Velbe Injection 10mg
SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT
Velbe injection 10mg.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Vinbiastine Sulphate Ph.Eur. 10mg as the base.
3. PHARMACEUTICAL FORM
Powder for solution for intravenous injection.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Velbe is an anti-neoplastic drug for intravenous use. Information available at present suggests that Velbe 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 Velbe, but less frequently than the more susceptible conditions listed above.
4.2 Posology and Method of Administration
This preparation is for intravenous use only. It should be administered only by individuals experienced in vinblastine administration.
FATAL IF GIVEN BY OTHER ROUTES. FOR INTRAVENOUS USE ONLY.
In case of mistaken administration by intrathecal route, see section 4.4.
The recommended dose for adults, the elderly and children is 6mg/m , usually administered no more frequently than once every seven days. For testicular tumours, the dosage may be increased to 0.2mg/kg administered on each of two consecutive days every three weeks.
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 3mg/100ml. Since metabolism and excretion are primarily hepatic, no modification is recommended for patients with impaired renal function.
The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily. This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes. (See ‘Interaction with other medicinal products and other forms of interaction’).
To prepare a solution containing 1mg/ml, add 10ml of sterile 0.9% sodium chloride intravenous infusion to the 10mg vial. The drug dissolves rapidly to give a clear solution.
The dose of Velbe solution may be injected either into the tubing of a running intravenous infusion of sodium chloride 0.9% or directly into a vein. In either case, the injection should be completed in about 1 minute. If care is taken to ensure that the needle is securely within the vein and that no solution containing vinblastine is spilled extravascularly, cellulitis and/or phlebitis will not occur.
To minimise further 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 250ml) 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 Velbe into an extremity in which the circulation is impaired, or potentially impaired, by such conditions as compressing or invading neoplasm, phlebitis or varicosity.
Cautiom If leakage into surrounding tissue should occur during intravenous administration of vinblastine, it may cause considerable irritation. The injection should be discontinued immediately, and any remaining portion of the dose should then be introduced into another vein. Local injection of hyaluronidase and the application of moderate heat to the area of leakage help disperse the drug and are thought to minimise discomfort and the possibility of cellulitis.
4.3 Contra-indications
In case of mistaken administration by intrathecal route, see section 4.4.
Vinblastine is contra-indicated in patients who are leucopenic, unless this is the result of the disease being treated. It should not be used in the presence of bacterial infection. Such infections must be brought under control with antiseptics or antibiotics before using vinblastine.
4.4 Special Warnings and Precautions for Use
This product is for intravenous use only. It should be administered by individuals experienced in the administration of vinblastine sulphate. The intrathecal administration of vinblastine sulphate usually results in death. Syringes containing this product should be labelled “FATAL IF GIVEN BY OTHER ROUTES. FOR INTRAVENOUS USE ONLY.” An auxiliary sticker is provided in the pack with this warning.
Extemporaneously prepared syringes containing this product must be packaged in an overwrap which is labelled “DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FATAL IF GIVEN BY OTHER ROUTES. FOR INTRAVENOUS USE ONLY.”
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.
Based on the published management of survival cases involving the related vinca alkaloid vincristine sulphate, if vinblastine is mistakenly given by the intrathecal route, the following treatment should be initiated immediately after the injection:
1. Removal of as much CSF as is safely possible through the lumbar access.
2. Insertion of an epidural catheter into the subarachnoid space via the intervertebral space above initial lumbar access and CSF irrigation with lactated Ringer’s solution. Fresh frozen plasma should be requested and, when available, 25ml should be added to every 1 litre of lactated Ringer’s solution.
3. Insertion of an intraventricular drain or catheter by a neurosurgeon and continuation of CSF irrigation with fluid removal through the lumbar access connected to a closed drainage system. Lactated Ringer’s solution
should be given by continuous infusion at 150ml/h, or at a rate of 75ml/h when fresh frozen plasma has been added as above.
The rate of infusion should be adjusted to maintain a spinal fluid protein level of 150mg/dl.
