4.1. Therapeutic indications

Vinblastine sulfate is a cytotoxic drug that arrests cell growth at the metaphase. Its actions are more pronounced on the rapidly dividing cell than on the normal cell. It appears to act, like vincristine, by binding to the microtubular proteins of the mitotic spindle, preventing polymerisation.

Information available at present suggests that vinblastine sulfate may be useful, either alone or in combination with other oncolytic drugs, for the treatment of: Hodgkin's disease; non-Hodgkin's lymphoma; carcinoma of the breast; methotrexate-resistant choriocarcinoma; renal cell carcinoma; testicular teratoma and seminoma; histiocytosis X. Other neoplasms occasionally show a marked response to vinblastine sulfate, but less frequently than the more susceptible conditions listed above.

4.2. Posology and method of administration

Posology

The recommended dose for adults, the elderly and children is 6 mg/m2, usually administered no more frequently than once every seven days. For testicular tumours, the dosage may be increased to 0.2 mg/kg administered on each of two consecutive days every three weeks.

To minimise the possibility of extravascular spillage, it is suggested that the syringe and needle be rinsed with venous blood before withdrawal. The dose should not be diluted in large volumes of diluent (ie, 100 to 250 ml) or given intravenously for prolonged periods (ranging from 30 to 60 minutes or more), since this frequently results in irritation of the vein and increases the chance of extravasation.

Because of the enhanced possibility of thrombosis, it is considered inadvisable to inject a solution of vinblastine sulfate into an extremity in which the circulation is impaired, or potentially impaired, by such conditions as compressing or invading neoplasm, phlebitis or varicosity.

Patients with hepatic impairment

As vinblastine is excreted principally by the liver, toxicity may be increased when there is hepatic insufficiency and it may be necessary to reduce initial doses in the presence of significantly impaired hepatic or biliary function. A reduction of 50% in the dose is recommended for patients having a direct serum bilirubin value above 3 mg/100 ml.

Patients with renal impairment

Since metabolism and excretion are primarily hepatic, no modification is recommended for patients with impaired renal function.

Vinblastine should not be given intramuscularly, subcutaneously or intrathecally.

Method of administration

The solution may be injected either directly into the vein or into the injection site of a running intravenous infusion. Injection of vinblastine sulfate may be completed in about one minute.

FOR INTRAVENOUS USE ONLY.

FATAL IF GIVEN BY OTHER ROUTES (see section 4.4)

In case of mistaken administration by intrathecal route, see section 4.4.

Syringes containing this product should be overlabelled with the intrathecal warning label provided - 'FOR INTRAVENOUS USE ONLY. FATAL IF GIVEN BY OTHER ROUTES'.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

For intravenous use only. Fatal if given by other routes (see section 4.4).

Vinblastine sulfate is contraindicated in patients who are leucopenic.

Vinblastine sulfate should not be used in the presence of bacterial infection. Such infections should be brought under control with antiseptics or antibiotics before the initiation of therapy with vinblastine sulfate.

4.4. Special warnings and precautions for use

Vinblastine sulfate is for intravenous use only. Vinblastine sulfate must be used only by physicians experienced in cytotoxic chemotherapy (see section 6.6).

After inadvertent intrathecal administration of vinca alkaloids, immediate neurosurgical intervention is required in order to prevent ascending paralysis leading to death. In a very small number of patients, life-threatening paralysis and subsequent death was averted but resulted in devastating neurological sequelae, with limited recovery afterwards.

The following treatment successfully arrested progressive paralysis in a single patient mistakenly given the related vincristine sulfate, intrathecally. This treatment should be initiated immediately:

1.

Removal of as much CSF as is safely possible through the lumbar access.

2.

Flushing with Lactated Ringer's solution by continuous infusion at 150 ml/h, through a catheter in a cerebral lateral ventricle and removed through lumbar access, until fresh plasma became available.

3.

Fresh frozen plasma, 25 ml, diluted with 1litre of Lactated Ringer's was then infused similarly at 75 ml/h. The rate of infusion should be adjusted to maintain a spinal fluid protein level of 150 mg/dl.

4.

