VELBE®
Lilly
Vinblastine Sulfate
Antineoplastic Agent
Action And Clinical Pharmacology: Vinblastine has been used for the palliative treatment of a variety of malignant neoplastic conditions. In susceptible clinical cases, vinblastine sulfate has produced temporary reduction in the size or temporary disappearance of some tumors. It has relieved pain and other symptoms and allowed some patients to regain appetite and weight. Periods of remission have varied from patient to patient.
Experimental data indicate that vinblastine’s action is different from that of other recognized antineoplastic agents. Tissue culture studies suggest an interference with metabolic pathways of amino acids leading from glutamic acid to the citric acid cycle and to urea. In vivo experiments tend to confirm the in vitro results. A number of studies in vitro and in vivo have demonstrated that vinblastine produces a stathmokinetic effect and various atypical mitotic figures. The therapeutic responses, however, are not fully explained by the cytological changes, since these changes are sometimes observed clinically and experimentally in the absence of any oncolytic effects.
Reversal of the antitumor effect of vinblastine by glutamic acid or tryptophan has been observed. In addition, glutamic acid and aspartic acid have protected mice from lethal doses of vinblastine sulfate. Aspartic acid was relatively ineffective in reversing the antitumor effect.
Other studies indicate that vinblastine has an effect on cell energy production required for mitosis and interferes with nucleic acid synthesis.
Pharmacokinetics: Pharmacokinetic studies in patients with cancer have shown a triphasic serum decay pattern following rapid i.v. 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 feces 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.
Hematologic Effects: Clinically, leukopenia is an expected effect of vinblastine and the level of the leukocyte count is an important guide to therapy with this drug. In general, the larger the dose employed, the more profound and longer lasting the leukopenia will be. The fact that the WBC count returns to normal levels after drug-induced leukopenia is an indication that the white cell producing mechanism is not permanently depressed. Usually, the white count has completely returned to normal after the virtual disappearance of white cells from the peripheral blood.
Following vinblastine therapy, the nadir in white blood cell count may be expected to occur 5 to 10 days after the last day of drug administration. Recovery of the white blood count is fairly rapid thereafter and is usually complete within another 7 to 14 days. With the smaller doses employed for maintenance therapy, leukopenia may not be a problem.
Although the thrombocyte count ordinarily is not 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 200 000 platelets/mm. When other chemotherapy or radiation has not been employed previously, thrombocyte reduction below the level of 200 000/mmis rarely encountered, even when vinblastine may be causing significant leukopenia. Rapid recovery from thrombocytopenia within a few days is the rule.
Vinblastine’s effect upon the red cell count and hemoglobin is usually insignificant when other therapy does not complicate the picture. It should be remembered, however, that patients with malignant disease may exhibit anemia even in the absence of any therapy.
Indications And Clinical Uses: In the palliative treatment of the following:
I. Frequently Responsive Malignancies: Generalized Hodgkin’s disease (Stages III and IV, Ann Arbor modification of Rye); lymphocytic lymphoma (nodular and diffuse, poorly and well differentiated); histiocytic lymphoma; mycosis fungoides (advanced stages); advanced carcinoma of the testis; Kaposi’s sarcoma; Letterer-Siwe disease (histiocytosis X).
II. Less Frequently Responsive Malignancies: choriocarcinoma resistant to other chemotherapeutic agents; carcinoma of the breast, unresponsive to appropriate endocrine surgery and hormonal therapy.
Current principles of chemotherapy for many types of cancer include the concurrent administration of several antineoplastic agents. For enhanced therapeutic effect without additive toxicity, agents with different dose limiting clinical toxicities and different mechanisms of action are generally selected. Therefore, although vinblastine is effective as a single agent in the aforementioned indications, it is usually administered in combination with other antineoplastic drugs. Such combination therapy produces a greater percentage of response than does a single agent regimen. These principles have been applied, for example, in the chemotherapy of Hodgkin’s disease.
Hodgkin’s Disease: Vinblastine has been shown to be one of the most effective single agents for the treatment of Hodgkin’s disease. Advanced Hodgkin’s disease has also been successfully treated with several multiple drug regimens that included vinblastine. Patients who had relapses after treatment with the MOPP program-mechlorethamine hydrochloride (nitrogen mustard), vincristine sulfate (Oncovin), prednisone, and procarbazine – have likewise responded to combination drug therapy that included vinblastine. A protocol using cyclophosphamide in place of nitrogen mustard and vinblastine instead of vincristine is an alternative therapy for previously untreated patients with advanced Hodgkin’s disease.
