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Vincristine Sulfate

Class: Antineoplastic Agents
VA Class: AN900
CAS Number: 2068-78-2
Brands: Marqibo

Medically reviewed on Oct 15, 2018

Warning

    Administration Route Warnings
  • For IV use only.131 204

  • Fatal if given by other routes.131 204 (See Intrathecal Administration under Cautions.)

  • To reduce the risk of fatal medication errors due to incorrect administration route, dilute conventional vincristine in a minibag;131 prominently label minibags or syringes containing the drug as being for IV use only.131 (See IV Administration of Conventional Vincristine under Dosage and Administration.)

    Extravasation
  • Extremely important to properly place IV needle or catheter before any vincristine is injected.131

  • Leakage into surrounding tissues may cause considerable irritation.131

  • Discontinue immediately if leakage occurs; administer remainder of the dose through another vein.131

  • Local treatment of leakage area (e.g., with hyaluronidase injection, application of moderate heat) may help disperse vincristine and minimize discomfort and possibility of cellulitis.131

    Limit to Qualified Personnel
  • For administration only by individuals experienced in the administration of vincristine.131

    Accidental Substitution
  • Liposomal and conventional formulations of vincristine have different dosages; verify drug name and dosage prior to preparation and administration.204

Introduction

See also: Xospata

Antineoplastic agent; vinca alkaloid.a 135 140

Uses for Vincristine Sulfate

Acute Lymphocytic Leukemia

Conventional vincristine: Component of combination chemotherapeutic regimens for the induction of remissions of childhood or adult acute lymphocytic (lymphoblastic) leukemia (ALL).136 141 142 143 144 145

Conventional vincristine: In non-high-risk childhood ALL, combination therapy with vincristine, an asparaginase preparation, and a corticosteroid (dexamethasone or prednisone) is used as an induction regimen.141 Intensive induction regimens with ≥4 drugs, including vincristine, an anthracycline (e.g., daunorubicin), an asparaginase preparation, and a corticosteroid, with or without cyclophosphamide, may improve event-free survival but cause greater toxicity.136 141 143 Some clinicians reserve 4- or 5-drug regimens for patients with high-risk childhood ALL;136 141 143 others elect to use such regimens for all patients with childhood ALL regardless of presenting features.141

Conventional vincristine: In adults, induction regimens typically include vincristine, prednisone, and an anthracycline; some regimens also add other drugs (e.g., an asparaginase preparation, cyclophosphamide).142

Liposomal vincristine: Used as a single agent for treatment of Philadelphia chromosome-negative (Ph) relapsed or refractory ALL in patients in second or greater relapse or in those whose disease has progressed following ≥2 prior therapies (designated an orphan drug by FDA for this condition214 ).204 205

Various drugs have been used for combination chemotherapy,136 141 142 143 144 145 and comparative efficacy of these regimens is continually being evaluated.141 142 143 144 145

Acute Myeloid Leukemia

Conventional vincristine: In various combination regimens for the treatment of acute myeloid (myelogenous, nonlymphocytic) leukemias (AML, ANLL),136 but the comparative efficacy of these combinations is continually being evaluated.a

Conventional vincristine: Component of second-line regimens for induction in AML.136

Hodgkin’s Disease

Conventional vincristine: Component of various chemotherapeutic regimens for Hodgkin’s disease;131 136 139 comparative efficacy of various regimens is continually being evaluated.137 138 139

Conventional vincristine: Used in combination with bleomycin, etoposide, doxorubicin, cyclophosphamide, procarbazine and prednisone (increased-dose BEACOPP regimen) for early or advanced Hodgkin’s disease.136 139

Conventional vincristine: Also used in combination with doxorubicin, bleomycin, vinblastine, mechlorethamine, etoposide, and prednisone (Stanford V regimen); mechlorethamine, procarbazine, doxorubicin, bleomycin, and prednisone (MOPP-ABV regimen); and cyclophosphamide, procarbazine, doxorubicin, bleomycin, vinblastine, dacarbazine, and prednisone (COPP-ABVD regimen) for Hodgkin’s disease.136 139

Non-Hodgkin’s Lymphoma

Conventional vincristine: Component of combination chemotherapeutic regimens for the treatment of non-Hodgkin’s lymphomas.131 136 Generally used with cyclophosphamide and prednisone with or without doxorubicin (i.e., CHOP or CVP regimen); rituximab usually administered with these regimens.210

Comparative efficacy of various regimens is continually being evaluated, and the best combination or sequence to achieve maximum response has not been established.a

Neuroblastoma

Conventional vincristine: Component of various regimens for the treatment of neuroblastoma.136

