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Drug Details

Navelbine 10 mg / ml concentrate for solution for infusion

• Drug Class Description
  Vinca alkaloïds and analogues - ATC Code: L01C A04
• Generic Name
  Vinorelbine tartrate
• Presentation
  Concentrate for solution for infusion. Navelbine is a clear colourless to pale yellow solution with a pH range from 3.3 to 3.8.
• Description
  Vinorelbine 10 mg/ml as vinorelbine tartrate Each 1ml vial contains 10 mg Vinorelbine as vinorelbine tartrate Each 4ml vial contains 40 mg Vinorelbine as vinorelbine tartrate Each 5ml vial contains 50 mg Vinorelbine as vinorelbine tartrate
• 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.

• Adult Dosage
  

  Strictly intravenous administration after appropriate dilution

  Intra-thecal administration of Navelbine may be fatal.

  Navelbine must only be administered by the intravenous route as an infusion over 6 – 10 minutes.

  Administration

  - It is recommended to infuse Navelbine 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 Navelbine. 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 patients with liver insufficiency

  The pharmacokinetics of Navelbine 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 Precautions.

  Administration in patients with renal insufficiency

  Given the minor renal excretion, there is no pharmacokinetic justification for reducing the dose of Navelbine in patients with renal insufficiency: see Precautions.

• Child Dosage
  

  Safety and efficacy in children have not been established and administration is therefore not recommended.

• Elderly Dosage
  

  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. Age does not modify the pharmacokinetics of vinorelbine.

   

• Contra Indications
  

  - 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

  - In combination with yellow fever vaccine

  - Pregnancy

  - Lactation

• Special Precautions
  

  Special warnings

  Navelbine 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 Navelbine, 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

  Special care should be taken when prescribing for patients with history of ischemic heart disease: see Averse Reactions.

  The pharmacokinetics of Navelbine is not modified in patients presenting moderate or severe liver impairment. For dosage adjustment in this specific patient group, see Dosage Information.

  As there is a low level of renal excretion there is no pharmacokinetic rationale for reducing the dose of Navelbine in patients with impaired kidney function.

  Navelbine 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.

  Caution must be exercised when combining Navelbine and strong inhibitors or inducers of CYP3A4: see Interactions, and its combination with phenytoin (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.

• Interactions
  

  Concomitant use contraindicated

  Yellow fever vaccine: as with all cytotoxics, risk of fatal generalised vaccine disease.

  Live attenuated vaccines: (for yellow fever vaccine, see concomitant use contraindicated) as with all cytotoxics, risk of generalised vaccine disease, possibly fatal. This risk is increased in patients already immunodepressed by their underlying disease. It is recommended to use an inactivated vaccine when one exists (e.g. poliomyelitis).

  Phenytoin: as with all cytotoxics, 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.

  Itraconazole: as with all vinca-alkaloids, increased neurotoxicity of vinca-alkaloids due to the decrease of their hepatic metabolism.

  Concomitant use to take into consideration

  Cisplatin: There is no mutual pharmacokinetic interaction when combining Navelbine with cisplatin over several cycles of treatment. However, the incidence of granulocytopenia associated with Navelbine use in combination with cisplatin is higher than associated with Navelbine single agent.

  Mitomycin C: risk of bronchospam and dyspnoea are increased, in rare case an interstitial pneumonitis was observed.

  Ciclosporin,tacrolimus:excessive immunodepression with risk of lymphoproliferation.

  As vinca alkaloids are known substrates for P_glycoprotein, and in the absence of specific study, caution should be exercised when combining Navelbine with strong modulators of this membrane transporter.

  The combination of Navelbine with other drugs with known bone marrow toxicity is likely to exacerbate the myelosuppressive adverse effects.

  As CYP3A4 is mainly involved in the metabolism of vinorelbine, combination with strong inhibitors of this isoenzyme (e.g. azole antifungals such as ketoconazole and itraconazole) could increase blood concentrations of vinorelbine and combination with strong inducers of this isoenzyme (e.g. rifampicin, phenytoin) could decrease blood concentrations of vinorelbine.

  Anticoagulant treatment: as with all cytotoxics, the frequency of INR (International Normalised Ratio) monitoring should be increased due to the potential interaction with oral anticoagulants and increased variability of coagulation in patients with cancer.

• Adverse Drug Reactions
  

  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 Navelbine treatment as with other vinca alkaloids.
  Rare:	Interstitial pneumonopathy has been reported in particular in patients treated with Navelbine in combination with mitomycin.

  Gastrointestinal disorders

  Very Common:	Stomatitis (G1-4: 15%, with Navelbine 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 Navelbine as single agent and (G3-4: 4.1%), with the combination of Navelbine 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 Navelbine as single chemotherapeutic agent).
  Rare:	Generalized cutaneous reactions have been reported with Navelbine.
  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 Navelbine 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 Navelbine followed by liberal flushing of the vein can limit these effects.