WARNINGS
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 usually results in death. Syringes containing this product should be labeled, using the auxiliary sticker provided to state ‘‘FATAL IF GIVEN INTRATHECALLY. FOR INTRAVENOUS 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.”
After inadvertent intrathecal administration of vinca alkaloids, immediate neurosurgical intervention is required in order to prevent ascending paralysis leading to death. In a vey small number of patients, life-threatening paralysis and subsequent death was averted but resulted in devastating neurological sequelae, with limited recovery afterwards.
There are no published cases of survival following intrathecal administration of vinblastine sulfate to base treatment on. However, based on the published management of survival cases involving the related vinca alkaloid vincristine sulfate, if vinblastine sulfate is mistakenly given by the intrathecal route, the following treatment should be initiated immediately after the injection:
- Remove as much CSF as is safely possible through the lumbar access.
- Insertion of an epidural catheter into the subarachnoid space via the intervertebral space above initial lumbar access and CSF irrigation with lactated Ringer’s solution. Fresh frozen plasma should be requested and, when available, 25 mL should be added to every 1 liter of lactated Ringer’s solution.
- Insertion of an intraventricular drain or catheter by a neurosurgeon and continuation of CSF irrigation with fluid removal through the lumbar access connected to a closed drainage system. Lactated Ringer’s solution should be given by continuous infusion at 150 mL/hour, or a rate of 75 mL/hour when fresh frozen plasma has been added as above.
The rate of infusion should be adjusted to maintain a spinal fluid protein level of 150 mg/dL.
The following measures have also been used in addition but may not be essential:
Glutamic acid, 10 grams, has been given intravenously over 24 hours, followed by 500 mg three times daily by mouth for 1 month. Folinic acid has been administered intravenously as a 100 mg bolus and then infused at a rate of 25 mg/hour for 24 hours, then bolus doses of 25 mg every 6 hours for 1 week. Pyridoxine has been given at a dose of 50 mg every 8 hours by intravenous infusion over 30 minutes. Their roles in the reduction of neurotoxicity are unclear.
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. Stomatitis and neurologic toxicity, although not common or permanent, can be disabling.
PRECAUTIONS
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 C 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.
Care should be recommended in patients with ischemic cardiac disease.
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 shouId be refrigerated for future use.
Information for Patients
The patient should be warned to report immediately the appearance of sore throat, fever, chills, or sore mouth. Advice should be given to avoid constipation, and the patient should be made aware that alopecia may occur and that jaw pain and pain in the organs containing tumor tissue may occur. The latter is thought possibly to result from swelling of tumor tissue during its response to treatment. Scalp hair will regrow to its pretreatment extent even with continued treatment with vinblastine sulfate. Nausea and vomiting, although not common, may occur. Any other serious medical event should be reported to the physician.
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 (See DOSAGE AND ADMINISTRATION). The presence of this drug or its metabolites in blood or body tissues is not known to interfere with clinical laboratory tests.
Drug Interactions
Solutions should be made with normal saline (with or without preservative) and should not be combined in the same container with any other chemical. Unused portions of the remaining solutions that do not contain preservatives should be discarded immediately.
The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included vinblastine sulfate has been reported to have reduced blood levels of the anticonvulsant and to have increased seizure activity. Dosage adjustment should be based on serial blood level monitoring. The contribution of vinblastine sulfate to this interaction is not certain. The interaction may result from either reduced absorption of phenytoin or an increase in the rate of its metabolism and elimination.
Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vinblastine sulfate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side effects. Enhanced toxicity has been reported in patients receiving concomitant erythromycin (see ADVERSE REACTIONS).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Aspermia has been reported in man. Animal studies suggest that teratogenic effects may occur. See WARNINGS 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.
Pregnancy
Teratogenic Effects; Pregnancy Category D
(See WARNINGS). 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 pediatric patients 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 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.
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