See

DESCRIPTION

: BOXED WARNING. 

This product is for intravenous use only. It should be administered by individuals experienced in the administration of vinblastine sulfate. The intrathecal administration of vinblastine sulfate has resulted in death. Syringes containing this product should be labeled ''WARNING - FOR IV 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 INTRAVENOUS USE ONLY. ''  The following treatment successfully arrested progressive paralysis in a single patient mistakenly given the related vinca alkaloid, vincristine sulfate, intrathecally. If vinblastine sulfate 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. 4. As soon as fresh frozen plasma becomes available, infuse fresh frozen plasma, 25 mL, diluted in 1 L of Lactated Ringer's solution through the cerebral ventricular catheter 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 intravenously 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 sulfate.

Usage In Pregnancy

Caution is necessary with the administration of all oncolytic drugs during pregnancy. Information on the use of vinblastine sulfate during human pregnancy is very limited. Animal studies with vinblastine sulfate suggest that teratogenic effects may occur. Vinblastine sulfate can cause fetal harm when administered to a pregnant woman. 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 apprised 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 (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 AND ADMINISTRATION section. Stomatitis and neurologic toxicity, although not common or permanent, can be disabling.

General

Toxicity may be enhanced in the presence of hepatic insufficiency.

If leukopenia with less than 2,000 white blood cells/mm³ occurs following a dose of vinblastine sulfate, the patient should be watched carefully for evidence of infection until the white-blood-cell 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, its use should be avoided 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 sulfate. Further use of the drug in such patients is inadvisable.

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 and may require aggressive treatment, particularly when there is pre-existing pulmonary dysfunction. The onset may be within minutes or several hours after the vinca is injected and may occur up to 2 weeks following a dose of mitomycin. Progressive dyspnea requiring chronic therapy may occur. Vinblastine should not be readministered.

The use of small amounts of vinblastine sulfate daily for long periods is not advised, 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 central-nervous-system damage, and even death occurred.

Care must be taken to avoid contamination of the eye with concentrations of vinblastine sulfate used clinically. If accidental contamination occurs, severe irritation (or, if the drug was delivered under pressure, even corneal ulceration) may result. The eye should be washed 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 Patients

See PATIENT INFORMATION section.

Drug Interactions

See DRUG INTERACTIONS section.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Aspermia has been reported in man. Animal studies suggest that teratogenic effects may occur. See

WARNINGS

section regarding impaired fertility. 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.

In vitro tests using hamster lung cells in culture have produced chromosomal changes, including chromatid breaks and exchanges, whereas tests using another type of hamster cell failed to demonstrate mutation. Breaks and aberrations were not observed on chromosome analysis of marrow cells from patients being treated with this drug.

It is not clear from the literature how this drug affects synthesis of DNA and RNA. Some believe that there is no interference. Others believe that vinblastine interferes with nucleic acid metabolism but may not do so by direct effect but possibly as the result of biochemical disturbance in some other part of the molecular organization of the cell. No inhibition of RNA synthesis occurred in rat hepatoma cells exposed in culture to noncytotoxic levels of vinblastine. Conflicting results have been noted by others regarding interference with DNA synthesis.

Carcinogenesis: There is no currently available evidence to indicate that vinblastine sulfate itself has been carcinogenic in humans since the inception of its clinical use in the late 1950's. Patients treated for Hodgkin's disease have developed leukemia following radiation therapy and administration of vinblastine sulfate in combination with other chemotherapy including agents known to intercalate with DNA. It is not known to what extent vinblastine sulfate may have contributed to the appearance of leukemia. Available data in rats and mice have failed to demonstrate clearly evidence of carcinogenesis when the animals were treated with the maximum tolerated dose and with one-half that dose for 6 months. This testing system demonstrated that other agents were clearly carcinogenic, whereas vinblastine sulfate was in the group of drugs causing slightly increased or the same tumor incidence as controls in one study and 1.5 to 2-fold increase in tumor incidence over controls in another study.

Usage in Pregnancy

Pregnancy Category D (See

WARNINGS

section). Vinblastine sulfate should be given to a pregnant woman only if clearly needed. Animal studies suggest that teratogenic effects may occur.

Pediatric Use

The dosage schedule for children is indicated under DOSAGE AND ADMINISTRATION.

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 in nursing infants from vinblastine sulfate, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.