Vincristine Sulfate

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 vincristine sulfate injection (vincristine sulfate) usually results in death. Syringes containing this product should be labeled, using the auxiliary sticker provided, to state “FATAL IF GIVEN INTRATHECALLY. FOR INTRAVENOUS USE ONLY.”

Extemporaneously prepared syringes containing this product must be packaged in an overwrap which is labeled “DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FATAL IF GIVEN INTRATHECALLY. FOR INTRAVENOUS USE ONLY.”

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.

Pregnancy Category D - 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 child-bearing potential should be advised to avoid becoming pregnant.

• Cancer
• Multiple Myeloma

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.131

• Care must be taken to avoid contact with the eyes as severe irritation and possibly corneal ulceration (especially if administered under pressure) can result; if contact occurs, immediately wash eyes with copious amounts of water.131

• Prophylactic regimen for constipation recommended for all patients receiving the drug.131

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer IV only by individuals experienced in the administration of the drug.131

Very irritating; must not administer IM, sub-Q, or intrathecally.131 Intrathecal administration almost always results in death.131 (See Boxed Warning.)

Management of patients mistakenly receiving intrathecal vincristine is a medical emergency.131 (See Intrathecal Administration under Cautions.)

Administer by IV injection, usually at weekly intervals.131 Inject appropriate quantity of solution either directly into a large central vein or into tubing of a running IV infusion of 0.9% sodium chloride or 5% dextrose injection.131

Has been administered as a slow IV infusion†.105 108 114 115 116 117

Extremely important to ensure that needle or catheter is securely within vein to avoid extravasation.131

If leakage occurs, discontinue injection immediately and administer remainder of dose through another vein; local treatment of the area may minimize discomfort and the possibility of cellulitis.131 HID (See Boxed Warning and also Local Effects under Cautions.)

Do not add extra fluid to vial prior to removal of dose or in an attempt to empty vial completely; withdraw solution into accurate dry syringe.131

It is recommended that vincristine doses be prepared as a diluted solution in a minibag or a 30-mL syringe to prevent inadvertent intrathecal administration of the drug.198 199 200

For adults, dilute the dose in 25 or 50 mL of 0.9% sodium chloride solution in a small-volume IV bag (i.e., minibag);198 199 alternatively, the dose may be diluted in 20 mL of 0.9% sodium chloride solution in a 30-mL syringe.199

For children, dilute the dose in a smaller volume of 0.9% sodium chloride solution in a small-volume IV bag.198

If prepared in a minibag or diluted in a 30 mL syringe, administer by IV injection over 5-10 minutes in adults; in children, administer at a slower rate.198

If administered undiluted, inject appropriate quantity of solution directly into a vein or into the tubing of a free-flowing infusion over a 1-minute period.131 HID

When diluted in a large volume of IV solution, has been administered as a slow IV infusion† (e.g., over 4–8 hours);108 114 continuous 4- or 5-day IV infusions† have also been used.105 115 116 117 Consult specialized references for specific information on slow IV infusion.a

To decrease pressure applied to the veins, experts recommend notusing an IV pump for vesicant drugs such as vincristine when administered by short infusion into a peripheral vein.201 202

When dispensing, must label syringe or container holding the individual dose with the statement: “Warning: Fatal if given intrathecally. For intravenous use only.”131 133

Enclose container or syringe holding the individual dose in an overwrap (e.g., plastic bag or similar wrap with typed label) bearing the statements: “Do not remove covering until moment of injection. Fatal if given intrathecally. For intravenous use only.”131 132 133 (See Intrathecal Administration under Cautions.)

