayed under pressure. In such a case, the eye must be immediately rinsed with physiological saline solution and the person should consult an ophthalmologist.
Great care must be exercised, as Vinorelbine levels may be influenced by strong inhibitors or inductors for CYP3A4 (see Interactions).
This medicinal product is generally not recommended in combination with attenuated live vaccines.
For information on pregnancy, lactation and fertility, see Use in Pregnancy & Lactation.
Suitable prophylaxis must be considered to avoid the risk of bronchial spasm, especially in combined treatment with mitomycin C. Patients receiving outpatient treatment must be instructed to consult a doctor if breathing becomes difficult.
Due to the low renal elimination, there is no pharmacokinetic rationale for reducing the dose in patients with renal insufficiency.
Effects on ability to drive and use machines: The effects on ability to drive and use machines have not been studied.
Use In Pregnancy & Lactation
Pregnancy: Only inadequate data are available concerning the use of Vinorelbine during pregnancy. Animal reproductive studies showed Vinorelbine to be embryo- and feto-lethal and teratogenic. This Product should not be used during pregnancy. Women with childbearing potential must use reliable contraception during treatment with Vinorelbine and inform their doctor if they become pregnant. Should pregnancy arise during the treatment, the patient must be informed of the risk to the unborn child and carefully monitored. The possibility of genetic counseling should be considered.
Lactation: It is not known whether vinorelbine passes into the breast milk. Breastfeeding should therefore be discontinued before starting a treatment with vinorelbine.
Fertility: Vinorelbine may have genotoxic effects. Men are therefore advised not to beget a child and for up to six months (at least three months) after receiving treatment with Vinorelbine. Women with childbearing potential must use reliable contraception during the treatment. The possibility of preserving sperm should be considered before commencing treatment, as Vinorelbine may cause irreversible infertility.
Adverse Reactions
Side effects which have been reported more frequently than in isolated cases are listed below according to organ system and frequency.
Frequency is defined on the basis of the following convention: 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), or unknown.
Infections and Infestations: Common: Infection.
Blood and lymphatic system disorders: Very common: Neutropenia, anemia.
Common: thrombocytopenia, febrile neutropenia, neutropenic sepsis with potentially fatal outcome.
Immune system disorders: Common: Allergic reactions (skin reactions, respiratory disorders).
Metabolism and nutrition disorders: Rare: Hyponatraemia.
Very rare: Syndrome of inadequate antidiuretic hormone hypersecretion (SIADH).
Nervous system disorders: Very common: Constipation (see also "Gastrointestinal disorders"), loss of deep tendon reflexes.
Common: Paresthesia with sensorimotor symptoms.
Rare: Loss of strength of the lower extremities, paralytic ileus (see also "Gastrointestinal disorders").
Very rare: Guillain-Barre Syndrome.
Cardiac disorders: Rare: Coronary heart disease, such as angina pectoris, ECG modifications, myocardial infarction.
Respiratory, thoracic and mediastinal disorders: Common: Dyspnoea, bronchial spasms.
Rare: Interstitial lung disease.
Gastrointestinal disorders: Very common: Constipation (see also "Nervous system disorders"), nausea, vomiting, diarrhoea, stomatitis, oesophagitis, anorexia.
Rare: Pancreatitis, paralytic ileus (see also "Nervous system disorders").
In the case of paralytic ileus, treatment can be resumed when normal gastrointestinal function has been restored.
Liver and gallbladder disorders: Very common: Changed hepatic function values (elevated total bilirubin, elevated alkaline phosphatase, elevated aspartate aminotransferase, elevated alanin aminotransferase).
Skin and subcutaneous tissue disorders: Very common: Alopecia.
Common: Skin reactions.
Musculoskeletal and connective tissue disorders and bone disease: Common: Myalgia, arthralgia.
Rare: Pain in the jaws.
Renal and urinary disorders: Common: Elevated creatinine.
General disorders and administration site disorders: Very common: Fatigue, fever, pain in various places, asthenia, erythema at the injection point, pain at the injection point, discoloration at the injection point, phlebitis at the injections point.
Rare: Necrosis at the injection site.
Drug Interactions
The probability of myelosuppressive side effects increases when Vinorelbine combines with other medicinal products of known myelotoxicity.
CYP3A4 is the most important enzyme involved in the degradation of Vinorelbine, and the concentration of Vinorelbine may be influenced by combination with an active agent inducing (e.g. phenytoin, phenobarbital, rifampicin, carbamazepine, Hypericum perforatum) or inhibiting the isoenzyme (such as itraconazole, ketoconazole, HIV-protease inhibitors, erythromycin, clarithromycin, telithromycin, nefazodone). (See Precautions). Vinorelbine is a substrate of P-glycoprotein, and simultaneous treatment with other medicinal products inhibiting (e.g. ritonavir, clarithromycin, cyclosporine, verapamil, quinidine) or inducing the same transport protein (see list of CYP3A4 inductors previously mentioned) can affect the concentration of Vinorelbine.
