Navelbine

Navelbine

vinorelbine tartrate

Manufacturer:

OEP Phils

Distributor:

Zuellig
Full Prescribing Info
Contents
Vinorelbine tartrate.
Description
Each Soft-Gelatin Capsule contains: Vinorelbine tartrate 27.70 mg equivalent to Vinorelbine 20 mg.
Vinorelbine tartrate 41.55 mg equivalent to Vinorelbine 30 mg.
Action
Pharmacology: Vinorelbine 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.
Vinorelbine blocks mitosis at G2-M, causing cell death in interphase or at the following mitosis.
Safety and efficacy of vinorelbine in pediatric 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: 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 of 80 mg/m2. Absolute bioavailability is approximately 40% and a simultaneous intake of food does not alter the exposure to vinorelbine.
Oral vinorelbine at 60 and 80 mg/m2 leads to blood exposure comparable to that achieved with intravenous vinorelbine at 25 and 30 mg/m2, respectively 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 lungs, as assessed by pulmonary surgical biopsies which showed concentration up to a 300-fold higher concentration than in serum. Vinorelbine is not found in the central nervous system.
Biotransformation: All metabolites of vinorelbine are formed by CYP3A4 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/ kg (range: 0.32-1.26 L/h/kg).
Renal elimination is low (<5 % of the dose administered) 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.
Special patients groups: Renal and liver 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 with vinorelbine due to the low level of renal elimination.
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 vinorelbine is contraindicated in these patients.
Elderly patients: A study with oral 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 vinorelbine Soft-Gelatin Capsule.
Pharmacokinetics/Pharmacodynamic relationships: A strong relationship has been demonstrated between blood exposure and depletion of leucocytes or PMNs.
Toxicology: Preclinical Safety Data: Mutagenic and carcinogenic potential: The interaction of vinorelbine with the achromatic spindle during mitosis may lead to an incorrect distribution of chromosomes. In animal studies, intravenous vinorelbine caused aneuploidy and polyploidy. It is possible that vinorelbine may also have mutagenic effects (induction of aneuploidy) in humans.
The carcinogenicity studies in which vinorelbine 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, vinorelbine 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.
Indications/Uses
Oral vinorelbine is indicated as a single agent and in combination chemotherapy in the treatment of non-small cell lung cancer and metastatic breast cancer.
Dosage/Direction for Use
As a single agent: The recommended regimen is: First three administrations: 60 mg/m2 of body surface area, administered once weekly.
Subsequent administrations: Beyond the third administration, it is recommended to increase the dose of vinorelbine 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 1.)

Click on icon to see table/diagram/image

Dose modification: For any administration planned to be given at 80 mg/m2, if the neutrophil count is below 500/mm3 or more than once between 500 and 1000/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 2.)

Click on icon to see table/diagram/image

It is possible to re-escalate 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 base 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: Vinorelbine Soft-Gelatin capsule must be given strictly by the oral route. It should be swallowed with water without chewing or sucking the capsule. It is recommended to take the capsule with some food.
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.
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.
Administration in patients with liver insufficiency: Vinorelbine 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), Vinorelbine should be administered at a dose of 50 mg/m2/week. The administration of vinorelbine in patients with severe hepatic impairment is contraindicated.
Administration in patients with renal insufficiency: Given the minor renal excretion, there is no pharmacokinetic justification for reducing the dose of vinorelbine in patients with serious renal insufficiency.
Overdosage
Symptoms: Overdosage with vinorelbine could produce bone marrow hypoplasia sometimes associated with infection, fever and paralytic ileus, and 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. A close monitoring of hepatic function is recommended.
Antidote: There is no known antidote for overdosage of vinorelbine.
Contraindications
Known hypersensitivity to vinorelbine or other vinca alkaloids or to any of the constituents.
Disease significantly affecting absorption.
Previous significant surgical resection of stomach or small bowel.
Severe hepatic insufficiency.
Neutrophil count <1500/mm3 or severe infection current or recent (within 2 weeks).
Platelet count <100000/mm3.
Patients requiring long-term oxygen therapy.
Pregnancy.
Lactation.
In combination with yellow fever vaccine.
Special Precautions
Special warnings: Vinorelbine Soft-Gelatin Capsule should be prescribed by a physician who is 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 mouth rinses with water or preferably a normal saline solution.
In the event of the capsule 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.
Vinorelbine Soft-Gelatin capsule is associated with a higher incidence of nausea/vomiting than the IV formulation. A primary prophylaxis with antiemetics is recommended.
Due to sorbitol content, patient with rare hereditary problems with fructose intolerance should not take the capsules.
Close haematological monitoring must be undertaken during treatment (determination of haemoglobin level and the leucocyte, neutrophil and platelet counts on the day of each new administration).
Dosing should be determined by haematological status: If the neutrophil count is below 1500/mm3 and/or the platelet count is below 100000/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, see 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 1000/mm3, the administration should not only be delayed but also reduced to 60 mg/m2 per week. It is possible to re-escalate the dose from 60 to 80 mg/m2 per week (see 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 vinorelbine 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.
Special precautions for use: Special care should be taken when prescribing for patients: With history of ischaemic heart disease; With poor performance status.
Vinorelbine should not be given concomitantly with radiotherapy if the treatment field includes the liver.
Oral vinorelbine 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 vinorelbine was not studied in patients with severe hepatic impairment, therefore its use is contraindicated in these patients.
As there is a low level of renal excretion there is no pharmacokinetic rationale for reducing the dose of vinorelbine in patients with impaired kidney function.
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: Vinorelbine is suspected to cause serious birth effects when administered during pregnancy. Vinorelbine is contraindicated in pregnancy.
In case of a vital indication a medical consultation concerning the risk of harmful effects for the child should be performed for the therapy of a pregnant patient. If pregnancy occurs anyhow during treatment, genetic counselling should be offered.
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 vinorelbine is excreted in human breast milk. The excretion of vinorelbine in milk has not been studied in animal studies. A risk to the suckling cannot be excluded therefore breast feeding must be discontinued before starting treatment with vinorelbine
Fertility: Men being treated with vinorelbine 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.
Use In Pregnancy & Lactation
Use in Pregnancy: Vinorelbine is suspected to cause serious birth effects when administered during pregnancy. Vinorelbine is contraindicated in pregnancy.
In case of a vital indication a medical consultation concerning the risk of harmful effects for the child should be performed for the therapy of a pregnant patient. If pregnancy occurs anyhow during treatment, genetic counselling should be offered.
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 vinorelbine is excreted in human breast milk. The excretion of vinorelbine in milk has not been studied in animal studies. A risk to the suckling cannot be excluded therefore breast feeding must be discontinued before starting treatment with vinorelbine
Fertility: Men being treated with vinorelbine 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 overall reported frequency 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 vinorelbine (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.
The reactions were described using the NCI common toxicity criteria: See Table 3.

