Navelbine

Navelbine

vinorelbine tartrate

Manufacturer:

Pierre Fabre

Distributor:

Orient Europharma
Full Prescribing Info
Contents
Vinorelbine tartrate.
Description
Navelbine Soft Capsule: (See Table 1.)

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Navelbine Solution for Injection: (See Table 2.)

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Excipients/Inactive Ingredients: Navelbine Soft Capsule: Fill Solution: Ethanol anhydrous; purified water; glycerol; Macrogol 400.
Shell capsule: Gelatin, glycerol 85%, anidrisorb 85/70 (D-sorbitol and 1,4-sorbitan), colouring agent E172 and E171 (red and/or yellow according to each strength), medium chain triglycerides, PHOSAL 53 MCT (phosphatidylcholine, glycerides, ethanol).
Edible printing ink: E120, hypromellose, propylene glycol.
Action
Pharmacotherapeutic group: Cytotoxic antineoplastic belonging to the vinca alkaloid family. ATC Code: L01C A04.
Pharmacology: Pharmacodynamics: Navelbine 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. Navelbine blocks mitosis at G2-M, causing cell death in interphase or at the following mitosis.
Safety and efficacy of Navelbine 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 tumors, 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.
Pharmacokinetics: Pharmacokinetic parameters of vinorelbine were evaluated in blood.
Absorption: Navelbine soft capsule: After oral administration, vinorelbine is rapidly absorbed and the Tmax is reached between 1.5 to 3 h with a blood concentration peak (Cmax) of approximately 130 ng/ml after a dose at 80 mg/m2.
Absolute bioavailability is approximately 40% and the simultaneous intake of food does not after the exposure to vinorelbine.
Oral vinorelbine at 60 and 80 mg/m2 leads to blood exposure comparable to that achieved with 25 and 30 mg/m2 of the IV form.
The blood exposure to vinorelbine increases proportionally with the dose up to 100 mg/m2.
Interindividual variability of the exposure is similar after administration by IV and oral routes.
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.
Binding to plasma proteins is weak (13.5%). Vinorelbine binds strongly to blood cells and especially to platelets (78%).
There is a significant uptake of vinorelbine in the lungs, as assessed by pulmonary surgical biopsies, which showed concentration up to a 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 sulphonic nor glucuronide conjugates are found.
Elimination: Navelbine soft capsule: 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 (range: 0.32-1.26 L/hr-1.kg-1).
Renal elimination is low (<5% of the dose administered for oral administration, <20% of the dose administered for intravenous administration) and consists mostly in parent compound. Biliary excretion is the predominant elimination route of both unchanged vinorelbine, which is the main recovered compound and its metabolites.
Navelbine solution for injection: 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 both metabolites and unchanged vinorelbine, which is the main recovered compound.
Special patient groups: Renal and Liver 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.
Navelbine soft capsule: Pharmacokinetics of orally administered vinorelbine were not modified after administration of 60 mg/m2 in patients with mild liver impairment (bilirubin <1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN) and of 50 mg/m2 in patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN,whatever the levels of ALAT and ASAT). No data is available for patients with severe liver impairment, therefore Navelbine is contraindicated in these patients (see Dosage & Administration and Precautions).
Navelbine solution for injection: 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 is not modified in patients presenting moderate or severe liver impairment. Nevertheless as a precautionary measure a reduced dose of 20 mg/m2 and close monitoring of haematological parameters is recommended in patient with severe liver impairment.
Elderly: A study with vinorelbine in elderly patients (≥70 years) with NSCLC demonstrated that pharmacokinetics of vinorelbine were not influenced by age. However, since elderly patients are frail, caution should be exercised when increasing the dose of Navelbine soft capsule (see Dosage & Administration) and Navelbine solution for injection.
Pharmacokinetics/Pharmacodynamics relationships: A strong relationship has been demonstrated between blood exposure and depletion of leucocytes or PMNs.
Toxicology: Preclinical Safety Data: Navelbine soft capsule: Mutagenic and carcinogenic potential: The interaction of Navelbine with the achromatic spindle during mitosis may lead to an incorrect distribution of chromosomes. In animal studies, intravenous Navelbine caused aneuploidy and polyploidy. It is possible that Navelbine may also have mutagenic effects (induction of aneuploidy) in humans.
The carcinogenicity studies in which Navelbine was administered intravenously once every two weeks in order to avoid the toxic effects of the product proved negative.