The combination of Vinorelbine and cisplatin (a very common combination) does not display any interactions as regards the pharmacological parameters of Vinorelbine. However, a higher incidence of granulocytopenia has been reported in patients receiving combined treatment with Vinorelbine and cisplatin as compared with those receiving Vinorelbine as monotherapy.
Simultaneous administration of vinca alkaloids and mitomycin C may increase the risk of bronchial spasm (see Precautions and Adverse Reactions).
Anticoagulant treatment is often provided on account of the elevated risk of thrombosis in conjunction with cancers. If it is decided to treat the patient with oral anticoagulants, the INR (international Normalized Ratio) must be checked more frequently on account of high intra-individual fluctuations in coagulability during the illness, as well as on account of possible interaction between the oral anticoagulants and anti-cancer chemotherapy.
Yellow fever vaccination is contraindicated due to the potential risk of a fatal systemic illness following vaccination.
Simultaneous administration of attenuated live vaccines (other than yellow fever) is not recommended on account of the risk of a systemic and potentially fatal illness following vaccination. The risk is greater in patients with immunosuppression due to the basic illness. Inactivated vaccines should be used where available (poliomyelitis).
Phenytoin: Simultaneous administration is not recommended. Convulsions may be exacerbated as a result of the decrease in gastrointestinal phenytoin resorption or toxicity may be increased or the efficacy of Vinorelbine may decrease due to the increase in hepatic metabolization of phenytoin.
Itraconazole: Simultaneous administration is not recommended due to possible elevated neurotoxicity.
Cyclosporine, tacrolimus: Excessive immunosuppression and the risk of a lymphoproliferative disorder must be taken into account.
Caution For Usage
Special Precautions for Disposal and Other Handling: The preparation and administration of Vinorelbin Ebewe 10 mg/ml - concentrate for solution for infusion should only be carried out by specially trained and qualified personnel. Suitable protective equipment, disposable gloves, face mask and disposable apron must be worn.
Any spillages and leakages must be wiped up.
All contact of the medicinal product with the eyes must be strictly avoided. The eye must be immediately rinsed with physiological saline solution if any contact occurs.
On completion, all exposed surfaces must be thoroughly cleaned. Hands and face should be thoroughly washed.
Vinorelbin Ebewe 10 mg/ml - concentrate for solution for infusion can be given as a slow bolus (5-10 minutes) after dilution in 20-50 ml physical saline solution or 50 mg/ml (5%) glucose solution or as a short infusion (20-30 minutes) after dilution in 125ml physical saline solution or 50 mg/ml (5%) glucose solution. Administration should be followed by an infusion of physiological saline solution to flush the vein.
Vinorelbin Ebewe 10 mg/ml - concentrate for solution for infusion may only be given intravenously. It is very important to ensure that the cannula is accurately placed in the vein before starting to infuse. If Vinorelbin Ebewe 10 mg/ml - concentrate for solution for infusion extravasates, during intravenous administration, a substantial irritation may occur. In this case, the infusion should be stopped, the vein should be flushed with physiological saline solution and the rest of the dose should be administered in another vein. In the event of extravasation, intravenous glucocorticoids may be given in order to reduce the risk of phlebitis.
Unused products or waste must be disposed of in accordance with the local regulations.
Incompatibilities: Vinorelbin Ebewe 10 mg/ml - concentrate for solution for infusion must not be diluted with alkaline solutions due to the risk of precipitation.
Vinorelbin Ebewe 10 mg/ml - concentrate for solution for infusion must not be combined with medicinal products other than those listed in Special Precautions for Disposal and Other Handling under Cautions for Usage.
Storage
Original Package: Store the medicinal product in a refrigerator (2°C-8°C). Do not freeze. Keep the vial in the outer carton to avoid exposure to light.
Storage conditions for the diluted medicinal product, see as follows.
Shelf-Life: Unopened package: The product should be used immediately after opening.
In-use shelf life: Diluted Vinorelbin Ebewe is chemically and physically stable for up to 24 hours under normal room light below 30°C when stored in polypropylene syringes, polyvinyl chloride bags and clear glass vials. However, to reduce microbiological hazard, use as soon as practicable after dilution. If storage is necessary, hold at 2°C to 8°C for not more than 24 hours.
ATC Classification
L01CA04 - vinorelbine ; Belongs to the class of plant alkaloids and other natural products, vinca alkaloids and analogues. Used in the treatment of cancer.
Presentation/Packing
Conc for soln for infusion (vial, clear, colorless to pale yellow solution) 10 mg/mL x 1's. 50 mg/5 mL x 1's.
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