Glutamic acid, 10 g, was given iv over 24 hours, followed by 500 mg tds by mouth for 1 month. Glutamic acid may not be essential.

Vinblastine SHOULD NOT BE GIVEN intramuscularly, subcutaneously or intrathecally.

Syringes containing this product should be over labelled with the intrathecal warning label provided - 'FOR INTRAVENOUS USE ONLY. FATAL IF GIVEN BY OTHER ROUTES'.

As with other antineoplastic agents, vinblastine may cause a severe local reaction on extravasation. If leakage into the surrounding tissue should occur during intravenous administration of vinblastine sulfate, the injection should be discontinued immediately and any remaining portion of the dose should be introduced into another vein. Local injection of hyaluronidase with the application of heat has been used to disperse the drug in order to minimise discomfort and the possibility of tissue damage. Cases of phlebitis and cellulitis have been reported.

Liver disease may alter the elimination of vinblastine in the bile, markedly increasing toxicity to peripheral nerves and necessitating a dosage modification in affected patients.

The dose-limiting factor is myelosuppression. In general, the larger the dose employed, the more profound and longer lasting the leucopenia will be. The fact that the granulocyte count returns to normal levels after drug-induced leucopenia is an indication that the granulocyte-producing mechanism is not permanently depressed.

Following therapy with vinblastine sulfate, the nadir in the granulocyte count may be expected to occur five to ten days after the last day of drug administration. Recovery of the granulocyte count is fairly rapid thereafter and is usually complete within another seven to fourteen days. If granulocytopenia with less than 1,000 granulocytes/mm3 occurs following a dose of vinblastine sulfate, the patient should be watched carefully for evidence of infection until the granulocyte count has returned to a safe level. Any infection must be brought under control immediately.

Patients should be carefully monitored for infection until the white cell count has returned to normal levels, if leucopoenia with less than 2000 white blood cells per mm3 occurs following a dose of vinblastine sulfate.

When cachexia or ulcerated areas of the skin are present, a more profound granulocytopenic response may be produced by vinblastine. Therefore, its use should be avoided in older persons suffering from either of these conditions.

Although the thrombocyte count is not usually significantly lowered by therapy with vinblastine sulfate, patients whose bone marrow has been recently impaired by prior therapy with radiation or with other oncolytic drugs may show thrombocytopenia (less than 150,000 platelets/mm3). When other chemotherapy or radiation has not been employed previously, thrombocyte reduction below the level of 150,000/mm3 is rarely encountered, even when vinblastine sulfate may be causing significant granulocytopenia. Rapid recovery from thrombocytopenia within a few days is the rule.

The effect of vinblastine sulfate upon the red blood cell count and hemoglobin is usually insignificant when other treatment does not complicate the picture.

In patients with malignant-cell infiltration of the bone marrow, the granulocyte and platelet counts have sometimes fallen drastically after moderate doses of vinblastine sulfate. Further use of the drug in such patients is inadvisable.

Breaks and aberrations were not observed on chromosome analysis of marrow cells from patients treated with vinblastine sulfate although chromosomal changes have been noted in some hamster lung cell in vitro tests.

Granulocytes and platelet counts have sometimes fallen precipitously after moderate doses of vinblastine sulfate in patients with malignant cell infiltration of the bone marrow. Further use of the drug in such patients is inadvisable.

Avoid contamination of the eye with vinblastine sulfate solution for injection. If accidental contamination occurs, severe irritation or corneal ulceration may result. The affected eye should be thoroughly irrigated with water immediately.

Vinblastine sulfate contains sodium

Vinblastine Sulfate contains 35.42 mg sodium in each vial, equivalent to 1.77% of the WHO maximum recommended daily intake (RDI) of 2 g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

When chemotherapy is being given in conjunction with radiation therapy through portals which include the liver, the use of vinblastine should be delayed until radiation therapy has been completed.

Vinblastine used as part of a combination regimen with mitomycin may result in fatal acute respiratory distress or failure and there have been cases of pulmonary infiltration or pulmonary oedema reported.