Reproduction studies: In animal reproduction studies, Navelbine has been shown to have embryolethal, fetolethal and teratogenic effects. The nontoxic dose in the rat was 0.26 mg/kg every 3 days.
After perinatal or postnatal administration to rats at a dose of 1.0 mg/kg IV every 3 days, retarded weight gain was observed in the offsprings until the 7th week of life.
Pharmacological Safety: No hemodynamic effect has been observed in dogs treated at the maximum tolerated dose; only non-significant minor repolarisation disorders appeared, as with the other vinca alkaloids tested. No effect on the cardiovascular system was observed in primates treated with repeated doses of vinorelbine for 39 weeks.
Animal overdosage: The symptoms of overdosage in the animals tested consisted of hair loss, abnormal behaviour (prostration, somnolence), pulmonary lesions, weight loss and varying degrees of bone marrow aplasia.
Navelbine solution for injection: Mutagenic and carcinogenic potential: Vinorelbine induced chromosome damages but was not mutagenic in Ames test. It is assumed that Navelbine can cause mutagenic effects (induction aneuploidy and polyploidy) in man.
Toxicity to reproduction: In animal reproductive studies, Navelbine was embryo-foeto-lethal and teratogenic.
Safety Pharmacology: 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 Navelbine over 39 weeks.
Indications/Uses
For treatment of Non-small cell lung cancer/Advanced Breast Cancer.
Dosage/Direction for Use
Navelbine soft capsule: Navelbine soft capsules must be given strictly by the oral route.
Navelbine soft capsules should be swallowed with water without chewing or sucking the capsule. It is recommended to take the capsule with some food.
As a single agent: The recommended regimen is: First three administrations: 60 mg/m2 of body surface area, administered once weekly.
Subsequent administrations: Beyond third administration, it is recommended to increase the dose of Navelbine soft capsules to 80 mg/m2 once weekly except in those patients for whom the neutrophil count dropped once below 500/mm3 or more than once between 500 and 1000/mm3 during the first three administrations at 60 mg/m2. (See Table 3.)

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Dose modification: For any administration planned to be given at 80 mg/m2, if the neutrophil count is below 500/mm3, the administration should be delayed until recovery and the dose reduced from 80 to 60 mg/m2 per week during the 3 following administrations. (See Table 4.)

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It is possible to reescalate the dose from 60 to 80 mg/m2 per week if the neutrophil count did not drop below 500/mm3 or more than once between 500 and 1000/mm3 during 3 administrations given at 60 mg/m2 according to the rules previously defined for the first 3 administrations.
For combination regimens, the dose and schedule will be adapted to the treatment protocol: Based on clinical studies, the oral dose of 80 mg/m2 was demonstrated to correspond to 30 mg/m2 of the IV form and 60 mg/m2 to 25 mg/m2.
This has been the basis for combination regimens alternating IV and oral forms improving patient's convenience.
For combination regimens, the dose and schedule will be adapted to the treatment protocol.
Even for patients with BSA ≥ 2 m2 the total dose should never exceed 120 mg per week at 60 mg/m2 and 160 mg per week at 80 mg/m2.
Administration in the elderly: Clinical experience has not detected any significant differences among elderly patients with regards to response rate, although greater sensitivity insome of these patients cannot be excluded. Age does not modify the pharmacokinetics of vinorelbine.
Administration in children: Safety and efficacy in children have not been established and administration is therefore not recommended (see Pharmacology: Pharmacodynamics under Actions).
Administration in patients with liver insufficiency: Navelbine can be administered at the standard dose of 60 mg/m2/week in patients with mild liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN). In patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT), Navelbine should be administered at a dose of 50 mg/m2/week. The administration of Navelbine in patients with severe hepatic impairment is not recommended as there is insufficient data to determine the pharmacokinetics, efficacy and safety of Navelbine in this population (see Pharmacology: Pharmacokinetics under Actions and 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 serious renal insufficiency (see Pharmacology: Pharmacokinetics under Actions and Precautions).
See Instructions for use and handling of Oral Navelbine under Cautions for Usage.
Navelbine solution for injection:
Strictly intravenous administration after appropriate dilution. Intra-thecal administration of NAVELBINE may be fatal. (See Instructions for use and handling under Cautions for Usage.)
As a single agent, the usual dose is 25 to 30 mg/m2 administered 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.
