Vinblastine

Vinblastine is a vinca alkaloid, a class of cell-cycle-specific cytotoxic medicines first studied in extracts of the periwinkle plant. It stops cells from dividing by interfering with the microtubules that form the mitotic spindle.

Mechanism of Action

• Tubulin binding: vinblastine binds to tubulin and disrupts microtubule function. It prevents tubulin from polymerising into microtubules and induces depolymerisation of microtubules that have already formed. This blocks the reorganisation of microtubules that interphase and mitosis require, and cells arrest in metaphase.
• Wider cytotoxicity: besides arresting mitosis, vinca alkaloids appear to be cytotoxic to non-proliferating cells in the G1–S phase.
• Effect on blood counts: leucopenia is the expected effect and the white cell count is the main guide to treatment. The higher the dose, the deeper and longer the leucopenia. The count usually reaches its lowest point 5–10 days after the last day of dosing and returns to normal within a further 7–14 days. At the lower maintenance doses leucopenia may not be a problem. Thrombocytopenia is less frequent than with other cytotoxic medicines but can occasionally be severe.

Pharmacokinetics

• Distribution: the volume of distribution is large, up to about 3.27 L/kg. In rats the highest radioactivity was found in the lungs, liver, spleen and kidneys 2 hours after injection. Vinblastine is bound mainly to serum proteins (more than 99%). It barely crosses the blood–brain barrier and does not appear in the cerebrospinal fluid after intravenous doses at therapeutic concentrations.
• Metabolism: it is metabolised in the liver, by CYP3A isoenzymes, to an active metabolite.
• Elimination: after a rapid intravenous injection the serum concentration falls in three phases, with large differences between and within patients: a rapid first phase (half-life about 4 minutes), a short second phase (about 1.6 hours) and a prolonged final phase (about 25 hours, range 17–31 hours). The main route of elimination is the bile, so abnormal biliary excretion can increase toxicity. After radiolabelled injection about 10% of the radioactivity was found in faeces and 14% in urine. Systemic clearance is 0.74 L/kg/h.

Vinblastine is sometimes given alone but is usually used together with other cytotoxic medicines and/or radiotherapy for the following malignant tumours.

Neoplasms that respond frequently

• Generalised Hodgkin disease (stages III and IV, Ann Arbor modification of the Rye staging system).
• Lymphocytic lymphoma (nodular and diffuse, poorly and well differentiated).
• Histiocytic lymphoma.
• Mycosis fungoides (advanced stages).
• Advanced testicular carcinoma.
• Kaposi sarcoma.
• Letterer-Siwe disease (histiocytosis X).

Neoplasms that respond less often

• Choriocarcinoma resistant to other chemotherapy.
• Breast carcinoma that has not responded to endocrine surgery and appropriate hormonal treatment.

• Hypersensitivity to vinblastine, to another vinca alkaloid or to any of the excipients.
• Leucopenia not caused by the tumour.
• Bacterial infections; they must be brought under control before treatment starts.
• Intrathecal administration.
• Breastfeeding.

The frequency of side effects is generally proportional to the dose, and most do not last longer than 24 hours.

Very common (≥1/10): leucopenia (the most common effect and usually the dose-limiting one); nausea, vomiting; hair loss (not complete; in some patients the hair begins to regrow during maintenance therapy).

Common (≥1/100 to <1/10): anaemia, thrombocytopenia, bone marrow failure; paraesthesia, loss of deep tendon reflexes; constipation, paralytic ileus, bleeding from an old peptic ulcer, haemorrhagic enterocolitis, rectal bleeding, anorexia, diarrhoea.

Uncommon (≥1/1,000 to <1/100): depression; pharyngitis; pain at the tumour site, malaise.

Rare (≥1/10,000 to <1/1,000): inappropriate antidiuretic hormone secretion (SIADH), at recommended and higher doses; malaise; sensation of deafness, peripheral neuritis, headache, convulsions, dizziness, and stroke in patients given combination chemotherapy with bleomycin, cisplatin and vinblastine; ototoxicity with vestibular damage and hearing loss (partial or total deafness, temporary or permanent, with dizziness, nystagmus and vertigo); sinus tachycardia, angina pectoris, atrioventricular block, arrhythmia.