Cases of respiratory distress with interstitial pulmonary infiltrates have been reported in patients given a regimen comprising vinblastine, mitomycin, with or without progesterone (MVP). Acute shortness of breath and severe bronchospasm have been reported following the administration of the vinca alkaloids. These reactions have been encountered most frequently when the vinca alkaloid was used in combination with mitomycin-C and may be serious when there is pre-existing pulmonary dysfunction. The onset may be within minutes, or several hours after the vinca is injected, and may occur up to 2 weeks following a dose of mitomycin. Progressive dyspnoea, requiring chronic therapy, may occur. Vinblastine should not be re-administered.

The simultaneous administration of phenytoin and anti-neoplastic chemotherapy combinations that included vinblastine sulfate have been reported to reduce blood levels of the anticonvulsant and to increase seizure activity. Although the contribution of the vinca alkaloids has not been established, dosage adjustment of phenytoin, based on serial blood level monitoring, may need to be made when it is used in combination with vinblastine sulfate.

Co-administration of cisplatin has been reported to cause higher plasma concentrations of vinblastine and severity of neutropenia may be altered when given in conjunction with cisplatin.

Following combined treatment with vinblastine, bleomycin and cisplatin, there have been reports of a decline in glomerular filtration rate which may be reversible, nephrotoxicity, pulmonary toxicity, peripheral sensory neuropathy, neurotoxicity, ototoxicity, azoospermia, irreversible high frequency hearing loss, Raynaud's phenomenon with digital ischemia and gangrene, hypertension and other vascular events (such as myocardial infarction and cerebrovascular accident).

Erythromycin may increase the toxicity of vinblastine which may cause increased severity of neutropenia, myalgia and constipation.

Serum levels of anticonvulsants may be reduced by cytotoxic drug regimes, which include vinblastine.

Amenorrhea has occurred in some patients treated with vinblastine sulfate in combination with other drugs. Recovery of menses was frequent.

There is no currently available evidence to indicate that vinblastine sulfate itself has been carcinogenic in humans, although some patients have developed leukaemia following radiation therapy and the administration of vinblastine sulfate in combination with alkylating agents.

Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vinblastine sulfate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side-effects.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females

Women of childbearing potential should be advised to avoid becoming pregnant while receiving vinblastine sulfate. Due to the potential for genotoxicity, teratogenicity, and embryo toxicity, female patients of reproductive potential are advised to use highly effective contraception during treatment and for at least 6 months following last dose of vinblastine sulfate.

Due to the potential for genotoxicity, male patients with female partners of reproductive potential are advised to use highly effective contraception during treatment and for at least 3 months following the last dose of vinblastine sulfate.

Pregnancy

Although information on the use of vinblastine during pregnancy is limited, the drug may cause foetal toxicity when administered to pregnant women. The drug causes resorption of foetuses in animals and produces gross foetal abnormalities in surviving offspring. There are no adequate and controlled studies to date using vinblastine in pregnant women, and the drug should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective. If vinblastine is administered during pregnancy or the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the foetus.

Fertility

The effect of vinblastine on fertility in humans is not fully known.

Based on clinical reports, male and female fertility may be compromised. Aspermia has been reported in men. Sperm abnormalities have been noticed in mice.

Additional studies in mice demonstrated no reduction in fertility in males. It is recommended to discuss fertility preservation with men and women prior to treatment.

Breast-feeding

It is not known whether vinblastine is excreted in human milk. Because of the potential for serious adverse reactions due to vinblastine in nursing infants, the mother should be advised not to breast-feed during the entire vinblastine sulfate therapy and for 1 week following last dose of treatment. Alternatively, a decision should be made whether to discontinue treatment with vinblastine sulfate, taking into account the importance of the drug to the mother.

4.7. Effects on ability to drive and use machines

The effect of vinblastine sulfate on the ability to drive or use machines has not been systematically evaluated.

4.8. Undesirable effects

The use of small amounts of vinblastine daily for long periods is not advisable, even though the resulting total dosage may be similar to the recommended dosage. Little or no therapeutic advantage has been demonstrated when such regimens have been used and side-effects are increased.

The incidence of side effects with vinblastine sulfate appears to be dose related and most do not persist longer than 24 hours. Neurological effects are uncommon but can occur and may last longer than 24 hours.