NAVELBINE may be administered by slow bolus (6-10 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 infusion to flush the vein.
Administration in the elderly: Clinical experience has not identified relevant differences in the elderly with regards to response rate, although greater sensitivity of some these patients cannot be excluded. Age does not modify the pharmacokinetics of vinorelbine.
Administration in patients with liver insufficiency: The pharmacokinetics of NAVELBINE is not modified in patients presenting 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 patient with severe liver impairment.
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.
Administration in children: Safety and efficacy in children have not been established and administration is therefore not recommended.
Overdosage
Symptoms: Overdosage with Navelbine could produce bone marrow hypoplasia sometimes associated with infection, fever and paralytic ileus.
Navelbine soft capsule: Hepatic disorders.
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.
Navelbine soft capsule: A close monitoring of hepatic function is recommended.
Antidote: There is no known antidote for overdosage of Navelbine.
Contraindications
Known hypersensitivity to vinorelbine or other vinca alkaloids or to any of the constituent.
Neutrophil count < 1500/mm3 or severe infection current or recent (within 2 weeks).
Platelet count < 100,000/mm3
Lactation (see Use in Pregnancy & Lactation).
In combination with yellow fever vaccine (see Interactions).
Navelbine soft capsule: Disease significantly affecting absorption.
Previous significant surgical resection of stomach or small bowel.
Patients requiring long-term oxygen therapy.
Warnings
Navelbine soft capsule: Navelbine soft capsule should be prescribed by a physician experienced in the use of chemotherapy with facilities for monitoring cytotoxic drugs.
If the patient chews or sucks the capsule by error, the liquid is an irritant. Proceed to rinse mouth with water or preferably a normal saline solution.
In the event of the capsule has being cut or damaged, the liquid content is an irritant, and so may cause damage if in contact with skin, mucosa or eyes. Damaged capsules should not be swallowed and should be returned to the pharmacy or to the physician in order to be properly destroyed.
If any contact occurs, immediate thorough washing with water or preferably with normal saline solution should be undertaken.
In the case of vomiting within a few hours after drug intake, never repeat the administration of this dose. Supportive treatment such as 5HT3 antagonists setron (e.g. ondansetron, granisetron) may reduce the occurrence of this (see Interactions).
Due to sorbitol content, patient with rare hereditary problems with fructose intolerance should not take the capsules.
Close haematological monitoring should be undertaken during treatment (determination of haemoglobin level and the leucocyte, neutrophil and platelet counts on the day of each new administration).
This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per dose.
Dosing should be determined by haematological status: 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 (see Dosage & Administration). 
For dose escalation from 60 to 80 mg/m2 per week, after the third administration please refer to section Dosage & Administration.
For the administrations given at 80 mg/m2, if the neutrophil count is below 500/mm3 or more than once between 500 and 1,000/mm3, the administration should not only be delayed but also reduced to 60 mg/m2 per week. It is possible to reescalate the dose from 60 to 80 mg/m2 per week, refer to section Dosage & Administration.
During clinical trials where treatments were initiated at 80 mg/m2, a few patients developed excessive neutropenic complications, including those with a poor performance status. Therefore it is recommended that the starting dose should be 60 mg/m2 escalating to 80 mg/m2 if the dose is tolerated as described in Dosage & Administration.
If patients present signs or symptoms suggestive of infection, a prompt investigation should be carried out.
Use of this medicine with live attenuated vaccines is not recommended (for yellow fever vaccine, see Contraindications).
Caution is recommended when Navelbine is used with strong inhibitors or inducers of cytochrome CYP3A4. Hence, the use of this medicine with phenytoin, fosphenytoin, itraconazole or posaconazole is not recommended (see Interactions).
Navelbine solution for injection: 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 hemoglobin 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/mm3 and/or the platelet count is below 100,000/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
Navelbine soft capsule: Special precautions for use: Special care should be taken when prescribing for patients: with history of ischemic heart disease (See Adverse Reactions); With poor performance status.
Navelbine should not be given concomitantly with radiotherapy if the treatment field includes the liver.
Oral Navelbine was studied in patients with liver impairment at the following doses: 60 mg/m2 in patients with mild liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN); 50 mg/m2 in patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT).
Safety and pharmacokinetics of vinorelbine were not modified in these patients at the tested doses.
Oral Navelbine was not studied in patients with severe hepatic impairment, therefore its use is not recommended in these patients (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
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 (see see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Navelbine solution for injection: Special care should be taken when prescribing for patients with history of ischaemic heart disease.
