Rx only

PRESERVATIVE FREE SOLUTION

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. The structural formula is as follows:

C46H56N4O10•H2SO4 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-dose only solution available for intravenous use in 2 mL (1 mg and 2 mg) vials. Each mL contains vincristine sulfate USP, 1 mg (1.08 µmol); mannitol, 100 mg; and water for injection, 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.

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.

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.

Patients with the demyelinating form of Charcot-Marie-Tooth syndrome should not be given VINCASAR PFS. Careful attention should be given to those conditions listed under WARNINGS and PRECAUTIONS.

This preparation is for intravenous use only. It should be administered by individuals experienced in the administration of vincristine sulfate injection. The intrathecal administration of VINCASAR PFS (vincristine sulfate injection) usually results in death.

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 as indicated for “FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.”

See OVERDOSAGE section for the treatment of patients given intrathecal VINCASAR PFS.

Pregnancy

Vincristine sulfate can cause fetal harm when administered to a pregnant woman. When pregnant mice and hamsters were given doses of vincristine sulfate that caused resorption of 23% to 85% of fetuses, fetal malformations were produced in those that survived. Five monkeys were given single doses of vincristine sulfate between days 27 and 34 of their pregnancies; 3 of the fetuses were normal at term, and 2 viable fetuses had grossly evident malformations at term. In several animal species, vincristine sulfate can induce teratogenesis as well as embryo death at doses that are nontoxic to the pregnant animal. 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.

Prior to the use of this drug, patients and/or their parents/guardian should be advised of the possibility of untoward symptoms.

In general, adverse reactions are reversible and are related to dosage. The most common adverse reaction is hair loss; the most troublesome adverse reactions are neuromuscular in origin.

When single, weekly doses of the drug are employed, the adverse reactions of leukopenia, neuritic pain, and constipation occur but are usually of short duration (i.e., less than 7 days). When the dosage is reduced, these reactions may lessen or disappear. The severity of such reactions seems to increase when the calculated amount of drug is given in divided doses. Other adverse reactions, such as hair loss, sensory loss, paresthesia, difficulty in walking, slapping gait, loss of deep-tendon reflexes, and muscle wasting, may persist for at least as long as therapy is continued. Generalized sensorimotor dysfunction may become progressively more severe with continued treatment. Although most such symptoms usually disappear by about the sixth week after discontinuance of treatment, some neuromuscular difficulties may persist for prolonged periods in some patients. Regrowth of hair may occur while maintenance therapy continues.

The following adverse reactions have been reported:

Hepatic veno-occlusive disease has been reported in patients receiving vincristine, particularly in pediatric patients, as part of standard combination chemotherapy regimens. Some of the patients had fatal outcomes; some who survived had undergone liver transplantation.

Side effects following the use of VINCASAR PFS are dose related. In pediatric patients under 13 years of age, death has occurred following doses of vincristine sulfate that were 10 times those recommended for therapy. Severe symptoms may occur in this patient group following dosages of 3 to 4 mg/m2. Adults can be expected to experience severe symptoms after single doses of 3 mg/m2 or more (see ADVERSE REACTIONS). Therefore, following administration of doses higher than those recommended, patients can be expected to experience exaggerated side effects. Supportive care should include the following: (1) prevention of side effects resulting from the syndrome of inappropriate antidiuretic hormone secretion (preventive treatment would include restriction of fluid intake and perhaps the administration of a diuretic affecting the function of Henle’s loop and the distal tubule); (2) administration of anticonvulsants; (3) use of enemas or cathartics to prevent ileus (in some instances, decompression of the gastrointestinal tract may be necessary); (4) monitoring the cardiovascular system; (5) determining daily blood counts for guidance in transfusion requirements.

Folinic acid has been observed to have a protective effect in normal mice that were administered lethal doses of vincristine sulfate (Cancer Res 1963;23:1390). Isolated case reports suggest that folinic acid may be helpful in treating humans who have received an overdose of vincristine sulfate. It is suggested that 100 mg of folinic acid be administered intravenously every 3 hours for 24 hours and then every 6 hours for at least 48 hours. Theoretically (based on pharmacokinetic data), tissue levels of vincristine sulfate can be expected to remain significantly elevated for at least 72 hours. Treatment with folinic acid does not eliminate the need for the above mentioned supportive measures.

Most of an intravenous dose of vincristine is excreted into the bile after rapid tissue binding (see CLINICAL PHARMACOLOGY). Because only very small amounts of the drug appear in dialysate, hemodialysis is not likely to be helpful in cases of overdosage. An increase in the severity of side effects may be experienced by patients with liver disease that is severe enough to decrease biliary excretion.

Enhanced fecal excretion of parenterally administered vincristine has been demonstrated in dogs pretreated with cholestyramine. There are no published clinical data on the use of cholestyramine as an antidote in humans.

There are no published clinical data on the consequences of oral ingestion of vincristine. Should oral ingestion occur, the stomach should be evacuated. Evacuation should be followed by oral administration of activated charcoal and a cathartic.

Treatment of patients following intrathecal administration of vincristine sulfate injection has included immediate removal of spinal fluid and flushing with Lactated Ringer’s, as well as other solutions and has not prevented ascending paralysis and death. In one case, progressive paralysis in an adult was arrested by the following treatment initiated immediately after the intrathecal injection:

1. As much spinal fluid was removed as could be safely done through lumbar access.
   
   
2. The subarachnoid space was flushed with Lactated Ringer’s solution infused continuously through a catheter in a cerebral lateral ventricle at the rate of 150 mL/h. The fluid was removed through a lumbar access.
   
   
3. As soon as fresh frozen plasma became available, the fresh frozen plasma, 25 mL, diluted in 1 L of Lactated Ringer’s solution was infused through the cerebral ventricular catheter at the rate of 75 mL/h with removal through the lumbar access. The rate of infusion was adjusted to maintain a protein level in the spinal fluid of 150 mg/dL.
   
   
4. Glutamic acid, 10 g, was given intravenously over 24 hours followed by 500 mg 3 times daily by mouth for 1 month or until neurological dysfunction stabilized. The role of glutamic acid in this treatment is not certain and may not be essential.

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 AS INDICATED FOR INTRAVENOUS USE ONLY-FATAL IF GIVEN BY OTHER ROUTES (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, USP 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.

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 diluted vincristine sulfate injection may be infused via a flexible plastic container directly into an intravenous catheter/needle or into a running intravenous infusion (see Drug Interactions below).

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.

VINCASAR PFS (vincristine sulfate injection, USP), preservative free solution is supplied as follows:

This product should be refrigerated. Discard unused solution. Protect from light and retain in carton until time of use. Store upright.

Store under refrigeration between 2° to 8°C (36° to 46°F).

1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

Distributed by:

Teva Pharmaceuticals USA, Inc.

Parsippany, NJ 07054

Rev. G 9/2020

Vincasar PFS®

(vinCRIStine sulfate

injection, USP)

PRESERVATIVE FREE SOLUTION

1 mg/mL

FOR INTRAVENOUS USE ONLY

FATAL IF GIVEN BY OTHER ROUTES

Caution: Cytotoxic Agent

1 mL Single-Dose Vial

REFRIGERATE

Protect From Light

TEVA

Vincasar PFS®

(vinCRIStine sulfate

injection, USP)

PRESERVATIVE FREE SOLUTION

2 mg/2 mL

(1 mg/mL)

FOR INTRAVENOUS USE ONLY

FATAL IF GIVEN BY OTHER ROUTES

Caution: Cytotoxic Agent

2 mL Single-Dose Vial

REFRIGERATE

Protect From Light

TEVA