The frequency grouping is defined using the following convention: Not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations

Not known

Pharyngitis

Neoplasms benign, malignant and unspecified (incl. cysts and polys)

Not known

Tumour pain

Blood and lymphatic system disorders

Not known

Neutropenia, Leucopeniaa, Thrombocytopenia, Anaemia

Endocrine disorders

Not known

Inappropriate anti-diuretic hormone secretionb

Metabolism and nutrition disorders

Not known

Anorexia

Psychiatric disorders:

Not known

Depression

Nervous system disorders

Not known

Cerebrovascular accidentc Convulsions, Numbness, Neuropathy peripheral, Loss of deep tendon reflexes, Paraesthesia Headache, Dizziness

Ear and labyrinth disorders

Not known

VIIIth nerve injuryd

Cardiac disorders

Not known

Myocardial infarctionc

Vascular disorders

Not known

Hypertension, Raynaud's phenomenone

Respiratory, thoracic and mediastinal disorders

Not known

Dyspnoeaf, Acute respiratory distressf

Gastrointestinal disorders

Not known

Haemorrhagic enterocolitis, Rectal bleeding, Peptic ulcer haemorrhage, Ileus, Nauseag, Vomitingg, Constipation, Oral mucosal blistering, Diarrhoea, Abdominal pain, Stomatitis

Skin and subcutaneous tissue disorders:

Not known

Blister, Alopeciah

Musculosketetal and connective tissue disorders

Not known

Myalgia, Bone pain, Jaw pain

Reproductive system and breast disorders

Not known

Aspermia

General disorders and administration site conditions

Not known

Injection site phlebitis, Injection site cellulitis (and in extreme cases skin exfoliation), Extravasation, Malaise, Asthenia

a Leucopoenia is the most common side effect and dose limiting factor.

b Syndrome of inappropriate ADH secretion has been reported with higher than recommended doses.

c In combination chemotherapy with vinblastine sulfate, bleomycin and cisplatin.

d Treatment with vinca alkaloids has resulted rarely in both vestibular and auditory damage to the eighth cranial nerve. Manifestations include partial or total deafness, which may be temporary or permanent, and difficulties with balance including dizziness, nystagmus, and vertigo. Particular caution is warranted when vinblastine sulfate is used in combination with other agents known to be ototoxic, such as the platinum-containing oncolytics.

e Raynaud's phenomenon has occurred when patients are being treated with vinblastine in combination with bleomycin and cisplatin for testicular cancer.

f reported when vinblastine is given in combinations with mitomycin (see section 4.5).

g antiemetics may be used to control nausea and vomiting.

h usually not total and in some cases the hair regrows during maintenance therapy).

Reporting of suspected adverse reactions

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.

4.9. Overdose

Side effects following the use of vinblastine are dose related. Therefore, following administration of more than the recommended dose, patients can be expected to experience these effects in an exaggerated fashion. Any dose that results in elimination of platelets and neutrophils from blood and marrow and their precursors from marrow is life-threatening.

The major effect of excessive doses of vinblastine will be on granulocytopoeisis, and this may be life-threatening.

In addition, neurotoxicity similar to that seen with vincristine sulfate may be observed.

Treatment: Supportive care should include: (1) prevention of the side effects that result from the syndrome of inappropriate secretion of antidiuretic hormone. This includes restriction of fluid intake and perhaps the use of a diuretic acting on the loop of Henle and distal tubule function; (2) administration of an anticonvulsant; (3) prevention and treatment of ileus; (4) monitoring the patient's cardiovascular system; and (5) daily blood counts for guidance in transfusion requirement and assessing the risk of infection.

There is no specific antidote. The use of folinic acid in addition to the other supportive measures recommended may be considered, although, unlike vincristine sulfate, studies have not been conducted to confirm its protective action.

There is no information regarding the effectiveness of dialysis nor of cholestyramine for the treatment of overdose.

Vinblastine sulfate in the dry state is irregularly and unpredictably absorbed from the gastro-intestinal tract following oral administration. Absorption of the solution has not been studied. If vinblastine sulfate is swallowed, activated charcoal in a water slurry may be given by mouth along with a cathartic. The use of cholestyramine in this situation has not been reported.