The pharmacokinetics of NAVELBINE is not modified in patients presenting moderate or severe liver impairment.
For dosage adjustment in this specific patient group, refer to DOSAGE AND ADMINISTRATION.
As there is low level of renal excretion there is no pharmacokinetic rationale for reducing NAVELBINE dose in patients with impaired kidney function. Refer to DOSAGE AND ADMINISTRATION.
Use of this medicinal product in combination with a live attenuated vaccine is not recommended (see contraindications for the yellow fever vaccine).
Caution is recommended when Navelbine is used at the same time as potent cytochrome CYP3A4 inhibitors or inductors. Hence, taking this medicinal product with phenytoin, fosphenytoin, itraconazole, ketoconazole or posaconazole is not recommended (see Interactions).
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 sodium chloride 9mg/ml (0.9%) solution for injection should be undertaken if any contact occurs.
NAVELBINE should not be administered concomitantly with radiotherapy where the field includes the liver.
Increased caution is required in Japanese patients as cases of interstitial lung disease have been reported more frequently in this population.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed but on the basis of the pharmacodynamic profile vinorelbine does not affect the ability to drive and use machines. However, caution is necessary in patient treated with vinorelbine considering some adverse effects of the drug.
Use In Pregnancy & Lactation
Use in Pregnancy: There are inadequate data on the use of vinorelbine in pregnant women. In reproductive studies conducted in animals, vinorelbine was embryotoxic and teratogenic (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Based on the results of these animal studies and the pharmacological action of the medicinal product there is a potential risk of embryonic and foetal abnormalities.
Navelbine must not be used during pregnancy unless the expected individual benefit manifestly exceeds the potential risks.
If a patient becomes pregnant during treatment the patient must be informed of the risks to the unborn child and monitored carefully. The possibility of genetic counselling should also be considered.
Women of child-bearing potential: Women of child-bearing potential must use effective contraception during treatment and up to 3 months after treatment.
Use in Lactation: It is unknown whether Navelbine is excreted in human breast milk. The excretion of Navelbine in milk has not been studied in animal studies. A risk to the suckling can not be excluded therefore breast feeding must be discontinued before starting treatment with Navelbine (see Contraindications).
Fertility: Men being treated with Navelbine are advised not to father a child during and up to 3 months after 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.
Adverse Reactions
The reactions were described using the NCI common toxicity criteria. (See Table 5.)

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Detailed 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).
Navelbine soft capsule: The overall reported incidence of undesirable effects was determined from clinical studies in 316 patients (132 patients with non small cell lung cancer and 184 patients with breast cancer) who received the recommended regimen of Navelbine (first three administrations at 60 mg/m2/week followed by 80 mg/m2/week).
Adverse reactions reported are listed as follows, by system organ and by frequency. Additional adverse reactions from Post Marketing experience have been added according to the MedDRA classification with the frequency Not known. (See Table 5.)
Undesirable effects reported with Navelbine soft capsule: Pre-marketing experience: The most commonly reported adverse drug reactions are bone marrow depression with neutropenia, anaemia and thrombocytopenia, gastrointestinal toxicity with nausea, vomiting, diarrhea, stomatitis and constipation. Fatigue and fever were also reported very commonly.
Post-marketing experience: Navelbine soft capsule is used as single agent or in combination with other chemotherapeutic agents such as cisplatin or capecitabin.
The most commonly system organ classes involved during post-marketing experience are: 'Blood and lymphatic system disorders', 'Gastrointestinal disorders' and 'General disorders and administration site conditions'. This information is consistent with the pre-marketing experience.
Infections and Infestations:
Very common: Bacterial, viral or fungal infections without neutropenia at different sites G1-4: 12.7%; G3-4: 4.4%. Common: Bacterial, viral or fungal infections resulting from bone marrow depression and/or immune system compromise (neutropenic infections) are usually reversible with an appropriate treatment. Neutropenic infection G3-4: 3.5%. Not known: Neutropenic sepsis; Complicated septicaemia, occasionally fatal.
Blood and lymphatic system disorders: Very common: Bone marrow depression resulting mainly in neutropenia G1-4: 71.5%; G3: 21.8%; G4: 25.9%, is reversible and is the dose limiting toxicity. Leucopenia G1-4: 70.6%; G3: 24.7%; G4: 6%. Anemia G1-4: 67.4%; G3-4: 3.8%. Thrombocytopenia G1-2: 10.8%. Common: G4 Neutropenia associated with fever over 38°C including febrile neutropenia: 2.8%.
