VINBLASTINE SULFATE- vinblastine sulfate injection, powder, lyophilized, for solution
Bedford Laboratories
WARNING
Caution � This preparation should be administered by individuals experienced in the administration of vinblastine sulfate. It is extremely important that the intravenous needle or catheter be properly positioned before any vinblastine sulfate is injected. Leakage into surrounding tissue during intravenous administration of vinblastine sulfate may cause considerable irritation. If extravasation occurs, 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.
FATAL IF GIVEN INTRATHECALLY. FOR INTRAVENOUS USE ONLY.
See WARNINGS for the treatment of patients given intrathecal vinblastine.
DESCRIPTION
Vinblastine Sulfate for Injection USP is vincaleukoblastine, sulfate (1:1) (salt). It is the salt of an alkaloid extracted from Vinca rosea Linn., a common flowering herb known as the periwinkle (more properly known as Catharanthus roseus G. Don). Previously, the generic name was vincaleukoblastine, abbreviated VLB. It is a stathmokinetic oncolytic agent. When treated in vitro with this preparation, growing cells are arrested in metaphase.
Chemical and physical evidence indicates that vinblastine sulfate has the molecular formula C46 H58 O9 N4 �H2 SO4 and that it is a dimeric alkaloid containing both indole and dihydroindole moieties.
Vinblastine sulfate is a white to off-white powder. It is freely soluble in water, soluble in methanol, and slightly soluble in ethanol. It is insoluble in benzene, ether, and naphtha.
The clinical formulation is supplied in a sterile form for intravenous use only. Vials of Vinblastine Sulfate for Injection USP contain 10 mg (0.011 mmol) of vinblastine sulfate, in the form of a white, amorphous, solid lyophilized plug, without excipients. After reconstitution with sodium chloride solution, the pH of the resulting solution lies in the range of 3.5 to 5.
CLINICAL PHARMACOLOGY
Experimental data indicate that the action of vinblastine sulfate 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 in vitro and in vivo studies have demonstrated that vinblastine sulfate 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 antitumor effect of vinblastine sulfate 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 sulfate has an effect on cell-energy production required for mitosis and interferes with nucleic acid synthesis. The mechanism of action of vinblastine sulfate has been related to the inhibition of microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage.
INDICATIONS AND USAGE
Vinblastine sulfate is indicated in the palliative treatment of the following:
Frequently Responsive Malignancies:
Generalized Hodgkin's disease (Stages III and IV, Ann Arbor modification of Rye staging system)
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)
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 sulfate 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 sulfate 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 sulfate. Patients who had relapses after treatment with the MOPP program� mechlorethamine hydrochloride (nitrogen mustard), vincristine sulfate, prednisone, and procarbazine�have likewise responded to combination-drug therapy that included vinblastine sulfate. A protocol using cyclophosphamide in place of nitrogen mustard and vinblastine sulfate instead of vincristine sulfate 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 sulfate alone, but better clinical results are achieved when vinblastine sulfate is administered concomitantly with other antineoplastic agents. The effect of bleomycin is significantly enhanced if vinblastine sulfate 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.
DOSAGE AND ADMINISTRATION
This preparation is for intravenous use only (see WARNINGS).
Special Dispensing Information
WHEN DISPENSING VINBLASTINE SULFATE IN OTHER THAN THE ORIGINAL CONTAINER, IT IS IMPERATIVE THAT IT BE PACKAGED IN THE PROVIDED OVERWRAP WHICH BEARS THE FOLLOWING STATEMENT: "DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FATAL IF GIVEN INTRATHECALLY. FOR INTRAVENOUS USE ONLY" (see WARNINGS). A syringe containing a specific dose must be labeled, using the auxiliary sticker provided, to state: "FATAL IF GIVEN INTRATHECALLY. FOR INTRAVENOUS USE ONLY".
Caution: It is extremely important that the intravenous needle or catheter be properly positioned before any vinblastine sulfate is injected. Leakage into surrounding tissue during intravenous administration of vinblastine sulfate may cause considerable irritation. If extravasation occurs, 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 minimize discomfort and the possibility of cellulitis.
There are variations in the depth of the leukopenic response which follows therapy with vinblastine sulfate. For this reason, it is recommended that the drug be given no more frequently than once every 7 days.
HOW SUPPLIED
Vinblastine Sulfate for Injection USP is supplied in packs of ten individually-boxed vials containing 10 mg lyophilized vinblastine sulfate.
NDC 55390-091-10.
Store vials in refrigerator, 2� to 8�C (36� to 46� F) to assure extended stability.