Not known: haemolytic anaemia; psychosis; neuralgia (for example in the face and jaw), peripheral neuropathy, vocal cord paralysis; tinnitus; myocardial infarction after combination chemotherapy with bleomycin, cisplatin and vinblastine; severe hypertension and hypotension, orthostatic hypotension, Raynaud’s phenomenon (reported in the same combination for testicular tumours); stomatitis, gastric pain, abdominal pain, parotid gland abnormalities; hepatic fibrosis; dermatitis, phototoxicity; muscle atrophy; urinary retention, thrombotic microangiopathy with renal failure; reduced fertility, aspermia; weakness, fever; pain at the injection site, especially after injection into small vessels.

Other reactions are reported without a frequency category. Acute respiratory distress with bronchospasm has followed treatment with vinca alkaloids; in patients given mitomycin C now or before, dyspnoea, rhonchi, abnormal lung infiltrates and lung disease can appear minutes to hours after vinblastine and up to 2 weeks after mitomycin C, and both medicines must then be stopped at once. Contact with the cornea can cause severe epithelial erosions with blepharospasm and eyelid swelling. Blistering in the mouth and on the skin has been reported. Leakage of the solution into the surrounding tissue (extravasation) during injection can lead to cellulitis, necrosis and thrombophlebitis.

• Oral anticoagulants: tumour disease raises the risk of thrombosis, and the clotting response varies widely during illness; if an oral anticoagulant is used, the INR should be checked more often.
• Other myelotoxic or neurotoxic agents, and radiotherapy over larger areas: the risk of toxicity rises. When chemotherapy is combined with radiotherapy to the liver, vinblastine should be delayed until the radiotherapy has finished.
• CYP3A inhibitors: vinblastine should be used with caution with medicines that inhibit CYP3A metabolism, and in patients with liver dysfunction, because side effects may start sooner or be more severe. Erythromycin may increase vinblastine toxicity. Itraconazole may increase the risk of neurotoxicity or paralytic ileus.
• Phenytoin and other anticonvulsants: cytotoxic treatment including vinblastine can lower phenytoin plasma levels and make seizures more frequent; phenytoin doses should be adjusted to plasma levels. Levels of other anticonvulsants may also fall.
• Digoxin: cytotoxic medicines including vinblastine can lower digoxin blood levels and reduce its effect.
• Mitomycin C: severe, sometimes irreversible lung toxicity has been reported, especially in already damaged lung tissue, including acute respiratory failure and lung infiltrates with the vinblastine–mitomycin–progesterone regimen.
• Bleomycin and cisplatin: Raynaud’s phenomenon and gangrene have followed vinblastine with bleomycin, and other vascular events (myocardial infarction, stroke) the combination of vinblastine, bleomycin and cisplatin. Cisplatin has been reported to raise vinblastine plasma concentrations, and vinblastine may add to the neurotoxicity of cisplatin and interferon and to the cardiotoxicity of interferon.
• Methotrexate and alkylating agents: vinblastine may increase the cellular uptake of methotrexate, and interactions with methotrexate and alkylating agents within the cell cycle may increase the overall cytotoxic effect. Interaction with other cytostatics and immunosuppressants, and with radiotherapy, can increase both therapeutic and toxic effects.
• Live attenuated vaccines: patients on immunosuppressive chemotherapy should not receive them, because of the risk of potentially fatal systemic disease, which is higher when the disease itself is immunosuppressive. Inactivated vaccines are recommended where available.
• Food and herbal products: grapefruit products should be avoided because they inhibit CYP3A and may raise vinblastine levels; St John’s wort induces CYP3A and may lower them, so caution is advised.

For intravenous use only. It is potentially fatal if given by any other route. Vinblastine is given by staff experienced in its use, under the strict supervision of an oncologist, preferably in a hospital experienced in this type of treatment. A white blood cell count is needed before every dose.

Starting Dose

• Adults: a single dose of 0.1 mg/kg (3.7 mg/m²) intravenously once a week, followed by a white cell count to judge the response.
• Children: a single dose of 2.5 mg/m² intravenously, followed by a white cell count.