Consider additional measures to prevent inadvertent intrathecal administration, including administering diluted vincristine solutions in minibags; preparing the medication at the time of administration; attaching a unique filter; dispensing separately from all other medications; dispensing directly to the individual who is administering the drug; conducting an independent check of the dose and route of administration for the drug both at the time of preparation and prior to administration; and administering vincristine in a separate room from rooms where intrathecal medications are administered.200

Dosage

Available as vincristine sulfate; dosage expressed in terms of the salt.131

Consult published protocols for the dosage of vincristine sulfate and other chemotherapeutic agents and the method and sequence of administration.a

Small daily doses are not recommended because they produce severe toxicity with no added therapeutic benefit.a

Pediatric Patients

In patients receiving asparaginase concomitantly, administer vincristine 12–24 hours before administration of asparaginase to minimize toxicity.131 (See Specific Drugs under Interactions.)

Do not administer while patient is receiving radiation therapy through ports that include the liver.131

Children weighing ≤10 kg: Initially, 0.05 mg/kg at weekly intervals.131 a

Children weighing >10 kg: Usually, 1.5–2 mg/m2 at weekly intervals.131

Determine subsequent doses by clinical and hematologic response and patient tolerance to obtain optimum therapeutic results with minimum adverse effects.a

Monitor carefully (e.g., history, physical examination) for neurologic toxicity.131 Dosage reduction may be necessary in preexisting neuromuscular disease or when other agents with neurotoxic potential are used.131 Some adverse neurologic effects (e.g., neuritic pain, constipation) may lessen or disappear when dosage is reduced.131

Perform CBC before administration of each dose; consider withholding next dose in patients with leukopenia or infectious complications.131 Leukopenia may lessen or disappear when the dosage of vincristine is reduced.131

Discontinue vincristine therapy in patients who develop progressive dyspnea.131

Adults

In patients receiving asparaginase concomitantly, administer vincristine 12–24 hours before administration of asparaginase to minimize toxicity.131 (See Specific Drugs under Interactions.)

Do not administer while patient is receiving radiation therapy through ports that include the liver.131

Usually, 1.4 mg/m2 at weekly intervals.131

Determine subsequent doses by clinical and hematologic response and patient tolerance to obtain optimum therapeutic results with minimum adverse effects.a

Monitor carefully (e.g., history, physical examination) for neurologic toxicity.131 Dosage reduction may be necessary in preexisting neuromuscular disease or when other agents with neurotoxic potential are used.131 Some adverse neurologic effects (e.g., neuritic pain, constipation) may lessen or disappear when dosage is reduced.131

Perform CBC before administration of each dose; consider withholding next dose in patients with leukopenia or infectious complications.131 Leukopenia may lessen or disappear when the dosage of vincristine is reduced.131

Discontinue vincristine therapy in patients who develop progressive dyspnea.131

Prescribing Limits

Adults

Maximum 2-mg dose recommended by some clinicians.a

Special Populations

Hepatic Impairment

In patients with a direct serum bilirubin concentration >3 mg/dL or other evidence of significant hepatic impairment, a 50% dose reduction recommended.131

Contraindications

• Demyelinating form of Charcot-Marie-Tooth syndrome.131

Warnings/Precautions

Warnings

Fatal if administered intrathecally; management of patients mistakenly receiving intrathecal vincristine is a medical emergency.131

Prognosis to date generally has been poor despite immediate efforts to remove spinal fluid and flush with lactated Ringer’s injection and other solutions, with such efforts failing to prevent ascending paralysis and death in almost all cases.131

In one adult patient, progression of paralysis was stopped when treatment was initiated immediately after inadvertent intrathecal injection of vincristine.131

Treatment consisted of immediate removal of as much CSF as safely possible via lumbar access, followed by flushing of the subarachnoid space with lactated Ringer’s solution infused continuously at a rate of 150 mL/hour through a catheter in a cerebral lateral ventricle and removal of fluid through a lumbar access.131

As soon as available, fresh frozen plasma (25 mL) diluted in 1 L of lactated Ringer’s solution was infused through the cerebral ventricular catheter at a rate of 75 mL/hour with removal of fluid through the lumbar access.131 The rate of infusion was adjusted to maintain a CSF protein concentration of 150 mg/dL.131 Glutamic acid was administered in a dose of 10 g given IV over 24 hours, followed by 500 mg orally 3 times daily for 1 month or until stabilization of neurologic status.131 134 The role of glutamic acid in this treatment is uncertain.131