Advanced testicular germinal cell cancers (embryonal carcinoma, teratocarcinoma, and choriocarcinoma) are sensitive to vinblastine alone, but better clinical results are achieved when vinblastine is administered concomitantly with other antineoplastic agents. The effect of bleomycin is significantly enhanced if vinblastine is administered 6 to 8 hours prior to the administration of bleomycin; this schedule permits more cells to be arrested during metaphase, the stage of the cell cycle in which bleomycin is active.
Contra-Indications: Vinblastine is contraindicated in patients who have significant granulocytopenia, unless this is a result of the disease being treated with vinblastine. It should not be used in the presence of bacterial infection. Such infections must be brought under control with antiseptics or antibiotics prior to the initiation of vinblastine sulfate therapy.
Manufacturers’ Warnings In Clinical States: Caution: Vinblastine is a potent drug and should be used only by physicians experienced with cancer chemotherapeutic drugs. Blood counts should be taken once or twice weekly. Discontinue or reduce the dosage upon evidence of abnormal depression of the bone marrow. This product is for i.v. use only. The intrathecal administration of vinblastine has resulted in death. Syringes containing this product should be labeled: “Warning – For i.v. use only”.
Extemporaneously prepared syringes containing this product must be packaged in an overwrap which is labeled “Do not remove covering until moment of injection. Fatal if given intrathecally. For i.v. use only.”
The following treatment successfully arrested progressive paralysis in a single patient mistakenly given the related vinca alkaloid, vincristine sulfate, intrathecally. If vinblastine is mistakenly administered intrathecally, this treatment is recommended and should be initiated immediately after the intrathecal injection: 1. Remove as much spinal fluid as can be safely done through the lumbar access. 2. Insert a catheter in a lateral cerebral ventricle for the purpose of flushing the subarachnoid space from above with removal through a lumbar access. 3. Initiate flushing through the cerebral catheter with lactated Ringer’s solution infused at the rate of 150 mL/h. Replace the lactated Ringer’s solution with fresh frozen plasma as soon as it becomes available. 4. Infuse fresh frozen plasma, 25 mL, diluted in 1 L of lactated Ringer’s solution at the rate of 75 mL/h with removal through the lumbar access. The rate of infusion should be adjusted to maintain a protein level in the spinal fluid of 150 mg/dL. 5. Administer 10 g of glutamic acid i.v. over 24 hours followed by 500 mg 3 times daily by mouth for 1 month or until neurological dysfunction stabilizes. The role of glutamic acid in this treatment is not certain and may not be essential.
The use of this treatment has not been reported following intrathecal vinblastine.
Pregnancy: Use oncolytic drugs cautiously during pregnancy. Information on the use of vinblastine during pregnancy is very limited. Although no abnormalities of the human fetus have been reported thus far, animal studies with vinblastine suggest that teratogenic effects may occur. Laboratory animals given this drug early in pregnancy suffer resorption of the conceptus; surviving fetuses demonstrate gross deformities. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, she should be informed of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Aspermia has been reported in man. Animal studies show metaphase arrest and degenerative changes in germ cells.
Leukopenia and granulocytopenia may reach dangerously low levels following administration of the higher recommended doses. It is therefore important to follow the dosage technique recommended under the Dosage section. Stomatitis and neurologic toxicity, although not common or permanent, can be disabling.
Precautions: Toxicity may be enhanced in the presence of hepatic insufficiency. If leukopenia with less than 2 000 white blood cells/mmoccurs following a dose of vinblastine watch the patient carefully for evidence of infection until the WBC count has returned to a safe level.
When cachexia or ulcerated areas of the skin surface are present, there may be a more profound leukopenic response to the drug; therefore, avoid its use in older persons suffering from either of these conditions.
In patients with malignant cell infiltration of the bone marrow, the leukocyte and platelet counts have sometimes fallen precipitously after moderate doses of vinblastine. Further use of the drug in such patients is inadvisable.
The use of small amounts of vinblastine daily for long periods is not advisable, even though the resulting total weekly dosage may be similar to that recommended. Little or no added therapeutic effect has been demonstrated when such regimens have been used. Strict adherence to the recommended dosage schedule is very important. When amounts equal to several times the recommended weekly dosage were given in 7 daily installments for long periods, convulsions, severe and permanent CNS damage, and even death occurred.
Acute shortness of breath and severe bronchospasm have been reported following the administration of vinca alkaloids. These reactions have been encountered most frequently when the vinca alkaloid was used in combination with mitomycin-C. The onset may be within minutes or several hours after the vinca is injected.
Avoid contamination of the eye with concentrations of vinblastine used clinically. If accidental contamination occurs, severe irritation (or, if the drug was delivered under pressure, even corneal ulceration) may result. Wash the eye with water immediately and thoroughly.
It is not necessary to use preservative-containing solvents if unused portions of the remaining solutions are discarded immediately. Unused preservative-containing solutions should be refrigerated for future use.