Increasing the Dose and Maintenance

• Do not give vinblastine more often than once every seven days. Daily low doses are not recommended, even if the weekly total is the same, because toxicity may be more frequent and more severe.
• The dose is raised step by step but never beyond the dose that lowers the white cell count to about 3,000 cells/mm³. Some adults reach this at 0.1 mg/kg (3.7 mg/m²); others need more than 0.3 mg/kg (11.1 mg/m²), and very rarely 0.5 mg/kg (18.5 mg/m²). Once that dose is found, the next lower dose is given weekly as maintenance. The maximum for adults is 0.5 mg/kg (18.5 mg/m²).
• Step schedule, adults / children (mg/m²): first dose 3.7 / 2.5; second 5.5 / 3.75; third 7.4 / 5.0; fourth 9.25 / 6.25; fifth 11.1 / 7.5.
• The next dose is not given until the white cell count is back to at least 4,000/mm³, even if seven days have passed. Anti-tumour activity can appear before leucopenia; if so, there is no need to raise later doses. Long-term maintenance is the highest dose that can be given, judged by checks every seven to fourteen days, without lowering the white cell count to a dangerous level.
• In children the usual dose is 7.5 mg/m²; 12.5 mg/m² has been given as a single agent.
• In combination therapy the dose and frequency may differ from the standard weekly doses; see the current medical literature and the SmPC.

Special Populations

• Hepatic impairment: if liver function is abnormal on the first day, the dose is reduced to half at moderately raised bilirubin, and treatment is withheld at higher bilirubin. The thresholds are given in units that cannot be read reliably, so the SmPC should be consulted.
• Renal impairment: the SmPC reasons that metabolism and elimination are mainly hepatic, and that no dose adjustment is needed; its wording at this point is inconsistent, so the SmPC should be consulted.
• Elderly and weakened patients: see Special Instructions.

Method of Administration

• It is given into a vein, not into a muscle, under the skin or into the spinal canal. Intrathecal administration causes potentially fatal neurotoxicity and is contraindicated.
• The dose can be injected into the tubing of a running intravenous drip or directly into a vein; direct injection suits outpatients. Either way, the injection should take about one minute.
• Make sure the needle is well placed and stays in the vein, to prevent leakage. To lower the chance further, the syringe and needle can be filled and emptied several times with venous blood before the needle is withdrawn. If leakage occurs, stop the injection at once and give the rest of the dose in another vein.
• Do not dissolve vinblastine in a large volume of solvent (100–250 mL) and do not give it as a slow infusion (30–60 minutes or longer), because this may increase the risk of irritation.
• Do not inject into a limb with circulatory problems, or one that may be affected by a compressive or invasive tumour, phlebitis or varicose veins, because of the higher chance of thrombosis.

Intravenous Use Only

Vinblastine sulfate must be given by the intravenous route only. Intrathecal injection causes potentially fatal neurotoxicity. Syringes containing vinblastine must carry a warning that the product is potentially fatal if given by any other route and is for intravenous use only. Syringes prepared at the time of use must also state that the covering is not to be removed until the moment of injection. If the product is supplied dissolved in a container other than the original vial, such as a syringe, the outer packaging must say that it is for intravenous use only. If vinblastine is given into the spinal canal by accident, the SmPC describes emergency measures that must start immediately; consult it at once.

Bone Marrow Suppression and Infection

If the white cell count falls below 2,000/mm³ after a dose, the patient must be watched closely for infection until it returns to normal. The granulocyte count may reach its lowest point 5–10 days after the last day of dosing, with recovery usually complete within a further 7 to 14 days. Patients with skin ulcers, and elderly or cachectic patients, are more sensitive to vinblastine-induced leucopenia, and the SmPC advises against its use in them. Patients with cancer cells infiltrating the bone marrow can have more severe marrow suppression. Thrombocytopenia may develop in patients whose bone marrow has recently been damaged by radiotherapy or earlier cytotoxic treatment. The effect on red cells and haemoglobin is usually not significant when the patient’s condition is not complicated by other treatments.

