Vinblastine

Vinblastine

Usual Diluents

Dilution Data

Preparation:  To prepare a solution containing 1 mg/mL of vinblastine sulfate, add 10 mL of Bacteriostatic Sodium Chloride Injection (preserved with benzyl alcohol) or 10 mL of Sodium Chloride Injection (unpreserved) to the 10 mg of Vinblastine Sulfate for Injection in the sterile vial. Do not use other solutions. The drug dissolves instantly to give a clear solution.

Unused portions of the remaining solutions made with normal saline that do not contain preservatives should be discarded immediately. Unused preservative-containing solutions made with normal saline may be stored in a refrigerator for future use for a maximum of 28 days.

Syringe:------------------------------
The dose of vinblastine sulfate (calculated to provide the desired amount) may be injected either into the tubing of a running intravenous infusion or directly into a vein over 2-3 minutes. 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 sulfate 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 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 vinblastine sulfate into an extremity in which the circulation is impaired or potentially impaired by such conditions as compressing or invading neoplasm, phlebitis, or varicosity.

Store vials in refrigerator, 2° to 8°C (36° to 46° F) to assure extended stability.

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:
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Frequently Responsive Malignancies:
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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).

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Less Frequently Responsive Malignancies:
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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.

CONTRAINDICATIONS
Vinblastine sulfate is contraindicated in patients who have significant granulocytopenia unless this is a result of the disease being treated. It should not be used in the presence of bacterial infections. Such infections must be brought under control prior to the initiation of therapy with vinblastine sulfate.

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.

Adult patients
It is wise to initiate therapy for adults by administering a single intravenous dose of 3.7 mg/m2 of body surface area (bsa). Thereafter, white-blood-cell counts should be made to determine the patient’s sensitivity to vinblastine sulfate.

A simplified and conservative incremental approach to dosage at weekly intervals for adults may be outlined as follows:

First dose...........................3.7 mg/m2 bsa

Second dose......................5.5 mg/m2 bsa

Third dose..........................7.4 mg/m2 bsa

Fourth dose........................9.25 mg/m2 bsa

Fifth dose...........................11.1 mg/m2 bsa

The above-mentioned increases may be used until a maximum dose not exceeding 18.5 mg/m2 bsa for adults is reached. The dose should not be increased after that dose which reduces the white-cell count to approximately 3000 cells/mm3. In some adults, 3.7 mg/m2 bsa may produce this leukopenia; other adults may require more than 11.1 mg/m2 bsa; and, very rarely, as much as 18.5 mg/m2 bsa may be necessary. For most adult patients, however, the weekly dosage will prove to be 5.5 to 7.4 mg/m2 bsa.

When the dose of vinblastine sulfate which will produce the above degree of leukopenia has been established, a dose of 1 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 sulfate should not be given until the white-cell count has returned to at least 4000/mm3. In some cases, oncolytic activity may be encountered before leukopenic effect. When this occurs, there is no need to increase the size of the subsequent doses (See PACKAGE INSERT for PRECAUTIONS).

Pediatric Patients
A review of published literature from 1993 to 1995 showed that initial doses of vinblastine sulfate in pediatric patients varied depending on the schedule used and whether vinblastine sulfate was administered as a single agent or incorporated within a particular chemotherapeutic regimen. As a single agent for Letterer-Siwe disease (histiocytosis X), the initial dose of vinblastine sulfate was reported as 6.5 mg/m2. When vinblastine sulfate was used in combination with other chemotherapeutic agents for the treatment of Hodgkin’s disease, the initial dose was reported as

6 mg/m2. For testicular germ cell carcinomas, the initial dose of vinblastine sulfate was reported as 3 mg/m2 in a combination regimen. Dose modifications should be guided by hematologic tolerance.

Patients with Renal or Hepatic Impairment
A reduction of 50% in the dose of vinblastine sulfate is recommended for patients having a direct serum bilirubin value above 3 mg/100 mL. Since metabolism and excretion are primarily hepatic, no modification is recommended for patients with impaired renal function.

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 program 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 remissions in patients with testicular cancer, unless maintained for at least 2 years, often result in early relapse.

Preparation:
To prepare a solution containing 1 mg/mL of vinblastine sulfate, add 10 mL of Bacteriostatic Sodium Chloride Injection (preserved with benzyl alcohol) or 10 mL of Sodium Chloride Injection (unpreserved) to the 10 mg of Vinblastine Sulfate for Injection in the sterile vial. Do not use other solutions. The drug dissolves instantly to give a clear solution.

Unused portions of the remaining solutions made with normal saline that do not contain preservatives should be discarded immediately. Unused preservative-containing solutions made with normal saline may be stored in a refrigerator for future use for a maximum of 28 days.

The dose of vinblastine sulfate (calculated to provide the desired amount) may be injected either into the tubing of a running intravenous 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 sulfate 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 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 vinblastine sulfate into an extremity in which the circulation is impaired or potentially impaired by such conditions as compressing or invading neoplasm, phlebitis, or varicosity.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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.

Manufactured by: Manufactured for:
Ben Venue Laboratories Bedford Laboratories™

December 2001 VIN-P02