VINCRISTINE SULFATE
Chemistry - Commonly referred to as a vinca alkaloid, vincristine sulfate is isolated from the plant
Cantharanthus roseus (Vinca rosea Linn) and occurs as a white or slightly yellow, hygroscopic, amorphous or crystalline powder that is freely soluble in water and slightly soluble in alcohol. Thecommercially available injection has a pH of 3-5.5. Vincristine sulfate has pKas of 5 and 7.4 andmay also be known as leurocristine sulfate or by the initials VCR, or LCR.
Vincristine sulfate is reportedly compatible with the following intravenous solutions and drugs:
D5W, bleomycin sulfate, cytarabine, fluorouracil, and methotrexate sodium. In syringes or at Y-sites with: bleomycin sulfate, cisplatin, cyclophosphamide, doxorubicin HCl, droperidol, fluorouracil, heparin sodium, leucovorin calcium, methotrexate sodium, metoclopramide HCl, mitomycin, and vinblastine sulfate.
Vincristine sulfate is reportedly incompatible with the following solutions or drugs: furosemide.
Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used.
It is suggested to consult specialized references for more specific information (e.g., Handbook on
Injectable Drugs by Trissel; see bibliography).
Vincristine also can induce thrombocytosis (mechanism unknown) and has some immunosuppressant activity.
Uses, Indications - Vincristine is used as an antineoplastic primarily in combination drug protocolsin dogs and cats in the treatment of lymphoid and hematopoietic neoplasms. In dogs, it may be usedalone in the therapy of transmissible venereal neoplasms.
Because vincristine can induce thrombocytosis (at low doses) and has some immunosuppressantactivity, it may also be employed in the treatment of immune-mediated thrombocytopenia.
Vincristine is extensively metabolized, presumably by the liver and is primarily excreted in thebile/feces. Lesser amounts are eliminated in the urine. The elimination half-life in dogs is reportedlybiphasic, with an alpha half-life of 13 minutes and a beta half life of 75 minutes.
Doses of vincristine are recommended to be reduced in patients with hepatic disease, but no clearguidelines have been established as to when, or how much to reduce the dose.
As vincristine may be a skin irritant, gloves and protective clothing should be worn when preparingor administering the medication. If skin/mucous membrane exposure occurs, thoroughly wash areawith soap and water.
Little is known about the effects of vincristine on developing fetuses, but it is believed that the drugpossesses some teratogenic and embryotoxic properties. It may also cause aspermia in males.
Extravasation injuries associated with perivascular injection of vincristine can range from irritationto necrosis and tissue sloughing. Because of the vessicant action of this drug, it is recommended touse a different needle for injecting the drug than the one used to withdraw it from the vial.
Recommendations of therapy for extravasation include discontinuing the infusion immediately atthat site and applying moderate heat to the area to help disperse the drug. Injections ofhyaluronidase have also been suggested to diffuse the drug. Others have suggested to apply ice tothe area to limit the drug's diffusion and minimize the area affected. Topical dimethyl sulfoxide(DMSO) has also been recommended by some to treat the area involved.
Overdosage, Acute Toxicity - In dogs, it is reported that the maximally tolerated dose of vincristine is 0.06 mg/kg every 7 days for 6 weeks. Animals receiving this dose showed signs of slightanemia, leukopenia, increased liver enzymes, and neuronal shrinkage in the peripheral and centralnervous systems.
In cats, the lethal dose of vincristine is reportedly 0.1 mg/kg. Cats receiving toxic doses showedsymptoms of weight loss, seizures, leukopenia, and general debilitation.
In humans, treatment of overdoses of vincristine include supportive care and attempting to preventthe effects associated with the syndrome of inappropriate antidiuretic hormone (fluid restriction andloop diuretics to maintain serum osmolality), anticonvulsants, prevention of ileus, cardiovascular andhematologic monitoring. There have been some reports of leucovorin calcium being used to treatvincristine overdoses in humans, but efficacy of this treatment has not yet been confirmed.
When used with asparaginase, additive neurotoxicity may occur. This is apparently less commonwhen asparaginase is administered after vincristine.
Drug/Laboratory Interactions - Vincristine may significantly increase both blood and urineconcentrations of uric acid.
Cantharanthus roseus (Vinca rosea Linn) and occurs as a white or slightly yellow, hygroscopic, amorphous or crystalline powder that is freely soluble in water and slightly soluble in alcohol. Thecommercially available injection has a pH of 3-5.5. Vincristine sulfate has pKas of 5 and 7.4 andmay also be known as leurocristine sulfate or by the initials VCR, or LCR.
Storage, Stability, Compatibility
Vincristine sulfate injection should be protected from lightand stored in the refrigerator (2-8°C).Vincristine sulfate is reportedly compatible with the following intravenous solutions and drugs:
D5W, bleomycin sulfate, cytarabine, fluorouracil, and methotrexate sodium. In syringes or at Y-sites with: bleomycin sulfate, cisplatin, cyclophosphamide, doxorubicin HCl, droperidol, fluorouracil, heparin sodium, leucovorin calcium, methotrexate sodium, metoclopramide HCl, mitomycin, and vinblastine sulfate.