Metabolism and nutrition disorders: Not known: Severe hyponatraemia.
Psychiatric disorders: Common: Insomnia G1-2: 2.8%.
Nervous system disorders:
Very common: Neurosensory disorders G1-2: 11.1% were generally limited to loss of tendon reflexes and infrequently severe. Common: Neuromotor disorders G1-4: 9.2%; G3-4: 1.3%. Headache: G1-4: 4.1%, G3-4: 0.6%. Dizziness: G1-4: 6%; G3-4: 0.6%. Taste disorders: G1-2: 3.8%. Uncommon: Ataxia grade 3: 0.3%.
Eye disorders: Common: Visual disorders G1-2: 1.3%.
Cardiac disorders: Uncommon: Heart failure and cardiac dysrhythmia. Not known: Myocardial infarction in patients with cardiac medical history or cardiac risk factors.
Vascular disorders: Common: Hypertension G1-4: 2.5%; G3-4: 0.3%. Hypotension G1-4: 2.2%; G3-4: 0.6%.
Respiratory system, thoracic and mediastinal disorders: Common: Dyspnoea G1-4: 2.8%; G3-4: 0.3%. Cough: G1-2: 2.8%.
Gastrointestinal disorders: Very Common: Nausea G1-4: 74.7%; G3-4: 7.3%. Vomiting G1-4: 54.7%; G3-4: 6.3%; supportive treatment (such as oral setrons) may reduce the occurrence of nausea and vomiting. Diarrhoea G1-4: 49.7%; G3-4: 5.7%. Anorexia G1-4: 38.6%; G3-4: 4.1%. Stomatitis G1-4:10.4%; G3-4: 0.9%. Abdominal pain: G1-4: 14.2%. Constipation G1-4: 19%; G3-4: 0.9% Prescription of laxatives may be appropriate in patients with prior history of constipation and/or who received concomitant treatment with morphine or morphine-mimetics. Gastric disorders: G1-4: 11.7%. Common: Oesophagitis G1-3: 3.8%; G3: 0.3%. Dysphagia: G1-2: 2.3%. Uncommon: Paralytic ileus G3-4: 0.9% [exceptionally fatal] treatments may be resumed after recovery of normal bowel mobility. Not known: Gastrointestinal bleeding.
Hepatobiliary disorders: Common: Hepatic disorders: G1-2: 1.3%.
Skin and subcutaneous tissue disorders: Very common: Alopecia usually mild in nature G1-2: 29.4% may occur. Common: Skin reactions G1-2: 5.7%.
Musculoskeletal and connective tissue disorders: Common: Arthralgia including jaw pain. Myalgia G1-4: 7%, G3-4: 0.3%.
Renal and urinary disorders: Common: Dysuria G1-2: 1.6%. Other genitourinary disorders G1-2: 1.9%.
General disorders and administration site conditions: Very common: Fatigue/malaise G1-4: 36.7%; G3-4: 8.5%. Fever G1-4: 13.0%, G3-4: 12.1%. Common: Pain including pain at the tumour site G1-4: 3.8%, G3-4: 0.6%. Chills: G1-2: 3.8%.
Investigations: Very common: Weight loss G1-4: 25%, G3-4: 0.3%. Common: Weight gain G1-2: 1.3%.
Undesirable effects with Navelbine, concentrate for infusion: Some undesirable effects were observed with Navelbine, solution for infusion during pre- and post-marketing experience which were not reported with Navelbine soft capsule: In order to provide the complete information and to further the safety of use of Navelbine soft capsule, these effects are presented below: Infections and Infestations: Uncommon: Septicemia (very rarely fatal).
Immune system disorders: Not known: Systemic allergic reactions as anaphylaxis, anaphylactic shock or anaphylactoid type reactions.
Endocrine disorders: Not known: Inappropriate antidiuretic hormone secretion (SIADH).
Vascular disorders: Uncommon: Flushing and peripheral coldness. Rare: Severe hypotension, collapse.
Respiratory system, thoracic and mediastinal disorders: Uncommon: Bronchospasm may occur as with other vinca alkaloids. Rare: Occasionally fatal Interstitial lung disease.
Gastrointestinal disorders: Rare: Pancreatitis.
Navelbine solution for injection: 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.
