VINCASAR PFS- vincristine sulfate injection, solution
Teva Parenteral Medicines, Inc.
WARNINGS
Caution-This preparation should be administered by individuals experienced in the administration of VINCASAR PFS. It is extremely important that the intravenous needle or catheter be properly positioned before any vincristine is injected. Leakage into surrounding tissue during intravenous administration of VINCASAR PFS 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 OVERDOSAGE section for the treatment of patients given intrathecal VINCASAR PFS.
DESCRIPTION
VINCASAR PFS (vincristine sulfate injection USP) is vincaleukoblastine, 22-oxo-, sulfate (1:1) (salt). It is the salt of an alkaloid obtained from a common flowering herb, the periwinkle plant (Vinca rosea Linn). Originally known as leurocristine, it has also been referred to as LCR and VCR.
C46 H56 N4 O10 �H2 SO4 M.W. 923.04
Vincristine Sulfate, USP is a white to slightly yellow powder. It is soluble in methanol, freely soluble in water, but only slightly soluble in 95% ethanol. In 98% ethanol, vincristine sulfate, USP has an ultraviolet spectrum with maxima at 221 nm (? +47,100).
VINCASAR PFS (vincristine sulfate injection USP) is a sterile, preservative-free, single use only solution available for intravenous use in 1 mg (1 mg/1 mL) and 2 mg (2 mg/2 mL) vials. Each mL contains vincristine sulfate, USP, 1 mg (1.08 �mol); mannitol, 100 mg; and water for injection USP, qs. Acetic acid and sodium acetate have been added for pH control. The pH of VINCASAR PFS ranges from 3.5 to 5.5. This product is a sterile solution for cancer/oncolytic use.
CLINICAL PHARMACOLOGY
The mechanisms of action of vincristine sulfate remain under investigation. The mechanism of action of vincristine sulfate has been related to the inhibition of microtubule formation in mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage.
Central nervous system leukemia has been reported in patients undergoing otherwise successful therapy with vincristine sulfate. This suggests that vincristine does not penetrate well into the cerebrospinal fluid.
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 5 minutes, 2.3 hours, and 85 hours respectively; however, the range of the terminal half-life in humans is from 19 to 155 hours. The liver is the major excretory organ in humans and animals. 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 (see PRECAUTIONS). About 80% of an injected dose of vincristine sulfate appears in the feces and 10% to 20% can be found in the urine. Within 15 to 30 minutes after injection, over 90% of the drug is distributed from the blood into tissue, where it remains tightly, but not irreversibly, bound.
Current principles of cancer chemotherapy involve the simultaneous use of several agents. Generally, each agent used has a unique toxicity and mechanism of action so that therapeutic enhancement occurs without additive toxicity. It is rarely possible to achieve equally good results with single-agent methods of treatment. Thus, vincristine sulfate is often chosen as part of polychemotherapy because of lack of significant bone-marrow suppression (at recommended doses) and of unique clinical toxicity (neuropathy). See DOSAGE AND ADMINISTRATION section for possible increased toxicity when used in combination therapy.
INDICATIONS AND USAGE
VINCASAR PFS is indicated in acute leukemia.
VINCASAR PFS has also been shown to be useful in combination with other oncolytic agents in Hodgkin�s disease, non-Hodgkin�s malignant lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms� tumor.
DOSAGE AND ADMINISTRATION
This preparation is for intravenous use only (see WARNINGS).
Neurotoxicity appears to be dose related. Extreme care must be used in calculating and administering the dose of VINCASAR PFS , since overdosage may have a very serious or fatal outcome.
The usual dose of VINCASAR PFS for pediatric patients is 1.5 to 2 mg/m2. For pediatric patients weighing 10 kg or less, the starting dose should be 0.05 mg/kg, administered once a week. The usual dose of VINCASAR PFS for adults is 1.4 mg/m2. A 50% reduction in the dose of VINCASAR PFS is recommended for patients having a direct serum bilirubin value above 3 mg/100 mL.
The drug is administered intravenously at weekly intervals.
TO REDUCE THE POTENTIAL FOR FATAL MEDICATION ERRORS DUE TO INCORRECT ROUTE OF ADMINISTRATION, VINCASAR PFS SHOULD BE DILUTED IN A FLEXIBLE PLASTIC CONTAINER AND PROMINENTLY LABELED FOR INTRAVENOUS USE ONLY (see WARNINGS).
The concentration of VINCASAR PFS is 1 mg/mL. Do not add extra fluid to the vial prior to removal of the dose. Withdraw the solution of VINCASAR PFS into an accurate dry syringe, measuring the dose carefully. Do not add extra fluid to the vial in an attempt to empty it completely.
Preparation for flexible plastic container
VINCASAR PFS when diluted with 0.9% sodium chloride injection in concentrations from 0.0015 mg/mL to 0.08 mg/mL is stable for up to 24 hours when protected from light or 8 hours under normal light at 25�C.
Preparation for syringe
Special Dispensing Information
When dispensing VINCASAR PFS in a syringe, it is imperative that it be packaged in the provided overwrap which bears the following statement: �DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FOR INTRAVENOUS USE ONLY � FATAL IF GIVEN BY OTHER ROUTES" (see WARNINGS). A syringe containing a specific dose must be labeled, using the auxiliary sticker provided, to state: �FOR INTRAVENOUS USE ONLY � FATAL IF GIVEN BY OTHER ROUTES."
Caution: It is extremely important that the intravenous needle or catheter be properly positioned before any vincristine is injected. Leakage into surrounding tissue during intravenous administration of VINCASAR PFS 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 will help disperse the drug and may minimize discomfort and the possibility of cellulitis.
VINCASAR PFS must be administered via an intact, free-flowing intravenous needle or catheter. Care should be taken that there is no leakage or swelling occurring during administration (see boxed WARNINGS).
The solution may be injected either directly into a vein or into the tubing of a running intravenous infusion (see Drug Interactions below). Injection of VINCASAR PFS should be accomplished within 1 minute.
Patients Receiving Radiation Therapy
VINCASAR PFS should not be given to patients while they are receiving radiation therapy through ports that include the liver. When VINCASAR PFS is used in combination with L-asparaginase, VINCASAR PFS should be given 12 to 24 hours before administration of the enzyme in order to minimize toxicity; administering L-asparaginase before VINCASAR PFS may reduce hepatic clearance of vincristine.
Drug Interactions
VINCASAR PFS should not be diluted in solutions that raise or lower the pH outside the range of 3.5 to 5.5. It should not be mixed with anything other than normal saline or glucose in water.
Whenever solution and container permit, parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Handling and Disposal
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate
