Vinorelbine

Vinorelbine is a semi-synthetic vinca alkaloid. Unlike other vinca alkaloids, the catharanthine part of its molecule has been structurally modified. It acts on the dynamic balance of tubulin in the cell’s microtubule system and blocks cell division.

Mechanism of Action

• Tubulin binding: vinorelbine inhibits tubulin polymerisation and binds preferentially to mitotic microtubules. It affects axonal microtubules only at high concentrations, and it induces less tubulin spiralisation than vincristine.
• Cell-cycle block: it blocks mitosis in the G2–M phase, so cells die in interphase or at the next mitosis. As with other antimicrotubule agents, the disruption of the microtubules leads to apoptosis of malignant cells.

Pharmacokinetics

The figures below are from the soft-capsule SmPC.

• Absorption: after an oral dose, peak concentration is reached in 1.5 to 3 hours, with a Cmax of about 130 ng/mL after 80 mg/m². Absolute bioavailability is about 40%, and food does not change absorption. Oral 60 and 80 mg/m² give a blood exposure comparable to intravenous 25 and 30 mg/m². Exposure rises in proportion to the dose up to 100 mg/m², with similar variability between patients after oral and intravenous doses.
• Distribution: mean steady-state volume of distribution 21.2 L/kg (range 7.5–39.7), indicating extensive tissue distribution. Binding to plasma proteins is weak (13.5%), but vinorelbine binds strongly to blood cells, especially platelets (78%). Lung uptake is marked: surgical lung biopsies showed concentrations up to 300 times those in serum. It has not been found in the central nervous system.
• Metabolism: all metabolites are formed by CYP3A4 except 4-O-deacetylvinorelbine, which is formed by carboxylesterases. This is the only active metabolite and the main one in blood. No sulphate or glucuronide conjugates are seen.
• Elimination: terminal half-life about 40 hours. Blood clearance is high, close to hepatic blood flow, at 0.72 L/h/kg (range 0.32–1.26). Renal elimination is low (less than 5% of the dose, mostly unchanged drug); biliary excretion is the main route for the metabolites and for intact vinorelbine.
• Special populations: the effect of kidney dysfunction on pharmacokinetics has not been evaluated, but no dose reduction is indicated because renal elimination is low.

The national SmPCs for the two forms give these indications for adults.

Soft capsules (Navelbine)

• Advanced breast cancer, as monotherapy or in combination with other agents.
• Advanced non-small cell lung cancer, as monotherapy or in combination with other chemotherapy.
• Adjuvant treatment of non-small cell lung cancer, in combination with platinum-based chemotherapy.

Concentrate for solution for infusion

• Non-small cell lung cancer (stage 3 or 4).
• Metastatic breast cancer (stage 4), as a single agent, in patients in whom chemotherapy with anthracyclines and taxanes has failed or is not suitable.

Both forms

• Hypersensitivity to vinorelbine, to other vinca alkaloids or to any of the excipients.
• Neutrophil count below 1,500/mm³, or severe current or recent (within 2 weeks) infection.
• Platelet count below 100,000/mm³.
• Breastfeeding (it must be stopped during treatment).
• Combination with yellow fever vaccine.

Soft capsules only

• Disease that significantly affects absorption.
• Previous significant surgical resection of the stomach or small intestine.
• Need for long-term oxygen therapy.

Concentrate for infusion only

• Intrathecal use.
• Women of childbearing potential who are not using effective contraception.

The most frequent reactions are bone marrow depression (mainly neutropenia, also anaemia and thrombocytopenia), gastrointestinal toxicity (nausea, vomiting, diarrhoea, stomatitis, constipation), fatigue and fever. Neutropenia is reversible and is the dose-limiting toxicity. The frequencies below are those of the soft-capsule SmPC, from 316 patients with non-small cell lung or breast cancer given the recommended schedule (grades are NCI toxicity grades).

Very common (≥1/10): bacterial, viral or fungal infections without neutropenia; neutropenia (grade 3 in 21.8% and grade 4 in 25.9%), leucopenia, anaemia, thrombocytopenia (grade 1–2); anorexia; neurosensory disorders (mostly loss of tendon reflexes); nausea (grade 3–4 in 7.3%), vomiting, diarrhoea, stomatitis, abdominal pain, constipation, gastric disorders; alopecia (usually mild); fatigue or malaise, fever; weight loss.

Common (≥1/100 to <1/10): neutropenic infections; grade 4 neutropenia with fever above 38 °C, including febrile neutropenia; insomnia; neuromotor disorders, headache, vertigo, taste disorders; visual disturbance; hypertension, hypotension; dyspnoea, cough; oesophagitis, dysphagia; liver disorders; skin reactions; arthralgia (including jaw pain), myalgia; dysuria and other genitourinary symptoms; pain (including tumour-site pain), chills; weight gain.

Uncommon (≥1/1,000 to <1/100): grade 3 ataxia; heart failure and cardiac dysrhythmia; paralytic ileus (grade 3–4, exceptionally fatal).

Not known: neutropenic sepsis, septicaemia and severe sepsis (sometimes fatal); grade 3–4 thrombocytopenia, pancytopenia; syndrome of inappropriate antidiuretic hormone secretion (SIADH); severe hyponatraemia; posterior reversible encephalopathy syndrome; myocardial infarction in patients with a cardiac history or risk factors; pulmonary embolism; gastrointestinal bleeding; transient rises in liver function tests.

The capsule SmPC adds that these further reactions have been reported with the intravenous form: systemic allergic reactions, severe paraesthesia, weakness of the lower limbs, heart rhythm disorders, flushing, peripheral coldness, collapse, angina pectoris, bronchospasm, interstitial lung disease, pancreatitis, palmar-plantar erythrodysaesthesia and acute respiratory distress syndrome.

Concentrate for infusion. The infusion SmPC lists, with its own frequencies: very common, injection-site reactions (erythema, burning, vein discolouration, local phlebitis), transient rises in liver function tests without symptoms, oesophagitis, neurological disorders including loss of deep tendon reflexes, and neutropenia (grade 3 in 24.3% and grade 4 in 27.8%), reversible within 5–7 days and not cumulative; rare, angioedema, severe hyponatraemia, ischaemic heart disease (angina pectoris, transient ECG changes, myocardial infarction, sometimes fatal), severe hypotension and collapse, interstitial lung disease (sometimes fatal), pancreatitis, generalised skin reactions and local necrosis; very rare, complicated septicaemia (sometimes fatal) and tachycardia, palpitations and rhythm disorders. Like other vinca alkaloids, vinorelbine has a moderate vesicant potency; local necrosis can be reduced by correct placement of the cannula or catheter and thorough irrigation of the vein.

Vinorelbine is metabolised mainly by CYP3A4 and is a P-glycoprotein substrate. The soft-capsule SmPC lists the points below; the infusion SmPC’s warnings agree on the vaccines, anticoagulants, phenytoin, azole antifungals and potent CYP3A4 modulators.

• Yellow fever vaccine: contraindicated, because of the risk of fatal systemic vaccine disease.
• Other live attenuated vaccines: not recommended, because of the risk of systemic, possibly fatal, vaccine disease, which is higher in patients immunosuppressed by their disease. An inactivated vaccine should be used where one exists (for example against poliomyelitis).
• Phenytoin: not recommended. Reduced absorption of phenytoin can worsen seizures, and phenytoin can increase liver metabolism of the cytotoxic and so lessen its effect.
• Itraconazole (and ketoconazole or posaconazole, per the infusion SmPC): not recommended. Vinca alkaloid neurotoxicity increases because liver metabolism falls.
• Potent CYP3A4 inhibitors and inducers: inhibitors (such as ketoconazole, itraconazole) can raise vinorelbine blood levels, and inducers (such as rifampicin, phenytoin) can lower them. Use caution.
• Mitomycin C: more bronchospasm and dyspnoea, and in rare cases interstitial pneumonitis.
• Potent P-gp modulators: use caution, as no specific studies exist.
• Ciclosporin, tacrolimus: excessive immunosuppression with a risk of lymphoproliferation.
• Oral anticoagulants: cancer raises thrombosis risk and the clotting response varies, so the INR should be monitored more often.
• Other myelosuppressive medicines: likely to add to bone marrow toxicity. With cisplatin there is no pharmacokinetic interaction, but granulocytopenia is more frequent than with vinorelbine alone.
• Lapatinib: more grade 3/4 neutropenia was suggested in a phase I study with intravenous vinorelbine; use this combination with caution.
• Other chemotherapy: no clinically significant pharmacokinetic interaction with paclitaxel, docetaxel, capecitabine or oral cyclophosphamide.
• Antiemetics: 5-HT3 antagonists such as ondansetron and granisetron do not change the pharmacokinetics of the capsules.
• Radiotherapy: do not give vinorelbine at the same time as radiotherapy if the treatment field includes the liver.
• Food: food does not affect the pharmacokinetics. Grapefruit products may raise vinorelbine levels and St John’s wort may lower them; use caution.

