Navelbine Capsule

Vinorelbine tartrate.

The active substance is vinorelbine (as tartrate) 20 or 30 mg.
Excipients/Inactive Ingredients: The solution contains: ethanol anhydrous; purified water; glycerol; macrogol 400.
The capsule shell contains: gelatin; glycerol 85%; sorbitol/sorbitan (anidrisorb 85/70); triglycerides, medium chain and PHOSAL 53 MCT (phosphatidylcholine; glycerides; ethanol anhydrous) and colouring agents (E171-titanium dioxide and E172 red and/or yellow iron oxide depending on the strength).
The edible printing ink contains: cochineal extract (E120), hypromellose, propylene glycol.

Pharmacotherapeutic group: Cytostatic - Antineoplastic drug.
Pharmacology: Mechanism of action: Navelbine is a cytostatic antineoplastic of the vinca alkaloid group. The molecular target of its activity is tubulin/microtubules dynamic equilibrium. Navelbine inhibits the polymerization of tubulin. lt acts preferentially on mitotic microtubules and affects axonal microtubules only at high concentration.
The effects on tubulin spiralization are Iower than with vincristine. Navelbine blocks mitosis in phase G2+M and induces cell death at interphase or at the following mitosis.
Pharmacokinetics: Absorption: After oral administration, vinorelbine is rapidly absorbed and the Tmax is reached between 1.5 to 3 h with a blood concentration peak (C_max) 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.
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 CYP 3A4 isoform of cytochromes P450, except 4-O-deacetylvinorelbine likely to be formed by carboxylesterases. 4-O-deacetylvinorelbine is the only active metabolite and the main one observed in blood. Neither sulfate nor glucuronide conjugates are found.
Elimination: The mean terminal half-life of vinorelbine is around 40 hours. Blood clearance is high, approaching hepatic blood flow, and is 0.72 l/h/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 group: 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 hepatic disorder (bilirubin <1.5 x ULN, and ALT and/or AST 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 ALT and AST).
Total clearance of vinorelbine was neither modified between mild and moderate liver impairment nor was it altered in hepatically impaired patients when compared with the clearance in patients with normal liver function. No data are available for patients with severe hepatic disorder, therefore the use of Navelbine is not recommended.
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 Navelbine soft capsule.
Pharmacokinetics/Pharmacodynamic relationships: A strong relationship has been demonstrated between blood exposure and depletion of leucocytes or PMNs.
Toxicology: Preclinical safety data: Vinorelbine induced chromosome damages but was not mutagenic in Ames test. It is assumed that vinorelbine can cause mutagenic effects (induction aneuploidy and polyploidy) in man. In animal reproductive studies, vinorelbine was embryo-feto-lethal and teratogenic. No haemodynamic effects were found in dogs receiving vinorelbine at maximal tolerated dose; only some minor, non-significant disturbances of repolarisation were found as with other vinca alkaloids tested. No effect on the cardiovascular system was observed in primates receiving repeated doses of vinorelbine over 39 weeks.

For non-small-cell lung cancer: In combination with platinum based therapy for the treatment of inoperable or stage IIIb or IV non-small cell lung cancer.
For breast cancer: In mono-therapy for the treatment of metastatic or relapsed breast cancer after or refractory to an anthracycline containing regimen. In combination with capecitabine for the treatment of metastatic or relapsed breast cancer after or refractory to an anthracycline containing regimen.

Navelbine must be strictly given by the oral route.
In monotherapy, the usual dose given is 60-80 mg/m² once weekly.
In combination chemotherapy, the dose and schedule will be adapted according to 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.
Dose modification: For any administration planned to be given at 80mg/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.
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 Table 1.)


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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 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.
The following table gives the dose required for appropriate ranges of body surface area (BSA): (See Table 2.)


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Administration: Navelbine must be given strictly by the oral route. Navelbine must be swallowed with water, without chewing or sucking the capsule. It is recommended to administer the capsule with some food.
Administration in patients with liver insufficiency: Navelbine can be administered at the standard dose of 60 mg/m²/week in patients with mild hepatic disorder (bilirubin <1.5 x ULN, and ALT and/or AST between 1.5 and 2.5 x ULN). In patients with moderate hepatic disorder (bilirubin between 1.5 and 3 x ULN, independent of ALT and AST), Navelbine should be administered at a dose of 50 mg/m²/week. The administration of Navelbine in patients with severe hepatic impairment is contra-indicated.
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.
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.

Overdosage with Navelbine soft capsules could produce bone marrow hypoplasia sometimes associated with infection, fever, paralytic ileus and hepatic disorders.
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.
There is no known antidote for overdosage of Navelbine.

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.
Neutrophil count <1500/mm³ or severe infection current or recent (within 2 weeks).
Platelet count <100000/mm³.
Lactation.
Patients requiring long-term oxygen therapy.
In combination with yellow fever vaccine.
Severe hepatic insufficiency.
Pregnancy.