The following measures have also been used in addition but may not be essential:
Glutamic acid has been given IV 10gm over 24 hours, followed by 500mg tds by mouth for 1 month. Folinic acid has been administered intravenously as a 100mg bolus and then infused at a rate of 25mg/h for 24 hours, then bolus doses of 25mg 6-hourly for 1 week. Pyridoxine has been given at a dose of 50mg 8-hourly by intravenous infusion over 30 minutes. Their roles in the reduction of neurotoxicity are unclear.
Aspermia has been reported in men. Animal studies show metaphase arrest and degenerative changes in germ cells. Amenorrhoea has occurred in some patients treated with vinblastine in combination with other drugs. Recovery of menses was frequent.
Stomatitis and neurological toxicity, although not common or permanent, can be disabling.
Precautions
Care must be taken to avoid contamination of the eye with concentrations of Velbe used clinically. If accidental contamination occurs, severe irritation (or, if the drug was delivered under pressure, even corneal ulceration) may result. The eye should be washed with water immediately and thoroughly.
Sperm abnormalities have been noticed in mice. Additional studies in mice demonstrated no reduction in fertility in males.
Myelosuppression: The dose-limiting factor is myelosuppression. Effective therapy with vinblastine is more likely to be followed by leucopenia than is the case with Oncovin (vincristine sulphate).
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, 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.
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If granulocytopenia with less than 1,000 granulocytes/mm occurs following a dose of vinblastine, 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.
When cachexia or ulcerated areas of the skin surface are present, there may be a more profound granulocytopenic response to the drug; 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, 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 may be causing significant granulocytopenia. Rapid recovery from thrombocytopenia within a few days is the rule.
The effect of vinblastine upon the red blood cell count and haemoglobin 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. 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 although chromosomal changes have been noted in some hamster lung cell in vitro tests.
There is no currently available evidence to indicate that vinblastine itself has been carcinogenic in humans, although some patients have developed leukaemia following radiation therapy and the administration of vinblastine in combination with alkylating agents.
Pharmaceutical precautions
Special dispensing information: When dispensing vinblastine in other than the original container, it is imperative that it be packed in an overwrap bearing the statement ‘DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FATAL IF GIVEN BY OTHER ROUTES. FOR INTRAVENOUS USE ONLY’. A syringe containing a specific dose must be labelled, using the auxiliary sticker provided in the pack with this warning.
Guidelines for the safe handling of antineoplastic agents: cytotoxic preparations should not be handled by pregnant staff.
Trained personnel should reconstitute and administer the drug. This should be performed in a designated area. The work surface should be covered with disposable plastic-backed absorbent paper.
Adequate protective gloves, mask and clothing should be worn. Precautions should be taken to avoid the drug accidentally coming into contact with the eyes. If accidental contamination occurs, the eyes should be washed with water thoroughly and immediately.
Use Luer-lock fitting on all syringes and sets. Large bore needles are recommended to minimise pressure and the possible formation of aerosols.
The latter may also be reduced by the use of a venting needle.
Adequate care and precaution should be taken in the disposal of items (syringes, needles, etc.) used to reconstitute cytotoxic drugs.
Vials of Velbe should be stored in a refrigerator between 2° and 8°C.
After reconstitution: after a portion of the solution has been removed from a vial, the remainder of the contents of the vial may be stored in a refrigerator for further use for 24 hours without significant loss of potency. When the reconstituted vial of Velbe is to be stored for more than 24 hours, it is essential to reconstitute with sterile 0.9% sodium chloride intravenous infusion preserved with 2.0% benzyl alcohol. Where preserved diluent is used, the reconstituted solution may be stored in a refrigerator for up to 28 days without significant loss of potency.
Whenever solution and container permit, parental drug products should be inspected visually for particulate matter and discolouration prior to administration.
4.5 Interactions 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 vinbiastine should be delayed until radiation therapy has been completed.
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 ymca 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 readministered.
The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations, that included vinblastine sulphate, 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.
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 sulphate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side-effects.