Treatment must be prescribed and supervised by a physician experienced in cancer chemotherapy, with facilities to monitor cytotoxic medicines. The two forms have separate doses; the capsule SmPC gives the conversion between them.

Soft Capsules (Oral Use Only)

• How to take: swallow the capsule whole with water, without chewing or sucking it. Taking it with some food is recommended. Never take it with a hot drink, which could dissolve the capsule quickly. The capsules are considered when intravenous administration is not possible.
• Monotherapy: 60 mg/m² of body surface area once a week for the first three administrations. From the fourth administration the dose is raised to 80 mg/m² once a week, except in patients whose neutrophil count fell below 500/mm³ once, or between 500 and 1,000/mm³ more than once, during the first three doses; they stay on 60 mg/m².
• Adjustment at 80 mg/m²: if the neutrophil count falls below 500/mm³, or between 500 and 1,000/mm³ more than once, delay the dose until recovery and reduce from 80 to 60 mg/m² weekly for the next three administrations. The dose can be raised to 80 mg/m² again if, during those three doses at 60 mg/m², the count did not fall below 500/mm³ and did not fall between 500 and 1,000/mm³ more than once.
• Combination regimens: dose and frequency follow the treatment protocol. In clinical studies oral 80 mg/m² corresponded to intravenous 30 mg/m², and oral 60 mg/m² to intravenous 25 mg/m²; this is the basis for regimens that alternate the intravenous and oral forms.
• Maximum total dose: in patients with a body surface area of 2 m² or more, the total dose must never exceed 120 mg a week at 60 mg/m² or 160 mg a week at 80 mg/m².
• Vomiting: if the patient vomits within a few hours of a dose, the dose is never repeated.
• Hepatic impairment: mild (bilirubin below 1.5 times the upper limit of normal, ALT and/or AST 1.5 to 2.5 times): 60 mg/m² a week. Moderate (bilirubin 1.5 to 3 times, whatever the ALT and AST): 50 mg/m² a week. Severe: not recommended, because data are insufficient.
• Renal impairment: no pharmacokinetic reason to reduce the dose, even in severe impairment.
• Elderly: no important differences in response; age does not change pharmacokinetics.
• Children: safety and efficacy are not established, and use is not recommended.

Concentrate for Solution for Infusion (Intravenous Use Only)

• Route: strictly intravenous, after dilution; section 6.6 of the SmPC gives the dilution and handling instructions. Intrathecal administration is contraindicated and may be fatal. It is given with the help of a physician with extensive experience of cytostatic treatment.
• Non-small cell lung cancer, single agent: 25–30 mg/m² once a week. In combination chemotherapy the schedule follows the protocol: the usual dose (25–30 mg/m²) may be used with a lower frequency, for example on days 1 and 5, or on days 1 and 8, every three weeks.
• Advanced or metastatic breast cancer: 25–30 mg/m² once a week.
• Limits: the maximum tolerated dose per administration is 35.4 mg/m² of body surface area, and the maximum total dose per administration is 60 mg.
• Hepatic impairment: pharmacokinetics are unchanged in moderate or severe impairment (bilirubin above 2 times the upper limit of normal and/or transaminases above 5 times), but as a precaution a reduced dose of 20 mg/m² and close monitoring of blood counts are recommended in severe impairment.
• Renal impairment: no pharmacokinetic reason for a dose reduction.
• Elderly: no relevant differences in response; age does not change pharmacokinetics.
• Children: safety and efficacy are not established, and use is not recommended.

Blood Counts and Infection

Haemoglobin, white cell, neutrophil and platelet counts are checked on the day of each administration of the capsules and before each infusion, because bone marrow depression is the main risk. Treatment is delayed until recovery if neutrophils are below 1,500/mm³ and/or platelets are below 100,000/mm³. Neutropenia is the main dose-limiting reaction; it is not cumulative, reaches its lowest point 7 to 14 days after a dose and recovers within 5–7 days. In studies that started at 80 mg/m², a few patients had complications from excessive neutropenia, which is why the capsule schedule starts at 60 mg/m². Any sign of infection needs immediate examination.

Nausea, Vomiting and Constipation

Capsule treatment causes more nausea and vomiting than the intravenous form, and primary antiemetic prophylaxis is recommended. For the infusion, antiemetic treatment is recommended because nausea and vomiting are very frequent. Laxatives may be appropriate in patients with a history of constipation, or taking morphine or morphine-like medicines.