The most commonly reported adverse drug reactions are bone marrow depression with neutropenia, anaemia, neurologic disorders, gastrointestinal toxicity with nausea, vomiting, stomatitis and constipation, transient elevations of liver function tests, alopecia and local phlebitis.
Infections and infestations: Common: bacterial, viral or fungal infection at different localization (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.
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 non-cumulative over time. Anaemia (G3-4: 7.4%). Common: Thrombocytopenia (G3-4: 2.5%) may occur but are seldom severe. Not known: Febrile neutropenia. Pancytopenia.
Immune system disorders: Not known: Systemic allergic reactions as anaphylaxis, anaphylactic shock or anaphylactoid 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 (G3-4: 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. These effects are generally reversible.
Cardiac disorders: Rare: Ischemic heart disease (angina pectoris, myocardial infarction, occasionally fatal). 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: Occasionally fatal interstitial lung disease.
Gastrointestinal disorders: Very Common: Stomatitis (G1-4: 15% with Navelbine as single agent). Nausea and vomiting (G1-2: 30.4% and G3-4: 2.2%). Anti-emetic therapy may reduce their occurrence.
Constipation is the main symptom (G3-4: 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. Rare: Paralytic ileus, treatment may be resumed after recovery of normal bowel mobility. Pancreatitis.
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. Not known: Palmo-plantar erythrodysesthesia.
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 (G3-4: 3.7% with NAVELBINE as single chemotherapeutic agent). Common: Asthenia, fatigue, fever, pain at different locations including chest pain and pain at the tumour site have been experienced by patients receiving NAVELBINE therapy. Rare: Local necrosis. Proper positioning of the intravenous needle or catheter and bolus injection followed by liberal flushing of the vein can limit these effects.
Reporting of side effects: 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 national reporting system: Online reporting: via http://npra.moh.gov.my.
Drug Interactions
Interactions common to all cytotoxics: Concomitant use contraindicated (see Contraindications): Yellow fever vaccine: Risk of fatal generalised vaccine disease.
Concomitant use not recommended (see Precautions): Live attenuated vaccines (for yellow fever vaccine, see concomitant use contraindicated): 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 when exists (poliomyelitis).
Phenytoin (and by extrapolation, fosphenytoin): risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic drug or loss of efficacy of the cytotoxic drug due to increased hepatic metabolism by phenytoin or fosphenytoin.
Interaction with special precaution for use: Oral anticoagulant: There is an increased thrombotic and haemorrhagic risk in case of tumoral diseases. There is an eventuality of interaction between oral anticoagulants and anticancer chemotherapy. Increased frequency of the INR (International Normalised Ratio) monitoring is required.
Macrolides (clarithromycin, erythromycin, telithromycin): Risk of increased toxicity of the anti-mitotic agent due to a reduction in its hepatic metabolism by clarithromycin, erythromycin or telithromycin. Close clinical and laboratory monitoring. Possibly, use an alternative antibiotic.
Cobicistat: Increased neurotoxicity of the antimitotic due to a reduction in its hepatic metabolism by cobicistat. Close clinical monitoring and possible adjustment of dosage of the anti-mitotic agent.
Concomitant use to take into consideration: Immunosuppressants (Ciclosporine, tacrolimus, everolimus, sirolimus): Excessive immuno-depression with risk of lymphoproliferation.
Interactions specific to vinca-alkaloids: Concomitant use not recommended (see Precautions.): Itraconazole, posaconazole, ketoconazole: increased neurotoxicity of vinca-alkaloids due to the decrease of their hepatic metabolism by itraconazole, ketoconazole or posaconazole.
Interaction with Special Precaution for Use: Protease inhibitors: Increase of vinca-alkaloids toxicity due to the decrease of their hepatic metabolism by protease inhibitors. Close clinical monitoring and eventually decrease of chemotherapy dosage is required.
Concomitant use to take into consideration: Mitomycin C: risk of pulmonary toxicity of mitomycin and the vinca alkaloids are increased (see Adverse Reactions).
As vinca-alkaloids are known as 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.
Interactions specific to vinorelbine: The combination of Navelbine with other drugs with known bone marrow toxicity is likely to exacerbate the myelosuppressive adverse effects.
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.
As CYP3A4 is mainly involved in the metabolism of vinorelbine, combination with strong inhibitors of this isoenzymes could increase blood concentration of vinorelbine and combination with strong inducers of this isoenzyme could decrease blood concentrations of vinorelbine.