Nervous System, Mouth and Bowel

Neurological toxicity and stomatitis, although neither frequent nor permanent, can be disabling. The peripheral nervous system should be monitored closely when adjusting the dose. Constipation may occur and usually responds to enemas and laxatives; it can cause impaction in the upper colon while the rectum looks empty, and an abdominal X-ray may help. Routine prevention of constipation is recommended in patients on high doses.

Strict Adherence to the Weekly Schedule

Small daily doses over long periods are not recommended. When more than the prescribed weekly dose, divided into seven daily doses, was given over a long period, seizures, severe permanent damage to the central nervous system and death occurred.

Lungs, Heart and Liver

Acute dyspnoea and severe bronchospasm have followed vinca alkaloids, more often when vinblastine is combined with mitomycin C. They can appear within minutes to hours of the injection, and up to 2 weeks after mitomycin C. Aggressive treatment may be needed, particularly with a history of lung disease. Most patients recover completely after bronchodilators, corticosteroids and oxygen, but some develop progressive dyspnoea that needs long-term corticosteroids; vinblastine must not be given to them again. Caution is needed in liver impairment, because elimination is probably delayed and the dose may need adjusting, and in ischaemic heart disease. The SmPC advises against using vinblastine with live attenuated vaccines, phenytoin or itraconazole.

Other Precautions

• In lymphoma, serum uric acid may rise while remission is being induced and should be monitored.
• Patients should avoid intense sunlight during treatment.
• If a secretion disorder of antidiuretic hormone is suspected, electrolytes and fluid volume should be checked. Orthostatic hypotension may worsen in older patients.
• Vinblastine must not touch the eyes. Spilled solution can damage skin and cornea; rinse at once with plenty of water. Use protective gloves, a mask and safety goggles when preparing and giving it, as for any cytostatic substance.
• Leakage into the tissue around the vein causes considerable irritation. Stop the injection and give the rest in another vein. Local injection of hyaluronidase and moderate heat at the site help to disperse the drug and reduce discomfort and the chance of cellulitis and phlebitis.
• There is no evidence that vinblastine is carcinogenic in humans, although some patients developed leukaemia after radiotherapy and vinblastine given with alkylating agents. No mutagenic potential has been shown so far, but as with all cytostatics caution is needed.
• Each vial contains less than 1 mmol (23 mg) of sodium, so it is essentially sodium-free.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: data are insufficient, the pharmacological effect points to possible harm, and preclinical studies showed genotoxicity, teratogenicity and other reproductive toxicity. Vinblastine should not be used in pregnancy unless strictly necessary. If it is, or if a patient becomes pregnant during treatment, she must be told of the risk to the foetus and monitored carefully, and genetic counselling should be considered.
• Contraception: men and women of childbearing age should use effective contraception during treatment and for at least 3 months, preferably 6 months, after treatment.
• Breastfeeding: it is not known whether vinblastine passes into milk. It is contraindicated, and breastfeeding must be stopped during treatment.
• Fertility: vinblastine can affect fertility in men and women. Aspermia has been described in humans, and reversible or irreversible infertility is possible. Some women treated in combination developed amenorrhoea, and menstruation often returned.

Effect on Driving

There are no data on the effect on the ability to drive. Given the side effects, a possible influence on driving should be kept in mind.

Keep unopened vials in a refrigerator at 2–8 °C. Do not freeze. As a refrigerated product, vinblastine needs cold-chain handling at 2–8 °C from dispatch to the pharmacy or ward. The powder dissolves in physiological saline to give a solution of pH 3.5–5; preparation and handling are described in the SmPC. Solvents containing preservatives are not needed if leftover portions are discarded at once; unused solutions that contain a preservative must be kept in a refrigerator. The vial is glass with a rubber stopper and an aluminium cap under a plastic cover, one vial per pack.

2 years. After a solution has been made and a portion withdrawn, the remainder can be kept in a refrigerator for 28 days without significant loss of potency.

Prescription only (Rx). Vinblastine is used under the strict supervision of an oncologist, preferably in a hospital experienced in this type of treatment, and is injected into a vein by staff experienced in its use. It is therefore supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.