Rhabdomyosarcoma

Conventional vincristine: Commonly used with dactinomycin, with or without cyclophosphamide, as an adjunct to surgery and/or radiation therapy.136 211

Wilms’ Tumor

Conventional vincristine: In children with Wilms’ tumor, generally used with dactinomycin (with or without doxorubicin) or in combination with doxorubicin, cyclophosphamide, and etoposide.136 212

Combination chemotherapy is superior to single-drug therapy as an adjunct to surgery and/or radiation therapy in prolonging relapse-free survival and overall survival.a

Brain Tumors

Conventional vincristine: Palliative treatment of various primary brain tumors.136

Conventional vincristine: Various first- and second-line regimens that typically include vincristine and lomustine with another antineoplastic agent, such as procarbazine or cisplatin, or a corticosteroid (prednisone) have been used in the treatment of astrocytic tumors (e.g., glioblastoma multiforme and anaplastic astrocytoma),136 150 151 medulloblastoma,136 152 153 and oligodendroglioma.136 154

AIDS-related Kaposi’s Sarcoma

Conventional vincristine: Used alone120 121 146 149 or in combination chemotherapy for the palliative treatment of AIDS-related Kaposi’s sarcoma.136 146 147 148 149 181

Small Cell Lung Cancer

Conventional vincristine: In combination with cyclophosphamide and doxorubicin (CAV) for the treatment of extensive-stage small cell lung cancer.136 187 Survival outcomes are similar with CAV or cisplatin/etoposide, and comparative efficacy is continually being evaluated.187

Conventional vincristine: Also used in combination with cyclophosphamide and etoposide for the treatment of extensive-stage small cell lung cancer.213

Current prognosis for small cell lung carcinoma is unsatisfactory regardless of stage; all patients are candidates for inclusion in clinical trials at the time of diagnosis.187

Other Uses

Conventional vincristine: Used in combination chemotherapy for osteosarcoma (including Ewing's sarcoma), multiple myeloma, and choriocarcinoma.136

Conventional vincristine: Used in combination with cyclophosphamide and prednisone (with or without doxorubicin) for chronic lymphocytic leukemia.136

Conventional vincristine: Used in combination with cisplatin and fluorouracil for hepatoblastoma.136

Conventional vincristine: Used in combination with cyclophosphamide and dacarbazine for pheochromocytoma.136

Conventional vincristine: Has been used for treatment of immune thrombocytopenic purpura.197 Used IV with some success for the treatment of thrombotic thrombocytopenic purpura,111 122 123 and the use of vincristine-loaded platelets has reportedly been useful in some cases for the management of autoimmune hemolytic anemia.112

Vincristine Sulfate Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.131 204

  • 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.131 204

Administration

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

For IV administration only.131 204 Very irritating; must not administer IM, sub-Q, or intrathecally.131 204 Intrathecal administration almost always results in death.131 204 (See Boxed Warning.)

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

IV Administration of Conventional Vincristine

Administer by IV infusion (preferably as a diluted solution in a minibag131 198 199 200 209 219 ), usually at weekly intervals.131

If administered by IV injection, 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

Extravasation

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

If leakage or swelling 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 (See Boxed Warning and also Local Effects under Cautions.)

Dilution

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 small-volume IV bag (i.e., minibag) to prevent inadvertent intrathecal administration of the drug;131 198 199 200 209 219 however, if the drug is prepared as a diluted solution in a syringe, a 30-mL syringe is recommended.199 200 208

If prepared in a minibag, dilute dose with an appropriate volume of 0.9% sodium chloride injection to a final concentration of 0.0015–0.08 mg/mL.131

Rate of Administration

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.131 208

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 not using an IV pump for vesicant drugs such as vincristine when administered by short infusion into a peripheral vein.201 202

Dispensing Precautions

When dispensing, must label syringe or infusion bag holding the individual dose with the statement: “Warning: For intravenous use only. Fatal if given by other routes.”131 206

Enclose syringe in an overwrap bearing the statements: “Do not remove covering until moment of injection. For intravenous use only. Fatal if given by other routes.”131 (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.200 209 219

IV Administration of Liposomal Vincristine

Administer by IV infusion; do not use in-line filter.204

Complete infusion within 12 hours of initiation of preparation.204

Commercially available as a 3-vial kit containing single-use vials of vincristine sulfate solution, sphingomyelin-cholesterol liposome suspension, and dibasic sodium phosphate solution.204 220 Preparation requires 60–90 minutes of dedicated and uninterrupted time.204 If deviations in the preparation process occur, discard the kit components and use a new kit to prepare liposomal vincristine sulfate.204

