Vinblastine Sulfate

VINBLASTINE SULFATE — vinblastine sulfate injection
Fresenius Kabi USA, LLC

Rx only

WARNINGS 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. FOR INTRAVENOUS USE ONLY — FATAL IF GIVEN BY OTHER ROUTES. See WARNINGS for the treatment of patients given intrathecal vinblastine sulfate injection.

DESCRIPTION:

Vinblastine sulfate 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 indicate that vinblastine sulfate is a dimeric alkaloid containing both indole and dihydroindole moieties. The accompanying structural formula has been proposed.

structure
(click image for full-size original)

Each mL contains: Vinblastine sulfate 1 mg; sodium chloride 9 mg; benzyl alcohol 0.9% (v/v) as a preservative; water for injection, q.s. (pH 3.5 to 5.0).

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 studies in vitro and in vivo 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 has been related to the inhibition of microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage.

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. 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 such as erythromycin. Enhanced toxicity has been reported in patients receiving concomitant erythromycin (see PRECAUTIONS). 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 nine 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 two hours after injection.

Hematologic Effects

Clinically, leukopenia is an expected effect of vinblastine sulfate, 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 white blood cell 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 therapy with vinblastine sulfate, the nadir in white blood cell count may be expected to occur five to ten 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 sulfate, 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 3). When other chemotherapy or radiation has not been employed previously, thrombocyte reduction below the level of 200,000/mm 3 is rarely encountered, even when vinblastine sulfate may be causing significant leukopenia. Rapid recovery from thrombocytopenia within a few days is the rule.

The effect of vinblastine sulfate 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 USAGE:

Vinblastine Sulfate Injection is indicated in the palliative treatment of the following:

I. 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)

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 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.

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