Handling the Capsules

The liquid inside the capsule is irritant. If the patient chews or sucks a capsule by mistake, rinse the mouth with water or, preferably, normal saline. If a capsule is broken or damaged, the contents can injure skin, mucous membranes or eyes; damaged capsules must not be taken but returned to the pharmacy or doctor for proper disposal. After any contact, wash at once with plenty of water or, preferably, normal saline.

Intravenous Use, Eyes and Leakage

The infusion is for intravenous use only. Vinorelbine must not touch the eyes: there is a risk of severe irritation and even corneal ulceration if it is sprayed under pressure; rinse the eyes at once with normal saline and contact an ophthalmologist. It has a moderate vesicant potency, so leakage into the tissue around the vein is avoided by correct cannula placement and thorough irrigation of the vein.

Lungs, Heart and Nerves

Lung toxicity has been reported with intravenous vinorelbine: acute severe bronchospasm, interstitial pneumonitis and acute respiratory distress syndrome (typically about a week after administration, range 3–8 days). The infusion must be stopped at once if unexplained dyspnoea or any sign of lung toxicity develops; protection against bronchospasm may be considered, especially with mitomycin C, and outpatients should report any dyspnoea. Interstitial lung disease has been reported more often in Japanese patients, who need special monitoring. Take special care in patients with a history of ischaemic heart disease and, for the capsules, in patients with poor performance status. Neurological examination, possibly with EMG, is advised during treatment or in patients at higher risk. After paralytic ileus, treatment can continue once bowel activity is back to normal.

Radiotherapy and Hepatic Impairment

Vinorelbine is not given with radiotherapy if the field includes the liver. Myelotoxicity is expected to increase with radiotherapy to the pelvis, spine or long bones, and after such radiotherapy within the previous 3 weeks. Doses in hepatic impairment are given above. Renal impairment needs no dose change.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: data are insufficient; animal studies showed embryotoxicity and teratogenicity. Vinorelbine should not be used in pregnancy unless the expected benefit clearly outweighs the potential risk. If pregnancy occurs, the patient must be told of the risk to the foetus and monitored closely, and genetic counselling should be considered.
• Contraception: because vinorelbine is genotoxic, women of childbearing potential must use effective contraception during treatment and for 7 months after it ends, and men for 4 months after it ends. Men are advised not to father a child during treatment and for 4 months afterwards, and genetic counselling is recommended for those who wish to conceive.
• Breastfeeding: it is unknown whether vinorelbine passes into human milk and a risk to the infant cannot be excluded, so breastfeeding is stopped before treatment begins.

Excipients of the Capsules

Each capsule contains 8.11 mg of sorbitol, which adds to sorbitol or fructose from other medicines and from the diet and may change the absorption of other oral medicines taken at the same time. It also contains 7.5 mg of alcohol (ethanol), less than 1 mL of beer or 1 mL of wine, which has no noticeable effect, and less than 1 mmol (23 mg) of sodium, so it is essentially sodium-free.

Effect on Driving

Studies have not been done and, from its pharmacological profile, vinorelbine is not expected to affect driving. Some side effects call for caution.

Both forms are kept in a refrigerator at 2–8 °C, so they need cold-chain handling from dispatch to the pharmacy or patient.

• Soft capsules: keep in a refrigerator at 2–8 °C and keep the blister closed until use. The pack is a PVC/PVDC/aluminium blister in a safety pack containing 1 capsule.
• Concentrate for infusion: keep in a refrigerator at 2–8 °C and do not freeze. Keep the vial in the outer carton to protect it from light. Storage of the diluted solution is covered under Shelf Life.

• Soft capsules: 3 years.
• Concentrate for infusion: 36 months unopened. The contents of an opened vial must be used immediately. After dilution with the recommended infusion solutions, the product is stable for 24 hours at 2–8 °C and at 25 °C; from a microbiological point of view it should be used immediately, and otherwise storage times are the user’s responsibility and should not exceed 24 hours at 2–8 °C unless dilution took place under controlled and validated aseptic conditions.

Prescription only (Rx), on the prescription of a physician experienced in cancer chemotherapy. The soft capsules are taken at home, so they are supplied to the patient or to the treating clinic on prescription, with cold-chain delivery at 2–8 °C. The concentrate for infusion is given in hospital under the supervision of a physician experienced in cytostatic treatment, so it is supplied to the hospital or clinic that administers it, also with cold-chain delivery at 2–8 °C.