Vincristine sulfate solution must be mixed with the sphingomyelin-cholesterol liposome suspension and dibasic sodium phosphate solution provided in the kit; the resultant liposomal vincristine sulfate injection concentrate must be diluted prior to IV infusion.204 220 Use the equipment provided by the manufacturer (i.e., water bath or block heater [use one heating apparatus but not both], calibrated thermometer, electronic timer, tongs).204

Do not admix with other drugs.204

Extravasation

Extremely important to ensure that the venous access line is secure and free-flowing to avoid extravasation.204

If extravasation is suspected, discontinue the infusion immediately and consider local treatments.204 (See Local Effects under Cautions.)

Preparation of Liposomal Vincristine Sulfate Injection Concentrate (Water Bath Method)

Prepare and maintain water bath outside the sterile area.204 Maintain water at a minimum depth of 8 cm and at a temperature of 63–67°C throughout preparation process.204

Perform all steps required to mix and dilute the product inside the sterile area using strict aseptic technique.204

Insert venting needle (or other suitable venting device) with a 0.2-µm filter into the vial containing dibasic sodium phosphate solution with the needle point positioned well above the surface of the solution.204 Inject 1 mL of sphingomyelin-cholesterol liposome suspension, then 5 mL of vincristine sulfate solution, into the vial.204 Remove the venting needle.204 Gently invert vial 5 times to mix; do not shake.204

Fit manufacturer-provided flotation ring around the vial neck, then place vial in the water bath for 10 minutes; use the calibrated thermometer and electronic timer to closely monitor water temperature and duration of flotation.204 After 10 minutes, remove vial from water bath using tongs to prevent burns, and remove flotation ring from the vial.204 Dry the vial exterior with a clean paper towel.204

Record the start time and temperature and the end time and temperature on the liposomal vincristine sulfate injection concentrate overlabel immediately after the vial is placed into the water bath and upon removal, respectively.204 Affix overlabel to vial.204 Gently invert vial 5 times to mix; do not shake.204

Resultant liposomal vincristine sulfate injection concentrate contains vincristine sulfate 0.16 mg/mL.204 Allow concentrate to come to room temperature (i.e., 15–30°C) over ≥30 minutes prior to dilution.204

Preparation of Liposomal Vincristine Sulfate Injection Concentrate (Block Heater Method)

Place block heater outside the sterile area.204 221

Perform all steps required to mix and dilute the product inside the sterile area using strict aseptic technique.204

Place 3 heating blocks in the block heater; place the block that will hold the vial containing the drug components between 2 blank blocks.204 Set controller of the block heater to 75°C and allow temperature to equilibrate to 73–77°C for 15 minutes.204 Maintain block heater temperature at 73–77°C throughout the preparation process.204

Insert venting needle (or other suitable venting device) with a 0.2-µm filter into the vial containing dibasic sodium phosphate solution with the needle point positioned well above the surface of the solution.204 Inject 1 mL of sphingomyelin-cholesterol liposome suspension, then 5 mL of vincristine sulfate solution, into the vial.204 Remove the venting needle.204 Gently invert vial 5 times to mix; do not shake.204

Place vial in the block heater for 18 minutes; use the calibrated thermometer and electronic timer to closely monitor block heater temperature and duration in block heater.204 After 18 minutes, remove vial from block heater using tongs to prevent burns.204

Record the start time and temperature and the end time and temperature on the liposomal vincristine sulfate injection concentrate overlabel immediately after the vial is placed in the block heater and upon removal, respectively.204 Affix overlabel to vial.204 Gently invert vial 5 times to mix; do not shake.204

Resultant liposomal vincristine sulfate injection concentrate contains vincristine sulfate 0.16 mg/mL.204 Allow concentrate to come to room temperature (i.e., 15–30°C) over ≥30 minutes prior to dilution.204

Dilution

To prepare the final diluted infusion, remove the volume of diluent equal to the total required volume of liposomal vincristine sulfate injection concentrate from a 100-mL bag of 5% dextrose or 0.9% sodium chloride injection; then add the total required volume of drug concentrate to the infusion bag.204

Complete the label supplied by the drug's manufacturer; affix label to bag.204

Rate of Administration

Administer over 1 hour.204

Dispensing Precautions

When dispensing, must label the infusion bag with the statement: “Warning: For intravenous use only. Fatal if given by other routes.”204 206

Dosage

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

Liposomal vincristine: Available as liposomal vincristine sulfate; dosage expressed in terms of vincristine sulfate.204