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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).
Adverse effects reported with Vinorelbine Soft-Gelatin 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: Vinorelbine Soft-Gelatin Capsule is used as single agent or in combination with other chemotherapeutic or targeted therapy agents.
The most common system organ classes involved during post-marketing experience are: 'Blood and lymphatic system disorders', 'Gastrointestinal disorders', 'Infections and infestations' 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.
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 G3: 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%; G 3-4: 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: 1.3%.
Investigations: Very common: Weight loss G1-4: 25%; G3-4: 0.3%.
Common: Weight gain G1-2: 1.3%.
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: Live attenuated vaccines (for yellow fever vaccine, see concomitant use contraindicated in the previous text): 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 (poliomyelitis).
Phenytoin (and by extrapolation, fosphenytoin): 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 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.
Concomitant use to take into consideration: Cyclosporine, tacrolimus, everolimus, sirolimus: excessive immuno-depression with risk of lymphoproliferation.
Interaction specific to vinca-alkaloids: Concomitant use not recommended: Itraconazole, posaconazole: increased neurotoxicity of vinca-alkaloids due to the decrease of their hepatic metabolism.
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 bronchospams and dyspnoea are increased. As vinca-alkaloids are known as substrates for P-glycoprotein, and in the absence of specific study, caution should be exercised when combining vinorelbine with strong modulators of this membrane transporter.
Interactions specific to vinorelbine: The combination of vinorelbine with other drugs with known bone marrow toxicity is likely to exacerbate the myelosuppressive adverse effects.
There is no mutual pharmacokinetic interaction when combining vinorelbine with cisplatin over several cycles of treatment. However, the incidence of granulocytopenia associated with vinorelbine use in combination with cisplatin is higher than associated with vinorelbine single agent.
No clinically significant pharmacokinetic interaction was observed when combining vinorelbine with several other chemotherapeutic agents (paclitaxel, docetaxel, capecitabine and oral cyclophosphamide).
As CYP3A4 is mainly involved in the metabolism of vinorelbine, combination with strong inhibitors of these isoenzymes could increase blood concentration of vinorelbine and combination with strong inducers of this isoenzyme could decrease blood concentrations of vinorelbine.
Anti-emetic drugs such as 5HT3 antagonists (e.g. ondansetron, granisetron) do not modify the pharmacokinetics of vinorelbine Soft-Gelatin Capsules.
Food does not modify the pharmacokinetics of vinorelbine.
Caution For Usage
Special Precautions for Disposal (and other Handling): Vinorelbine Soft-Gelatin capsule 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. Vinorelbine Soft-Gelatin Capsule 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 Vinorelbine Soft-Gelatin 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 aluminum foil.
Storage
Store at temperatures between 2°C to 8°C (in a refrigerator).
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
Softgel cap 20 mg x 1's. 30 mg x 1's.
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