Vincristine Sulfate Injections USP

VINCRISTINE SULFATE INJECTION USP

Faulding

Antineoplastic

Action And Clinical Pharmacology: The mode of action of vincristine has not been completely delineated. Evidence is available from in vitro studies that vincristine inhibits spindle formation and is associated with the reversible binding of vincristine to spindle proteins in the S phase. Vincristine has also been found to interfere with RNA synthesis. It has also been shown to stop cell reproduction in metaphase, but it is not known if this effect is related to the above actions.

Following the rapid i.v. administration of vincristine, a triphasic elimination pattern is seen with half-lives of 5 minutes, 2.3 hours and 85±69 hours, respectively. Large interpatient variation occurs in both the terminal elimination half-life and the volume of distribution of vincristine. Vincristine is excreted mainly by way of the liver with about 80% of the dose being recovered in the feces and 10 to 20% in urine. Over 90% of vincristine is distributed into tissue within 15 to 30 minutes after injection, where it is tightly but not irreversibly bound.

Because some patients who are responding to vincristine therapy have CNS leukemia, it has been suggested that the drug dose does not penetrate into cerebrospinal fluid.

Vincristine has not been found to have a consistent or significant influence on platelet count or morphology or red blood cells. If thrombocytopenia is present when treatment with vincristine is initiated the condition may improve prior to the appearance of bone marrow remission.

At the recommended doses of vincristine patients with normal bone marrow function will not develop significant leukopenia.

Indications And Clinical Uses: In the treatment of acute leukemia. It has also been used in combination with other antineoplastic drugs in Hodgkin’s disease, soft-tissue sarcoma, bony-tissue sarcoma, sarcomas of specialized structures, breast cancer, small cell cancer of the lung, cancer of the uterine cervix, malignant melanoma, colorectal cancer, non-Hodgkin’s lymphoma and Wilms’ tumor.

The simultaneous use of several cancer chemotherapy drugs is common practice. Generally drugs with different dose limiting clinical toxicities and different mechanisms of action are selected in order to obtain an increase in therapeutic response without added toxicity. Rarely is it possible to obtain equally as good a response with single antineoplastic agent treatment. Therefore, vincristine is often part of polychemotherapy because at the recommended doses it does not cause a significant suppression of bone marrow or neuropathy.

In children multiple-agent chemotherapy of malignant disease is also common. Vincristine should be considered for use with other oncolytic agents in the treatment of neuroblastoma, osteogenic sarcoma, Ewing’s sarcoma, rhabdomyosarcoma, Wilms’ tumor, Hodgkin’s disease, non-Hodgkin’s lymphomas, embryonal carcinoma of the ovaries and rhabdomyosarcoma of the uterus.

Although not recommended as a primary treatment, vincristine may be useful in the treatment of true idopathic thrombocytopenia purpura which has been shown to be refractory to splenectomy and treatment with steroids. Administration of the recommended dose of vincristine weekly for 3 to 4 weeks has resulted in permanent remission in some patients. However, if no response is obtained after 3 to 6 doses it is unlikely that there will be any beneficial effects with additional administration.

Contra-Indications: There are no contraindications to the administration of vincristine, but careful attention should be given to those conditions listed under Warnings and Precautions. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Caution: Vincristine is a potent drug and should be used only by physicians experienced with cancer chemotherapeutic drugs. Blood counts should be taken once or twice weekly. Discontinue or reduce the dosage upon evidence of abnormal depression of the bone marrow. Vincristine is fatal if given intrathecally; vincristine is for i.v. use only.

Pregnancy: No human or animal data is available which provides information on whether vincristine affects fertility in humans or whether it has teratogenic effects in animals or other adverse effects on the fetus.

Therefore, the physician should weigh the relative benefits of the administration of vincristine against the potential risks before giving the drug to individuals of childbearing age.

Precautions: As with other oncolytics vincristine has been associated with the development of acute uric acid nephropathy. If leukopenia or infection develops the physician should carefully consider whether to administer additional doses of vincristine.

As vincristine does not cross the blood-brain barrier in significant quantities with pre-existing neuromuscular disease and when given with other drugs which have neuromuscular toxic potential, attention should be given to the dose of vincristine used and the development of neurologic side effects.

Avoid contamination of the eyes with vincristine. If accidental contamination occurs, severe irritation or corneal ulceration may result and the eye should immediately be rinsed with copious quantities of water.

Adverse Reactions: Adverse reactions are generally reversible and dose related, with the most common being hair loss and the most troublesome being neuromuscular in origin.

Neuromuscular: There is often a sequence in the development of neuromuscular side effects, with sensory impairment and paresthesias developing initially. Neuritic pain and motor difficulties may develop with continued administration. No agent is known which can reverse the neuromuscular effects of vincristine. Vincristine may cause an exacerbation of the signs and symptoms of pre-existing neurologic disorders.

Convulsions, often with hypertension, have been observed in a few patients given vincristine. As well, ataxia, foot drop, paresthesia and numbness of the digits have been reported.

Gastrointestinal: Upper colon fecal impaction (constipation) may occur but on physical examination, the rectum may be empty. Colic and abdominal pain together with an empty rectum may mislead the clinician. A flat film of the abdomen is useful in diagnosing this condition. High enemas and laxatives are effective treatment for this side effect. It is recommended that routine treatment for constipation be used prophylactically in patients administered vincristine.

Paralytic ileus may also occur, particularly in young children and in the elderly. This condition will reverse itself if vincristine is temporarily discontinued and the patient is given symptomatic care.

Abdominal cramps, vomiting and diarrhea have also been reported.

Renal: In elderly patients with obstructive uropathy, increased urinary retention may occur. If such patients are receiving other medications which may enhance urinary retention, they should be temporarily withdrawn during the first few days of viscristine therapy.

