Z-Blastin

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 fl owering 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 C46H58O9N4•H2SO4 and that it is a dimeric alkaloid containing both indole and dihydroindole moieties. The structural formula is as follows:

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.

Vinblastine sulfate (vinblastine sulfate injection) 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 (vinblastine sulfate injection) 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 (vinblastine sulfate injection) 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 (vinblastine sulfate injection) . 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 (vinblastine sulfate injection) . A protocol using cyclophosphamide in place of nitrogen mustard and vinblastine sulfate (vinblastine sulfate injection) 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 (vinblastine sulfate injection) alone, but better clinical results are achieved when vinblastine sulfate (vinblastine sulfate injection) is administered concomitantly with other antineoplastic agents. The effect of bleomycin is significantly enhanced if vinblastine sulfate (vinblastine sulfate injection) 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.

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 (vinblastine sulfate injection) 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.

• Read the label carefully before use

• Store in a cool and dry place, away from sunlight

• Keep out of the reach of children

General

Toxicity may be enhanced in the presence of hepatic insufficiency. In patients with malignant-cell infiltration of the bone marrow, the leukocyte and platelet counts have sometimes fallen precipitously after moderate doses of vinblastine sulfate (vinblastine sulfate injection) . Further use of the drug in such patients is inadvisable.

Laboratory Tests

Since 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 sulfate. Following administration of vinblastine sulfate, 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 preexisting bone marrow damage is present and also with the higher recommended doses. The presence of this drug or its metabolites in blood or body tissues is not known to interfere with clinical laboratory tests.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Aspermia has been reported in man. Animal studies suggest that teratogenic effects may occur. Animal studies have shown metaphase arrest and degenerative changes in germ cells. Amenorrhea has occurred in some patients treated with the combination consisting of an alkylating agent, procarbazine, prednisone and vinblastine sulfate. Its occurrence was related to the total dose of these 4 agents used. Recovery of menses was frequent. The same combination of drugs given to male patients produced azoospermia; if spermatogenesis did return, it was not likely to do so with less than 2 years of unmaintained remission.

Mutagenicity:

Tests in Salmonella typhimurium and with the dominant lethal assay in mice failed to demonstrate mutagenicity. Sperm abnormalities have been noted in mice. Vinblastine sulfate has produced an increase in micronuclei formation in bone marrow cells of mice; however, since vinblastine sulfate inhibits mitotic spindle formation, it cannot be concluded that this is evidence of mutagenicity. Additional studies in mice demonstrated no reduction in fertility of males. Chromosomal translocations did occur in male mice. First-generation male offspring of these mice were not heterozygous translocation carriers.

Preganancy

Teratogenic Effects; Pregnancy Category . Vinblastine sulfate should be given to a pregnant woman only if clearly needed. Animal studies suggest that teratogenic effects may occur.

Nursing Mothers

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 sulfate 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.