In a phase I clinical study examining a combination of intravenous vinorelbine and lapatinib an increased incidence of grade 3/4 neutropenia was suggested. In this study the recommended dose of intravenous vinorelbine was 22.5 mg/m2 on days 1 and 8 every 3 weeks in combination with 1000 mg of lapatinib administered daily. This type of combination must therefore be administered with caution.
Navelbine soft capsule: No clinically significant pharmacokinetic interaction was observed when combining Navelbine with several other chemotherapeutic agents (paclitaxel, docetaxel, capecitabine and oral cyclophosphamide).
Anti-emetic drugs such as 5HT3 antagonists (e.g. ondansetron, granisetron) do not modify the pharmacokinetics of Navelbine soft capsules (see Precautions).
Food does not modify the pharmacokinetics of vinorelbine.
Caution For Usage
Instructions for Use and Handling: Navelbine soft capsule: Navelbine, soft capsules is to be swallowed whole with water, without chewing or sucking on the capsule. It is recommended that the capsule be taken at the end of a meal.
Navelbine, soft capsules is intended for oral administration only.
For safety reasons, any unused or damaged capsule should be returned to the physician or pharmacist to be destroyed according to the usual applicable procedure for cytotoxic substances.
Instructions for use and handling of Navelbine, soft capsules: To open the tamper-proof packaging: Cut the blister with scissors along the black line.
Gently peel back the white film covering the blister.
Press on the clear plastic to push the capsule through the aluminium foil.
For precautions for use, see Precautions.
Navelbine solution for injection: The preparation and administration of NAVELBINE should be carried out by trained staff. Suitable eye protection, disposable gloves, face mask and disposable apron should be worn. Eventual spillage or leakage should be mopped up.
In case of contact with the eye, immediate liberal washing of the eye with sodium chloride 0.9% solution for injection should be undertaken. In case of accidental skin projection, proceed with a cleaning with water and mild soap followed by a thorough washing with water.
On completion, any exposed surface should be thoroughly cleaned and hands and face washed.
There is no content/container incompatibility between NAVELBINE and neutral glass bottle, PVC bag, vinyl acetate bag or infusion set with PVC tubing.
It is recommended to infuse NAVELBINE over 6-10 minutes after dilution in 20-50 ml of sodium chloride 0.9% solution for injection or in glucose solution for injection 5%. After administration the vein should be thoroughly flushed with at least 250 ml of isotonic solution.
NAVELBINE 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 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 normal saline, and the extravasated product should be removed, and the remaining dose administered in another vein. Application of mild heat facilitates product diffusion, and seems to reduce risk of cellulitis. In case of extravasations, to reduce the risk of phlebitis IV glucocorticoids could be administered immediately. Pregnant women should be warned, and avoid handling cytotoxic agents.
Before any administration, injection solution should be visually inspected so as to detect presence of particles or discoloration.
Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Navelbine soft capsule: Not applicable.
Navelbine solution for injection:
NAVELBINE should not be diluted in alkaline solutions (risk of precipitation).
This medicinal product must not be mixed with other medicinal product except those mentioned previously in Instructions for Use and Handling.
Storage
Navelbine soft capsule: Store between +2°C and +8°C (in refrigerator). Store in the original container. Keep the immediate packaging tightly closed.
Navelbine solution for injection: To be stored in a refrigerator (between +2°C and 8°C) and protected from light. Do not freeze.
Shelf-Life: Navelbine soft capsule: 36 months.
Navelbine solution for injection: The shelf-life of the medicinal product as packaged for sale is 3 years.
After diluting NAVELBINE in sodium chloride 9 mg/ml (0.9%) solution for injection or in glucose solution for injection 5%, chemical and physical in-use stability has been demonstrated for 8 days at room temperature (20°C ± 5°C) or in the refrigerator (2°C to 8°C) protected from light, in neutral glass bottle, PVC and vinyl acetate bags.
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 under the responsibility of the user and would normally not be longer than 24 hours at 2° to 8°C, unless preparation has taken place in controlled and validated aseptic conditions.
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
Soft cap 20 mg (light-brown, soft capsule printed N20) x 1's. 30 mg (pink, soft capsule printed N30) x 1's. Inj (clear, colourless to pale yellowish solution in vial) 10 mg/mL x 1 mL x 10's. 50 mg/5 mL x 5 mL x 10's.
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