Information for the Patient: The patient should be warned to report immediately the appearance of sore throat, fever, chills, or sore mouth. Advice should be given to avoid constipation, and the patient should be made aware that alopecia may occur and that jaw pain and pain in the organs containing tumor tissue may occur. The latter is thought possibly to result from swelling of tumor tissue during its response to treatment. Scalp hair will regrow to its pretreatment extent even with continued treatment with vinblastine. Nausea and vomiting, although not common, may occur. Any other serious medical event should be reported to the physician.
Laboratory Tests: Since the dose-limiting clinical toxicity is the result of depression of the white-blood-cell count, it is imperative that this count be obtained just before the planned dose of vinblastine. Following administration of vinblastine, a fall in the white-blood-cell count may occur. The nadir of this fall is observed from 5 to 10 days following a dose. Recovery to pretreatment levels is usually observed from 7 to 14 days after treatment. These effects will be exaggerated when pre-existing bone marrow damage is present and also with the higher recommended doses (see Dosage). The presence of this drug or its metabolites in blood or body tissues is not known to interfere with clinical laboratory tests.
Drug Interactions: Vinblastine should not be diluted with solvents that raise or lower the pH of the resulting solution from between 3.5 and 5. Solutions should be made with normal saline (with or without preservative) and should not be combined in the same container with any other chemical.
The simultaneous oral or i.v. administration of phenytoin and antineoplastic chemotherapy combinations that include vinblastine have been reported to have reduced blood levels of the anticonvulsant and to have increased seizure activity. Dosage adjustment should be based on serial blood level monitoring. The contribution of vinblastine to this interaction is not certain. The interaction may result from either reduced absorption of phenytoin or an increase in the rate of its metabolism and elimination.
Pregnancy: Vinblastine should be given to a pregnant woman only if clearly needed. Animal studies suggest that teratogenic effects may occur.
Children: The dosage schedule for children is indicated under Dosage.
Lactation: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from vinblastine 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.
Adverse Reactions: Prior to the use of the drug, advise patients of the possibility of untoward symptoms.
In general, the incidence of side effects attending the use of vinblastine appears to be related to the size of the dosage employed. With the exception of epilation and leukopenia, adverse reactions usually have not persisted for longer than 24 hours. Leukopenia, the most common adverse reaction, is usually the dose-limiting factor.
The following are manifestations which have been reported as adverse reactions, the most common reactions are in bold face.
Hematologic: leukopenia (granulocytopenia), anemia, thrombocytopenia (myelosuppression).
Dermatologic: alopecia is common. A single case of light sensitivity associated with this product has been reported.
Gastrointestinal: constipation anorexia, nausea, vomiting, abdominal pain, ileus, vesiculation of the mouth, pharyngitis, diarrhea, hemorrhagic enterocolitis, bleeding from an old peptic ulcer, rectal bleeding.
Neurologic: numbness of digits (paresthesias), loss of deep-tendon reflexes, peripheral neuritis, mental depression, headache, convulsions.
Cardiovascular: hypertension. Cases of unexpected myocardial infarction and cerebrovascular accidents have occurred in patients undergoing combination chemotherapy with vinblastine, bleomycin, and cisplatin. Raynaud’s phenomenon has also been reported with this combination.
Pulmonary: See Precautions.
Miscellaneous: malaise, bone pain, weakness, pain in tumor-containing tissue, dizziness, jaw pain, skin vesiculation, Raynaud’s phenomenon when patients are being treated with vinblastine in combination with bleomycin and cis-platinum for testicular cancer. The syndrome of inappropriate secretion of antidiuretic hormone has occurred with higher than recommended doses.
Nausea and vomiting usually may be controlled easily by antiemetic agents. When epilation develops, it frequently is not total, and, in some cases, hair regrows while maintenance therapy continues.
Extravasation during i.v. injection may lead to cellulitis and phlebitis. If the amount of extravasation is great, sloughing may occur.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: 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 (see Pharmacology, Contraindications, Warnings, Precautions and Adverse Effects). There is no specific antidote. In addition, neurotoxicity similar to that with vincristine sulfate may be observed. Since the major route of excretion may be through the biliary system, toxicity from this drug may be increased when there is hepatic insufficiency.
In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. Overdoses of vinblastine have been reported rarely. The following is provided to serve as a guide should such an overdose be encountered.
