V

Vincristine

Trade Names
Oncovin, VCR
 

Classification
Vinca alkaloid, antimicrotubule agent

Category
Chemotherapy drug

Drug Manufacturer
Eli Lilly

Mechanism of Action
 

• Plant alkaloid derived from the periwinkle plant Catharanthus roseus.
• Cell cycle–specific with activity in the mitosis (M) phase.
• Inhibits tubulin polymerization, disrupting formation of microtubule assembly during mitosis. This results in an arrest in cell division, ultimately leading to cell death.
• May also inhibit DNA, RNA, and protein synthesis.

Mechanism of Resistance
 

• Overexpression of the P170 glycoprotein encoded by the multidrug-resistant gene, resulting in enhanced efflux of drug and decreased intracellular drug accumulation. Cross-resistance may be observed with other natural products, such as taxanes, epipodophyllotoxins, anthracyclines, and actinomycin-D.
• Mutations in α- and β-tubulin proteins with decreased affinity to vincristine.

Absorption
Not available for oral use and administered only by the IV route.

Distribution
Widely and rapidly distributed into body tissues within 30 minutes of administration. Poor penetration across the blood-brain barrier and into the CSF.

Metabolism
Metabolized in the liver by the cytochrome P450 microsomal system. The majority of vincristine (80%) is excreted in bile and feces. Only 15%–20% of the drug is recovered in urine. Terminal half-life is long, on the order of 85 hours.

Indications
 

1. Acute lymphoblastic leukemia.
2. Hodgkin's and non-Hodgkin's lymphoma.
3. Multiple myeloma.
4. Rhabdomyosarcoma.
5. Neuroblastoma.
6. Ewing's sarcoma.
7. Wilms' tumor.
8. Chronic leukemias.
9. Thyroid cancer.
10. Brain tumors.
11. Trophoblastic neoplasms.

Dosage Range
 

1. Doses usually vary between 0.5 and 1.4 mg/m². The total individual dose should be limited to 2 mg to prevent the development of neurotoxicity.
2. Continuous infusion: 0.4 mg/day IV continuous infusion for 4 days, as part of the VAD regimen for multiple myeloma.

Drug Preparation
 

• Available in 1, 2, and 5 mg vials at a concentration of 1 mg/mL for IV use.
• Vials should be refrigerated until use.
• Dilute drug in either 0.9% sodium chloride or 5% dextrose.
• Inspect the reconstituted solution for particulate matter and discoloration before administration.

Drug Interaction 1
Drugs metabolized by liver P450 system―Vincristine should be used with caution in patients receiving medications that inhibit drug metabolism via the hepatic cytochrome P450 system.

Drug Interaction 2
Phenytoin―Vincristine reduces the blood levels of phenytoin and its subsequent efficacy through either reduced absorption of phenytoin or an increase in the rate of its metabolism and/or elimination.

Drug Interaction 3
Digoxin―Vincristine reduces the blood levels of digoxin resulting in decreased efficacy.

Drug Interaction 4
Cisplatin and paclitaxel―Concurrent administration of vincristine with other neurotoxic agents such as cisplatin and paclitaxel may increase the risk and severity of neurotoxicity.

Drug Interaction 5
L-Asparaginase―When used in combination with L-asparaginase, vincristine should be administered 12–24 hours before L-asparaginase as L-asparaginase inhibits vincristine clearance.

Drug Interaction 6
Methotrexate―Vincristine increases the cellular uptake of methotrexate resulting in enhanced antitumor activity and host toxicity.

Drug Interaction 7
Filgrastim―Concurrent use of vincristine with filgrastim may result in severe atypical neuropathy.

Special Considerations
 

1. Use with caution in patients with abnormal liver function as increased toxicity may be observed. Dose reduction is necessary in this setting.
2. Vincristine should be infused as a rapid push over 1 minute in a side port of a free-flowing IV line to avoid extravasation. If extravasation occurs, the infusion should be discontinued immediately. Application of ice to the area of leakage along with elevation of involved extremity may minimize discomfort and the possibility of cellulitis. In severe cases, a plastic surgeon should be consulted.
3. Contamination of the eye may lead to severe irritation and even corneal ulceration. If accidental contamination occurs, the eyes should be washed immediately and thoroughly.
4. Patients should be warned about the risk of constipation upon starting therapy, and a bowel regimen including stool softeners and high-fiber diet should be initiated. Patients should be advised to seek medical attention if persistent nausea, vomiting, and abdominal pain develop after beginning therapy.
5. Careful baseline neurologic evaluation should be performed before starting therapy and at the start of each cycle. The onset of severe signs and/or symptoms of neurotoxicity warrants immediate discontinuation of the drug. Avoid the simultaneous use of drugs associated with neurologic toxicity. Risk factors for neurotoxicity include elderly patients and those with preexisting neuropathies and/or neuromuscular disorders.
6. Overdose of vincristine may be treated with leucovorin 100 mg IV every 3 hours for the first 24 hours and then every 6 hours for 48 hours. Other supportive measures should be considered, including prevention of SIADH; use of anticonvulsants, enemas, or cathartics to prevent ileus; monitoring of the cardiovascular system; and monitoring of CBC.
7. Pregnancy category D. Not known if excreted in milk.

Toxicity 1
Neurotoxicity. Most commonly observed dose-limiting toxicity. Clinical manifestations are variable, and include peripheral neuropathy (paresthesias, paralysis, and loss of deep tendon reflexes), autonomic nervous system dysfunction (orthostasis, sphincter problems, and paralytic ileus), cranial nerve palsies, ataxia, cortical blindness, seizures, and coma. Bone, back, limb, jaw, and parotid gland pain may also occur.
 

Toxicity 2
Constipation, abdominal pain, and paralytic ileus are common. A prophylactic bowel regimen for constipation is recommended. Nausea, vomiting, and diarrhea can also occur, but are rare.
 

Toxicity 3
Alopecia, skin rash, and fever.
 

Toxicity 4
Vesicant. Extravasation may cause local tissue injury, inflammation, and necrosis.
 

Toxicity 5
Myelosuppression. Generally mild and much less significant than with vinblastine.
 

Toxicity 6
Syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
 

Toxicity 7
Hypersensitivity reactions.
 

Toxicity 8
Azoospermia and amenorrhea may be permanent.