4.6 Pregnancy and lactation
Usage in pregnancy: Caution is necessary with the use of all oncolytic drugs during pregnancy. Information on the use of vinblastine during human pregnancy is very limited but vinbiastine can cause foetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. Animal studies with vinblastine suggest that teratogenic effects may occur. Laboratory animals given this drug early in pregnancy suffer resorption of the conceptus; surviving foetuses demonstrate gross deformities.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving vinblastine. If Velbe is used during pregnancy or if the patient becomes pregnant while receiving this drug, she should be informed of the potential hazard to the foetus.
Usage in nursing mothers: It is not known whether vinblastine is excreted in human milk. Because of the potential for serious adverse reactions due to Velbe in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.
4.7 Effects on ability to drive and use machines
None known
4.8 Undesirable effects
Leucopenia is the most common adverse reaction and is usually the dose-limiting factor.
In general, the incidence of side-effects attending the use of Velbe appears to be related to the size of dosage employed. Symptoms commonly encountered when high doses are employed include constipation, abdominal pain, ileus and myalgia.
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 constipation which may be encountered responds well to such usual measures as enemas and laxatives. Constipation may take the form of upper colon impaction and the rectum may be found to be empty on physical examination. A flat film of the abdomen is useful in demonstrating this condition. A routine prophylactic regimen against constipation is recommended for patients receiving high doses of vinblastine.
The following symptoms may occur after usual doses of vinblastine:
Haematological: Leucopenia, thrombocytopenia, anaemia.
Gastro-intestinal: Nausea, vomiting, constipation, ileus, diarrhoea, anorexia, abdominal pain, rectal bleeding, pharyngitis, haemorrhagic enterocolitis, bleeding from an old peptic ulcer.
Neurological: Numbness, paraesthesiae, peripheral neuritis, mental depression, loss of deep tendon reflexes, headache, convulsions. Treatment with ymca 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 sulphate is used in combination with other agents known to be ototoxic, such as the platinum-containing oncolytics.
Pulmonary: See under ‘Interactions’.
Cutaneous: Stomatitis, ulceration of the skin and alopecia. When alopecia develops it is frequently not total and, in some cases, hair regrows while maintenance therapy continues.
Cardiovascular: Hypertension. Cases of unexpected myocardial infarction and cerebrovascular accidents have occurred in patients undergoing combination chemotherapy with vinblastine, bleomycin and cisplatin.
Miscellaneous: Malaise, weakness, dizziness, bone pain, jaw pain and pain in tumour-containing tissue. Injection site reaction (see ‘Posology and Method of Administration’). Syndrome of inappropriate ADH secretion has been reported with higher than recommended doses. Raynaud’s phenomenon has occurred when patients are being treated with vinblastine in combination with bleomycin and cisplatin for testicular cancer.
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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
4.9 Overdose
Side-effects following the use of vinbiastine 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.
Overdoses occurring during prolonged, consecutive day infusions may be more toxic than the same total dose given by rapid IV injection.
In addition, neurotoxicity similar to that seen with Oncovin (vincristine sulphate) may be observed.
Supportive care should include: (a) 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; (b) administration of an anticonvulsant; (c) prevention and treatment of ileus; (d) monitoring the patient’s cardiovascular system; (e) daily blood counts for guidance in transfusion requirement and assessing the risk of infection.
The major effect of excessive doses of vinblastine will be on granulocytopoiesis, and this may be life-threatening.
There is no specific antidote. The use of folinic acid in addition to the other supportive measures recommended may be considered, although, unlike vincristine, 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 overdosage.
Vinbiastine in the dry state is irregularly and unpredictably absorbed from the gastrointestinal tract following oral administration. Absorption of the solution has not been studied. If vinblastine 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.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Studies suggest that vinblastine sulphate acts by interfering with metabolic pathways of amino acids. Other studies have demonstrated that vinblastine sulphate produces a stathmokinetic effect and various atypical mitotic figures. The therapeutic responses, however, are not fully explained by the cytologic changes, since these changes are sometimes observed clinically and experimentally in the absence of any oncolytic effects.
Reversal of the anti-tumour effect of vinblastine sulphate by glutamic acid or tryptophan has been observed. In addition, glutamic acid and aspartic acid have protected mice from lethal doses of vinbiastine sulphate. Aspartic acid was relatively ineffective in reversing the anti-tumour effect.