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.131 Avoid pregnancy during therapy.131 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.131

Do not administer while patient is receiving radiation therapy through ports that include the liver.131

Sensitivity Reactions

Allergic reactions126 129 131 (i.e., anaphylaxis,126 131 rash,131 edema131 ) temporally related to vincristine therapy reported in patients receiving the drug as part of combination chemotherapy regimens.126 129 131

Major Toxicities

Major and dose-limiting adverse effect; severity may vary greatly among patients.a

Adverse neuromuscular effects often occur in a sequence with early development of sensory impairment and paresthesia followed by neuritic pain and motor difficulties as therapy is continued.131

Most frequent manifestation is peripheral (mixed sensorimotor) neuropathy; occurs in nearly every patient.a

Earliest and most consistent peripheral neuropathy indication is asymptomatic depression of the Achilles reflex; loss of other deep tendon reflexes occurs in most patients after ≥3 weekly doses and peripheral paresthesias, especially numbness, pain, and tingling, are common.a

Wrist drop, foot drop, cranial nerve palsy, atrophy, cramps, ataxia, slapping gait, and difficulty in walking or inability to walk may occur if prolonged or high-dose therapy is given.a

Cranial nerve palsies may account for headaches and jaw pain; jaw pain usually occurs within 24 hours after the first and/or second dose of vincristine and rarely recurs.a Pain in other areas (e.g., pharyngeal, parotid gland, bone, back, limb) and myalgia have been reported and may be severe.131

Cranial nerve palsies and muscular weakness involving the larynx may produce hoarseness and vocal cord paresis, including potentially life-threatening bilateral vocal cord paralysis; those involving extrinsic eye muscles may cause ptosis, double vision, and optic and extraocular neuropathy.a Optic atrophy with blindness or transient cortical blindness has been reported.131

Peripheral neuritis (both mononeuritis and polyneuritis) and neuralgia also occur frequently.a

Autonomic toxicity (e.g., severe constipation or obstipation and abdominal cramps) may occur; a adynamic ileus occurs frequently, especially in young children.a Constipation may take the form of upper-colon impaction; a flat abdominal film may be used to facilitate diagnosis so the physician is not misled by presentation of colicky abdominal pain coupled with an empty rectum.131 May treat constipation with high enemas and laxatives;131 a routine prevention regimen (e.g., laxatives, enemas) usually is recommended.131 Constipation usually persists <7 days with once weekly dose administration;131 in children, abdominal cramps and adynamic ileus usually also disappear in ≤1 week.a

Urinary tract disturbances (e.g., bladder atony, incontinence, urinary retention, nocturia, oliguria, dysuria, polyuria) have also been reported.a Whenever possible, discontinue other drugs causing urinary retention during the first few days after administration of vincristine, particularly in geriatric patients.131

Other autonomic effects include orthostatic hypotension, abnormal Valsalva response, defective sweating, and myoclonic jerks.a

CNS effects (e.g., altered consciousness, depression, agitation, insomnia, hallucinations, seizures [often with hypertension], progressive encephalopathy, respiratory difficulties, coma) have occurred.a Seizures followed by coma have been reported in several pediatric patients.131

Neurotoxic effects may be additive with those of other neurotoxic agents and spinal cord irradiation.a Use with caution and monitor dosage and toxicity in patients receiving other neurotoxic drugs or in those with preexisting neuromuscular disease.a

General Precautions

Highly toxic drug with a low therapeutic index; therapeutic response is not likely to occur without some evidence of toxicity.a Administer only under constant supervision of clinicians experienced in therapy with cytotoxic agents.a