Vincristine sulfate is reportedly incompatible with the following solutions or drugs: furosemide.
Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used.
It is suggested to consult specialized references for more specific information (e.g., Handbook on
Injectable Drugs by Trissel; see bibliography).
Pharmacology - VINCRISTINE SULFATE
Vincristine apparently binds to microtubular proteins (tubulin) in the mitoticspindle, thereby preventing cell division during metaphase. It also interferes with amino acidmetabolism by inhibiting glutamic acid utilization and preventing purine synthesis, citric acid cycleand urea formation. Tumor resistance to one vinca alkaloid does not imply resistance to another.Vincristine also can induce thrombocytosis (mechanism unknown) and has some immunosuppressant activity.
Uses, Indications - Vincristine is used as an antineoplastic primarily in combination drug protocolsin dogs and cats in the treatment of lymphoid and hematopoietic neoplasms. In dogs, it may be usedalone in the therapy of transmissible venereal neoplasms.
Because vincristine can induce thrombocytosis (at low doses) and has some immunosuppressantactivity, it may also be employed in the treatment of immune-mediated thrombocytopenia.
Pharmacokinetics - VINCRISTINE SULFATE
Vincristine is administered IV as it is unpredictably absorbed from the GItract. After injection it is rapidly distributed to tissues. In humans, approximately 75% is bound totissue proteins and the drug does not appreciably enter the CNS.Vincristine is extensively metabolized, presumably by the liver and is primarily excreted in thebile/feces. Lesser amounts are eliminated in the urine. The elimination half-life in dogs is reportedlybiphasic, with an alpha half-life of 13 minutes and a beta half life of 75 minutes.
Contraindications, Precautions, Reproductive Safety
Vincristine should be used with cautionin patients with hepatic disease, leukopenia, infection, or preexisiting neuromuscular disease.Doses of vincristine are recommended to be reduced in patients with hepatic disease, but no clearguidelines have been established as to when, or how much to reduce the dose.
As vincristine may be a skin irritant, gloves and protective clothing should be worn when preparingor administering the medication. If skin/mucous membrane exposure occurs, thoroughly wash areawith soap and water.
Little is known about the effects of vincristine on developing fetuses, but it is believed that the drugpossesses some teratogenic and embryotoxic properties. It may also cause aspermia in males.
Adverse Effects, Warnings
Although structurally related to, and having a similar mechanism ofaction as vinblastine, vincristine has a different adverse reaction profile. Vincristine is much lessmyelosuppressive (mild leukopenia) at usual doses than is vinblastine, but may cause moreperipheral neurotoxic effects. Neuropathic symptoms may include proprioceptive deficits, spinalhyporeflexia, or paralytic ileus with resulting constipation. In humans, vincristine commonly causesmild sensory impairment and peripheral paresthesias. These may also occur in animals, but are notusually noted due to difficulty in detection. Additional y, in small animals, vincristine may causeincreased liver enzymes, inappropriate ADH secretion, jaw pain, alopecia, stomatitis or seizures.Extravasation injuries associated with perivascular injection of vincristine can range from irritationto necrosis and tissue sloughing. Because of the vessicant action of this drug, it is recommended touse a different needle for injecting the drug than the one used to withdraw it from the vial.
Recommendations of therapy for extravasation include discontinuing the infusion immediately atthat site and applying moderate heat to the area to help disperse the drug. Injections ofhyaluronidase have also been suggested to diffuse the drug. Others have suggested to apply ice tothe area to limit the drug's diffusion and minimize the area affected. Topical dimethyl sulfoxide(DMSO) has also been recommended by some to treat the area involved.
Overdosage, Acute Toxicity - In dogs, it is reported that the maximally tolerated dose of vincristine is 0.06 mg/kg every 7 days for 6 weeks. Animals receiving this dose showed signs of slightanemia, leukopenia, increased liver enzymes, and neuronal shrinkage in the peripheral and centralnervous systems.
In cats, the lethal dose of vincristine is reportedly 0.1 mg/kg. Cats receiving toxic doses showedsymptoms of weight loss, seizures, leukopenia, and general debilitation.
In humans, treatment of overdoses of vincristine include supportive care and attempting to preventthe effects associated with the syndrome of inappropriate antidiuretic hormone (fluid restriction andloop diuretics to maintain serum osmolality), anticonvulsants, prevention of ileus, cardiovascular andhematologic monitoring. There have been some reports of leucovorin calcium being used to treatvincristine overdoses in humans, but efficacy of this treatment has not yet been confirmed.
Drug Interactions
In humans who have previously or simultaneously received mitomycin-Cwith vinca alkaloids, severe bronchospasm has occurred.When used with asparaginase, additive neurotoxicity may occur. This is apparently less commonwhen asparaginase is administered after vincristine.
Drug/Laboratory Interactions - Vincristine may significantly increase both blood and urineconcentrations of uric acid.