Some studies indicate that vinblastine sulphate has an effect on cell-energy production required for mitosis and interferes with nucleic acid synthesis. The mechanism of Velbe has been related to the inhibition of microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage.
5.2 Pharmacokinetic properties
Pharmacokinetic studies in patients with cancer have shown a triphasic serum decay pattern following rapid intravenous injection. The initial, middle and terminal half-lives are 3.7 minutes, 1.6 hours and 24.8 hours, respectively. The volume of the central compartment is 70% of body weight, probably reflecting very rapid tissue binding to formed elements of the blood. Extensive reversible tissue binding occurs. Low body stores are present at 48 and 72 hours after injection. Since the major route of excretion may be through the biliary system, toxicity from this drug may be increased when there is hepatic excretory insufficiency. Following injection of tritiated vinblastine in the human cancer patient, 10% of the radioactivity was found in the faeces and 14% in the urine; the remaining activity was not accounted for. Similar studies in dogs demonstrated that, over 9 days, 30% to 36% of radioactivity was found in the bile and 12% to 17% in the urine. A similar study in the rat demonstrated that the highest concentrations of radioactivity were found in the lung, liver, spleen and kidney 2 hours after injection.
5.3 Preclinical safety data
Sperm abnormalities have been noted in mice. Additional studies in mice demonstrated no reduction in fertility of males. Breaks and aberrations were not observed on chromosome analysis of marrow cells from patients treated with vinblastine, although chromosomal changes have been noted in some hamster lung cell in vitro tests.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
None.
6.2 Incompatibilities
Velbe should never be mixed with any other drug and should not be diluted with solvents that raise or lower the pH from between 3.5 and 5.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Vials of Velbe should be stored in a refrigerator between 2°C and 8°C.
After reconstitution: After a portion of the solution has been removed from a vial, the remainder of the contents of the vial may be stored in a refrigerator for future use for 24 hours without significant loss of potency. When the reconstituted vial is to be stored for more than 24 hours, it is essential to reconstitute with sterile 0.9% sodium chloride intravenous infusion preserved with 2.0% benzyl alcohol. Where preserved diluent is used, the reconstituted solution may be stored in a refrigerator for up to 28 days without significant loss of potency.
6.5 Nature and contents of container
Type 1 10ml glass vial with rubber stopper, aluminium seal and polypropylene cap containing 10mg of vinblastine sulphate powder for solution for intravenous injection.
6.6 Special Precautions for Disposal
Special dispensing information: When dispensing vinblastine sulphate in other than the original container, it is imperative that it be packaged in an overwrap bearing the statement “DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FATAL IF GIVEN BY OTHER ROUTES. FOR INTRAVENOUS USE ONLY.” A syringe containing a specific dose must be labelled, using the auxiliary sticker provided in the pack, with this warning.
Guidelines for the safe handling of anti-neoplastic agents: Cytotoxic preparations should not be handled by pregnant staff.
Trained personnel should reconstitute and administer the drug. This should be performed in a designated area. The work surface should be covered with disposable plastic-backed absorbent paper.
Adequate protective gloves, masks and clothing should be worn. Precautions should be taken to avoid the drug accidentally coming into contact with the eyes. If accidental contamination occurs, the eye should be washed with water thoroughly and immediately.
Use Luer-lock fittings on all syringes and sets. Large bore needles are recommended to minimise pressure and the possible formation of aerosols.
The latter may also be reduced by the use of a venting needle.
Adequate care and precaution should be taken in the disposal of items (syringes, needles, etc) used to reconstitute cytotoxic drugs.
Whenever solution and container permit, parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration.
7 MARKETING AUTHORISATION HOLDER
Genus Pharmaceuticals Limited
T/A Genus Pharmaceuticals
Linthwaite
Huddersfield
HD7 5QH, UK
8. MARKETING AUTHORISATION NUMBER
PL 06831/0116
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
14/02/2007
10 DATE OF REVISION OF THE TEXT
20/11/2014