Polyuria and dysuria have been reported.

Hematologic: No consistent or significant effects of vincristine on platelets or red blood cells have been observed. If thrombocytopenia is present when vincristine therapy is initiated, it may actually improve before the development of marrow remission.

At the recommended doses of vincristine, patients with normal bone marrow function will not develop significant leukopenia.

Other: Weight loss, fever, cranial nerve manifestations, oral ulceration and headache have all been reported.

The syndrome resulting from inappropriate antidiuretic hormone secretion has been observed in some patients treated with vincristine. This syndrome has been described in association with several disease states. It includes high urinary sodium excretion together with hyponatremia; renal or adrenal disease, hypotension, dehydration, azotemia, and clinical edema are absent. With fluid deprivation, improvement occurs in the hyponatremia and in the renal loss of sodium.

The side effects of leukopenia, neuritic pain, and constipation which may be associated with the single weekly administration of recommended doses of vincristine are usually of a short duration of less than 7 to 10 days. These reactions may lessen or disappear if the dosage is reduced. The side effects appear to increase when the drug is given in divided doses. Other side effects such as hair loss, sensory loss, paresthesia, slapping gait, difficulty in walking, loss of deep-tendon reflexes and muscle wasting may persist while vincristine therapy is continued. In most instances, these side effects disappear by about the sixth week after stopping vincristine therapy, but neuromuscular signs may persist for prolonged periods in some patients.

After i.v. administration of vincristine, the drug is primarily secreted in the bile after rapid tissue binding. Therefore, in patients with significant liver disease vincristine excretion may be decreased resulting in an increase in the severity of side effects. Hemodialysis is not likely to be of significant value in instances of overdosage as only small quantities of the drug appear in the dialysate.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Because the toxic effects of vincristine are dose related, exaggerated side effects will be experienced in those administered an overdose. Supportive care in the treatment of symptoms should include: prevention of side effects resulting from the syndrome of inappropriate secretion of antidiuretic hormone which would include restriction of fluid intake and possibly the administration of a diuretic with a mechanism of action on the loop of Henle and the distal tubes; administration of anticonvulsant doses of phenobarbital; use of cathartic type laxatives to prevent ileus; monitoring the cardiovascular system; daily blood counts for guidance in transfusion requirements. tag_DosageDosage

Dosage And Administration: Extreme care must be used in calculating and administering the dose of vincristine, since overdosage may have a very serious or fatal outcome.

The drug is given i.v. at weekly intervals.

Adults: The usual dose of vincristine is 1.4 mg/m

Children: The usual dose of vincristine is 2 mg/m

Other dosage schedules have been used.

For children weighing 10 kg or less, the initial dose of vincristine should be 0.05 mg/kg once a week, with careful increasing of dosing thereafter based on effects.

Vincristine should not be administered to patients receiving radiation therapy through ports that include the liver.

When vincristine is used in combination with L-asparaginase, it should be given 12 to 24 hours prior to administration of the enzyme in order to minimize toxicity because L-asparaginase may reduce hepatic clearance of vincristine.

Administration: Vincristine solution may be injected either directly into a vein or into the tubing of an i.v. infusion. Injection of the solution may be completed in about 1 minute.

Caution: It is extremely important to be certain that the needle is properly positioned in the vein before any vincristine is injected. If leakage into the surrounding tissue should occur during i.v. administration of vincristine, it may cause considerable irritation. 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.

Safe Handling: Preparation of Vinca alkaloids, including vincristine, should be done in a biological safety cabinet. Personnel preparing Vinca alkaloids should wear safety glasses. If accidental skin contact occurs, the skin should be washed thoroughly. Incineration temperatures of 1 000°C or more should be sufficient for Vinca alkaloid wastes. If for any reason, a Vinca alkaloid needs to be returned to Faulding (Canada) Inc., proper precautions should be taken in packing these materials for transport.

Vincristine solutions should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Further dilution: The solution may be further diluted with 0.9% sodium chloride injection or 0.5% dextrose injection if desired.

Stability: The further diluted solution must be used within 6 hours if stored at room temperature or 24 hours if refrigerated and protected from light.

Dispensing of Pharmacy Bulk Vials: Pharmacy Bulk Vials contain 1 mg/mL vincristine sulfate in 5 mL of sterile, unpreserved solution (see Supplied).

The availability of Pharmacy Bulk Vials is restricted to hospitals with a recognized i.v. admixture program.

Pharmacy Bulk Vials are intended for multiple dispensing for i.v. use only employing a single puncture (see Safe Handling).

The Pharmacy Bulk Vial content should be dispensed within 8 hours. Any unused solution should be discarded. The diluted solutions prepared from the Pharmacy Bulk Vial should be used within 24 hours, when kept at room temperature, from the time of puncture of the Pharmacy Bulk Vial.

Pharmacy Bulk Vials contain no preservatives. Care must be taken to minimize the potential for inadvertent introduction of microorganisms during manipulation in the hospital environment.

Storage: Store in refrigerator between 2 and 8°C. Protect from light.

Availability And Storage: Pharmacy Bulk Vials: Each mL of sterile, unpreserved solution contains: vincristine sulfate USP 1 mg and mannitol 100 mg. Vials of 5 mL.

Prefilled Syringes: Each mL of solution contains: vincristine sulfate USP 1 mg and mannitol 100 mg. Prefilled syringes of 2 mL.

Vials: Each mL of solution contains: vincristine sulfate USP 1 mg and mannitol 100 mg, with Water for Injection USP. Single-dose, rubber-stoppered vials of 1 and 2 mL.

VINCRISTINE SULFATE INJECTION USP Faulding Antineoplastic

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