Hyperuricemia may result from extensive purine catabolism accompanying rapid cellular destruction in some patients receiving vincristine, especially those with non-Hodgkin’s lymphomas or leukemia.a In some patients, uric acid nephropathy may result.131 Monitor serum uric acid concentrations frequently during first 3–4 weeks of therapy; take appropriate measures to prevent hyperuricemia related to rapid leukemic cell lysis.131 Minimize hyperuricemic effects by adequate hydration, alkalinization of the urine, and/or administration of allopurinol.a

Anemia, leukopenia, and thrombocytopenia have been reported.131 Use caution in presence of leukopenia or complicating infection.131

Hematologic toxicity produced by vincristine is less than that produced by most other antineoplastic agents.a

Manufacturers recommend that CBC be performed before each dose.131

Thrombocytopenia (if present when therapy is initiated) may improve before appearance of bone marrow remission.a

If CNS leukemia is diagnosed, additional chemotherapy agents may be required; vincristine does not cross blood-brain barrier in adequate amounts.131

Acute shortness of breath and bronchospasm, which can be severe or life threatening, have occurred; reported most frequently when mitomycin was administered concomitantly.131

Such reactions may occur a few minutes to several hours after administration of a vinca alkaloid, or up to 2 weeks after mitomycin dose.131

Progressive dyspnea, which may require chronic therapy, can occur in patients receiving vincristine; do not readminister to these patients.131

Hypertension and hypotension reported.131 CAD131 and MI124 127 128 130 131 have occurred in patients receiving vincristine in combination with other antineoplastic agents but causal relationship not established;131 some patients who developed MI had previously received radiation to the mediastinal area, but MI also reported in patients with no history of radiation to mediastinal area or risk factors for CAD.124 128 130

Tissue irritant; may cause phlebitis and necrosis.a Extravasation can result in pain and cellulitis.a

Manufacturers state that local injection of hyaluronidase and application of moderate heat may decrease local reactions resulting from extravasation;131 however, some clinicians prefer to treat extravasation with cold compresses, dilution with 0.9% sodium chloride injection or infiltration of sodium bicarbonate (5 mL of 8.4% injection), and/or local injection of hydrocortisone.a

Eighth cranial nerve damage, which may be evident as vestibular manifestations (e.g., dizziness, nystagmus, vertigo) and by auditory manifestations (e.g., varying degrees of hearing impairment including partial or total deafness) that may be temporary or permanent, reported in patients receiving vinca alkaloids.131

Use vincristine concomitantly with other potentially ototoxic drugs (e.g., platinum-containing antineoplastic agents) with extreme caution.131 (See Specific Drugs under Interactions.)

Vincristine-induced alopecia is common; reversible with discontinuance and in some cases, hair may regrow during maintenance therapy.131

Specific Populations

Category D.131 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Not known whether vincristine or its metabolites are distributed into milk. Discontinue nursing or the drug.131

Use with caution and reduce dosage in patients with obstructive jaundice or other substantial hepatic impairment.a (See Hepatic Impairment under Dosage and Administration)

Common Adverse Effects

Asymptomatic depression of the Achilles reflex, loss of deep tendon reflexes, peripheral paresthesias (numbness, pain, and tingling), hair loss, leukopenia, neuritic pain, constipation, sensory loss, wrist drop, foot drop, cranial nerve palsy, atrophy, cramps, ataxia, difficulty walking, inability to walk, slapping gait, muscle wasting, cranial nerve palsies, headache, jaw pain.131

• Mechanism of action not fully elucidated; vincristine and other vinca alkaloids exert cytotoxic effects by binding to tubulin, the protein subunit of the microtubules that form the mitotic spindle.135 140

• Formation of vincristine-tubulin complexes prevents polymerization of the tubulin subunits into microtubules, induces depolymerization of microtubules resulting in inhibition of microtubule assembly and cellular metaphase arrest.135

• In high concentrations, also exerts complex effects on nucleic acid and protein synthesis.a

• Exerts some immunosuppressive activity.a

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name