Supportive care should include the following: (1) prevention of side effects that result from the syndrome of inappropriate secretion of antidiuretic hormone (this would include restriction of the volume of daily fluid intake to that of the urine output plus insensible loss and perhaps the administration of a diuretic affecting the function of the loop of Henle and the distal tubule); (2) administration of an anticonvulsant; (3) prevention of ileus; (4) monitoring the cardiovascular system; and (5) determining daily blood counts for guidance in transfusion requirements and assessing the risk of infection. The major effect of excessive doses of vinblastine will be myelosuppression, which may be life-threatening. There is no information regarding the effectiveness of dialysis nor of cholestyramine for the treatment of overdosage.
Vinblastine 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. Symptoms of overdose will appear when greater-than-recommended doses are given. Any dose of vinblastine that results in elimination of platelets and neutrophils from blood and marrow and their precursors from marrow should be considered life-threatening. The exact dose that will do this in all patients is unknown. Overdoses occurring during prolonged, consecutive-day infusions may be more toxic than the same total dose given by rapid i.v. injection. The i.v. median lethal dose in mice is 10 mg/kg body weight; in rats, it is 2.9 mg/kg. The oral median lethal dose in rats is 7 mg/kg.
Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of, or in addition to, gastric emptying if the drug has been swallowed. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal.
Dosage And Administration: Caution: It is extremely important that the needle be properly positioned in the vein before this product is injected.
If leakage into surrounding tissue should occur during i.v. 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 minimize discomfort and the possibility of cellulitis.
There are variations in the depth of the leukopenic response which follows therapy with vinblastine. For this reason, it is recommended that the drug be given no more frequently than once every 7 days. It is wise to initiate therapy for adults by administering a single i.v. dose of 3.7 mg/mof body surface area (bsa). Thereafter, white-blood-cell counts should be made to determine the patient’s sensitivity to vinblastine.
The above mentioned increases may be used until a maximum dose (not exceeding 18.5 mg/mbsa for adults and 12.5 mg/mbsa for children) is reached. The dose should not be increased after that dose which reduces the white-cell count to approximately 3 000 cells/mm In some adults, 3.7 mg/mbsa may produce this leukopenia; other adults may require more than 11.1 mg/mbsa; and, very rarely, as much as 18.5 mg/mbsa may be necessary. For most adult patients, however, the weekly dosage will prove to be 5.5 to 7.4 mg/mbsa.
When the dose of vinblastine which will produce the above degree of leukopenia has been established, a dose one increment smaller than this should be administered at weekly intervals for maintenance. Thus, the patient is receiving the maximum dose that does not cause leukopenia. It should be emphasized that, even though 7 days have elapsed, the next dose of vinblastine should not be given until the white-cell count has returned to at least 4 000/mm In some cases, oncolytic activity may be encountered before leukopenic effect. When this occurs, there is no need to increase the size of subsequent doses.
The duration of maintenance therapy varies according to the disease being treated and the combination of antineoplastic agents being used. There are differences of opinion regarding the duration of maintenance therapy with the same protocol for a particular disease; for example, various durations have been used with the MOPP programme in treating Hodgkin’s disease. Prolonged chemotherapy for maintaining remissions involves several risks, among which are life threatening infectious diseases, sterility, and possibly the appearance of other cancers through suppression of immune surveillance.
In some disorders, survival following complete remission may not be as prolonged as that achieved with shorter periods of maintenance therapy. On the other hand, failure to provide maintenance therapy in some patients may lead to unnecessary relapse; complete remission in patients with testicular cancer, unless maintained for at least 2 years, often result in early relapse.
To prepare a solution containing 1 mg of vinblastine/mL, add 10 mL of Sodium Chloride Injection (preserved with phenol or benzyl alcohol) to the 10 mg of vinblastine in the sterile vial. Other solutions are not recommended. The drug dissolves instantly to give a clear solution. After a solution has been made in this way and a portion of it has been removed from a vial, the remainder of the vial’s contents may be stored in a refrigerator for 14 days without significant loss of potency.
The dose of vinblastine (calculated to provide the desired amount) may be injected either into the tubing of a running i.v. infusion or directly into a vein. The latter procedure is readily adaptable to outpatient therapy. In either case, the injection may be completed in about 1 minute. If care is taken to insure 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 minimize further the possibility of extravascular spillage, it is suggested that the syringe and needle be rinsed with venous blood before withdrawal of the needle. The dose should not be diluted in large volumes of diluent (i.e., 100 to 250 mL) or given i.v. 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 into an extremity in which the circulation is impaired or potentially impaired by such conditions as compressing or invading neoplasm, phlebitis, or varicosity.
Special Dispensing Information: When dispensing vinblastine in other than the original container, e.g., a syringe containing a specific dose, it is imperative that it be packaged in an overwrap bearing the statement: “Do not remove covering until moment of injection. Fatal if given intrathecally. For i.v. use only” (see Warnings).
VELBE® Lilly Vinblastine Sulfate Antineoplastic Agent
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