Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Consilient Health Limited, 5<sup>th</sup> Floor, Beaux Lane House, Mercer Street Lower, Dublin 2, Ireland
Vinorelbine 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 doctor 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, do not re-administer. Supportive treatment such as 5HT3 antagonists (e.g. ondansetron, granisetron) may reduce the occurrence of this (see section 4.5).
Vinorelbine soft capsule is associated with a higher incidence of nausea/vomiting than the intravenous formulation.
Primary prophylaxis with antiemetics and administration of the capsules with some food is recommended as this has also been shown to reduce the incidence of nausea and vomiting (see section 4.2).
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.
This medicine contains 38.44mg sorbitol in each 20mg soft capsule.
The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.
The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.
Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product.
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:
For the administrations given at 80mg/m², if the neutrophil count is below 500/mm³ or more than once between 500 and 1000 /mm³, then the treatment should be delayed until recovery. The administration should not only be delayed but also reduced to 60mg/m² per week. It is possible to reescalate the dose from 60 to 80 mg/m² per week (see section 4.2).
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 section 4.2.
If patients present signs or symptoms suggestive of infection, a prompt investigation should be carried out.
Special care should be taken when prescribing for patients with:
Vinorelbine 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 (see section 4.3).
Caution must be exercised when combining Vinorelbine and strong inhibitors or inducers of CYP3A4 (see section 4.5), and its combination with phenytoin (like all cytotoxics) and with itraconazole (like all vinca alkaloids) is not recommended.
Oral vinorelbine has been studied in patients with hepatic disorder at the following dosages:
The safety and pharmacokinetics of vinorelbine were not changed in these patients at the tested doses.
Oral vinorelbine has not been studied in patients with severe hepatic disorder, therefore the use in these patients is not recommended (see sections 4.2, 5.2).
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 (see sections 4.2, 5.2).
Yellow fever vaccine: as with all cytotoxics, risk of fatal generalised vaccine disease (see section 4.3).
Live attenuated vaccines: (for yellow fever vaccine, see concomitant use contraindicated) as with all cytotoxics, risk of generalised vaccine disease, possibly fatal. This risk is increased in patients already immunodepressed by their underlying disease. It is recommended to use an inactivated vaccine when one exists (e.g. poliomyelitis) (see section 4.4).
Phenytoin: as with all cytotoxics, 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.
Itraconazole: as with all vinca-alkaloids, increased neurotoxicity of vinca-alkaloids due to the decrease of their hepatic metabolism.
Cisplatin: 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.
Mitomycin C: risk of bronchospasm and dyspnoea are increased, in rare case an interstitial pneumonitis was observed.
Ciclosporin, tacrolimus: excessive immunodepression with risk of lymphoproliferation.
As vinca-alkaloids are known 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.
The combination of Vinorelbine with other drugs with known bone marrow toxicity is likely to exacerbate the myelosuppressive adverse effects.
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 this isoenzyme (e.g. azole antifungals such as ketoconazole and itraconazole) could increase blood concentrations of vinorelbine and combination with strong inducers of this isoenzyme (e.g. rifampicin, phenytoin) could decrease blood concentrations of vinorelbine.
Anti-emetic drugs such as 5HT3 antagonists (e.g. ondansetron, granisetron) do not modify the pharmacokinetics of vinorelbine soft capsules (see section 4.4).
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 1,000 mg. This type of combination should be administered with caution.
Anticoagulant treatment: as with all cytotoxics, the frequency of INR (International Normalised Ratio) monitoring should be increased due to the potential interaction with oral anticoagulants and increased variability of coagulation in patients with cancer.
Food does not modify the pharmacokinetics of vinorelbine.
There are insufficient data available on the use of vinorelbine in pregnant women. Studies in animals have shown embryotoxicity and teratogenicity (see section 5.3). On the basis of the results of animal studies and the pharmacological action of the medicinal product, there is a potential risk of embryonic and foetal abnormalities.
Vinorelbine should therefore not be used during pregnancy, unless the individual awaited benefit clearly outweighs the potential risks. If pregnancy occurs during treatment, the patient should be informed about the risks for the unborn child and be monitored carefully. The possibility of genetic counselling should be considered.
Women of child-bearing potential must use effective contraception during treatment and up to 3 months after treatment.
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 Vinorelbine (see section 4.3).
Men being treated with Vinorelbine 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.
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 patients treated with vinorelbine considering some adverse effects of the drug: see section 4.8.
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 80mg/m²/week).
Adverse reactions reported are listed below, 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: 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, Not known Post marketing reports.
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: Vinorelbine soft capsule is used as single agent or in combination with other chemotherapeutic agents such as cisplatin, or capecitabine.
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.
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.
Very common: Bone marrow depression resulting mainly in neutropenia G1-4: 71.5%; G3: 21.8%; G 4: 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%.
Not known: Severe hyponatraemia
Common: Insomnia: G1-2: 2.8%
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%,
Common: Visual disorders G1-2: 1.3%
Uncommon: Heart failure and cardiac dysrhythmia
Not known: Myocardial infarction in patients with cardiac medical history or cardiac risk factors.
Common: Hypertension G1-4: 2.5%; G3-4: 0.3%; Hypotension G1-4: 2.2%; G3-4: 0.6%
Common: Dyspnoea G1-4: 2.8%; G3-4: 0.3%. Cough: G1-2: 2.8%
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 5HT3 antagonists (ondansetron) may reduce the occurrence of nausea and vomiting (see section 4.4); Diarrhoea G1-4: 49.7%; G3-4: 5.7%; Anorexia G1-4: 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 receive concomitant treatment with opioid analgesics (see section 4.4), 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
Common: Hepatic disorders: G1-2: 1.3%
Common: Skin reactions G1-2: 5.7%
Common: Arthralgia including jaw pain, Myalgia: G1-4: 7%, G3-4: 0.3%
Common: Dysuria G1-2: 1.6%, Other genitourinary disorders G1-2: 1.9%
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%
Very common: Weight loss G1-4: 25%, G3-4: 0.3%
Common: Weight gain G1-2: 1.3%
Some undesirable effects were observed with vinorelbine, concentrate for solution for infusion during pre- and postmarketing experience which were not reported with vinorelbine soft capsule.
In order to provide the complete information and to further the safety of use of Vinorelbine soft capsule, these effects are presented below.
Some undesirable effects were observed with vinorelbine, concentrate for infusion during pre- and post-marketing experience which were not reported with vinorelbine soft capsule:
In order to provide the complete information and to further the safety of use of Vinorelbine soft capsule, these effects are presented below:
Uncommon: Septicemia (very rarely fatal)
Not known: Systemic allergic reactions were reported as anaphylaxis, anaphylactic shock or anaphylactoid type reaction.
Not known: Inappropriate antidiuretic hormone secretion (SIADH)
Uncommon: Flushing and peripheral coldness
Rare: Severe hypotension, collapse
Uncommon: Bronchospasm may occur as with other vinca alkaloids.
Rare: Interstitial pneumonopathy has been reported in particular in patients treated with vinorelbine in combination with mitomycin.
Rare: Pancreatitis
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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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