Special warnings: Navelbine 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 (e.g. ondansetron, granisetron) may reduce the occurrence of this.
Navelbine soft capsule is associated with a higher incidence of nausea/vomiting than the i.v formulation. Primary prophylaxis with antiemetics and administration of the capsule with some food is recommended as this has also been shown to reduce the incidence of nausea and vomiting.
Patients receiving concomitant morphine or opioid analgesics: laxatives and careful monitoring of bowel mobility are recommended. Prescription of laxatives may be appropriate in patients with prior history of constipation.
Due to sorbitol content, patient with rare hereditary problems with fructose intolerance should not take the capsules.
This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per dose.
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.
For dose escalation from 60 to 80 mg/m² per week, after the third 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 reescalate the dose from 60 to 80 mg/m² per week.
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.
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 ischaemic heart disease; with poor performance status.
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, and its combination with phenytoin (like all cytotoxics) and with itraconazole (like all vinca alkaloids) is not recommended. Oral Navelbine has been studied in patients with hepatic disorder at the following dosages: 60 mg/m² in patients with mild hepatic disorder (bilirubin <1.5 x ULN, and ALT and/or AST from 1.5 to 2.5 x ULN); 50 mg/m² in patients with moderate hepatic disorder (bilirubin between 1.5 and 3 x ULN, independent of ALT and AST level). Total clearance of vinorelbine was neither modified between mild and moderate liver impairment nor was it altered in hepatically impaired patients when compared with the clearance in patients with normal liver function. Oral Navelbine has not been studied in patients with severe hepatic impairment, therefore the use in these patients is contra-indicated. 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.
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 has no effect on the ability to drive and use machines. However, caution is necessary in patients treated with vinorelbine considering some adverse effects of the drug.

Pregnancy: Navelbine is suspected to cause serious birth effects when administered during pregnancy. Navelbine is contra-indicated in pregnancy. In case of a vital indication for treatment with Navelbine during pregnancy a medical consultation concerning the risk of harmful effects for the child should be conducted. If pregnancy occurs 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.
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 child cannot be excluded therefore breast feeding must be discontinued before starting treatment with Navelbine.
Fertility: Men being treated with Navelbine are advised not to father a child during and minimally 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 reported are listed as follow, by system organ and by frequency.
The reactions were described using the NCI common toxicity criteria. (See Table 3.)


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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, diarrhoea, stomatitis and constipation. Fatigue and fever were also reported very commonly.
Post-marketing experience: 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 and sometimes 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, 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 5HT₃ antagonists (ondansetron)) may reduce the occurrence of Nausea and vomiting. Diarhoea G1-4: 49.7%; G3-4: 5.7%. Anorexia G 1-4: 38.6%; G 3-4: 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 morphinemimetics. 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] treatment 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 G 1-4: 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%.

Interactions common to all cytotoxics: Due to the increased thrombotic risk in the case of tumoral disease, the use of anticoagulative treatment is frequent. As the intra-individual variability of the coagulability during diseases is high and there is the risk of interaction between oral anticoagulants and anticancer therapy, if the patient is treated with oral anticoagulants, increasing the frequency of INR (International Normalised Ratio) monitoring is recommended.
Concomitant use contraindicated: Yellow fever vaccine: risk of fatal generalised vaccine disease.
Concomitant use not recommended: Live attenuated vaccines (for yellow fever vaccine, see concomitant use contraindicated as previously mentioned): 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: as with all cytotoxics, exacerbation of convulsions can be observed with phenytoin 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.
Concomitant use to take into consideration: Ciclosporine, tacrolimus: excessive immunodepression with risk of lymphoproliferation.
Interactions specific to vinca-alkaloids: Concomitant use not recommended: Itraconazole: increases neurotoxicity of vinca-alkaloids due to the decrease of their hepatic metabolism.
Concomitant use to take into consideration: Mitomycin C: risk of bronchospams and dyspnoea are increased, in rare case an interstitial pneumonitis was observed.
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 in combination with cisplatin was higher than the one associated with Navelbine single agent.
No clinically significant pharmacokinetic interaction was observed when combining Navelbine 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 this isoenzyme (e.g. ketoconazole, 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.
Anti-emetic drugs such as 5HT₃ antagonists (e.g. ondansetron, granisetron) do not modify the pharmacokinetics of Navelbine soft capsules.
An increased incidence of grade 3/4 neutropenia has been suggested when intravenous vinorelbine and lapatinib were associated in one clinical phase I study. In this study, the recommended dose of intravenous form of vinorelbine in a 3-weekly schedule on day 1 and day 8 was 22.5 mg/m² when combined with daily lapatinib 1000 mg. This type of combination should be administered with caution.
Food does not modify the pharmacokinetics of vinorelbine.

Any unused product or waste material should be disposed of in accordance with local requirements.
Instructions for use/handling: To open the packaging: 1. Cut the blister along the black dotted line.
2. Peel the foil off.
3. Push the capsule through the aluminium foil.

Store at 2°C - 8°C (in a refrigerator).
Shelf-Life: The shelf-life of the medicinal product as packaged for sale is 36 months for Navelbine soft capsule 20 mg and 30 mg.

Cytotoxic Chemotherapy

L01CA04 - vinorelbine ; Belongs to the class of plant alkaloids and other natural products, vinca alkaloids and analogues. Used in the treatment of cancer.

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