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

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

Do not substitute liposomal vincristine for other vincristine formulations, or vice versa.204

Pediatric Patients

General Dosage (Conventional Vincristine)

In patients receiving asparaginase concomitantly, administer conventional 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

IV (Conventional Vincristine)

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

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

Dosage Modification for Toxicity and Contraindications for Continued Therapy (Conventional Vincristine)
Neurologic Toxicity

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

Hematologic Toxicity

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 dosage is reduced.131

Pulmonary Toxicity

Discontinue conventional vincristine therapy in patients who develop progressive dyspnea.131

Adults

General Dosage (Conventional Vincristine)

In patients receiving asparaginase concomitantly, administer conventional 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

IV (Conventional Vincristine)

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

Philadelphia Chromosome-negative (Ph) Relapsed or Refractory ALL (Liposomal Vincristine)
IV (Liposomal Vincristine)

2.25 mg/m2 once weekly.204

Dosage Modification for Toxicity and Contraindications for Continued Therapy (Conventional Vincristine)
Neurologic Toxicity

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

Hematologic Toxicity

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 dosage is reduced.131

Pulmonary Toxicity

Discontinue conventional vincristine therapy in patients who develop progressive dyspnea.131

Dosage Modification for Toxicity and Contraindications for Continued Therapy (Liposomal Vincristine)
Neurologic Toxicity

Monitor carefully (e.g., history, physical examination) for neurologic toxicity.204 Dosage reduction may be necessary, particularly in patients with preexisting neuromuscular disease and those receiving other agents with neurotoxic potential.204

If grade 3 peripheral neuropathy (severe symptoms resulting in interference with self-care activities of daily living) occurs, withhold drug.204 If toxicity persists or worsens despite interruption of therapy, discontinue liposomal vincristine therapy.204 If peripheral neuropathy improves to grade 2 or less, resume liposomal vincristine therapy at a reduced vincristine sulfate dosage of 2 mg/m2.204

If persistent grade 2 peripheral neuropathy (moderate symptoms resulting in interference with instrumental activities of daily living) occurs, withhold drug.204 If toxicity worsens to grade 3 or 4 despite interruption of therapy, discontinue liposomal vincristine therapy.204 If toxicity improves, resume liposomal vincristine therapy at a reduced vincristine sulfate dosage of 2 mg/m2.204

If patient has persistent grade 2 peripheral neuropathy at a dosage of 2 mg/m2, withhold liposomal vincristine therapy for ≤7 days.204 If toxicity worsens despite interruption of therapy, discontinue liposomal vincristine.204 If toxicity improves to grade 1, resume liposomal vincristine therapy at a further reduced vincristine sulfate dosage of 1.825 mg/m2.204

If patient has persistent grade 2 peripheral neuropathy at a dosage of 1.825 mg/m2, withhold liposomal vincristine therapy for ≤7 days.204 If toxicity worsens despite interruption of therapy, discontinue liposomal vincristine.204 If toxicity improves to grade 1, resume liposomal vincristine therapy at a further reduced vincristine sulfate dosage of 1.5 mg/m2.204

Hematologic Toxicity

Perform CBC before administration of each dose.204

If grade 3 or 4 neutropenia, thrombocytopenia, or anemia occurs, consider dosage reduction or temporary interruption of liposomal vincristine therapy and provide supportive care measures.204

Hepatic Toxicity

If hepatotoxicity occurs, consider dosage reduction or temporary interruption of liposomal vincristine therapy.204

Other Nonhematologic Toxicity

If fatigue occurs, consider dosage reduction, temporary interruption, or discontinuance of liposomal vincristine therapy.204

Prescribing Limits

Adults

IV (Conventional Vincristine)

Maximum 2-mg dose recommended by some clinicians.a

Special Populations

Hepatic Impairment

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

Liposomal vincristine: Manufacturer makes no specific dosage recommendations.204

Cautions for Vincristine Sulfate

Contraindications

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

  • Intrathecal administration.131 (See Intrathecal Administration under Cautions.)

    Liposomal Vincristine
  • Demyelinating conditions, including Charcot-Marie-Tooth syndrome.204

  • Hypersensitivity to liposomal or conventional vincristine or any ingredient in the liposomal vincristine formulation.204

  • Intrathecal administration.204 (See Intrathecal Administration under Cautions.)

Warnings/Precautions

Warnings

Intrathecal Administration

Fatal if administered intrathecally; management of patients mistakenly receiving intrathecal vincristine is a medical emergency.131 204

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 conventional 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

Local Effects

Tissue irritant; may cause phlebitis and necrosis.a (See Administration under Dosage and Administration.) 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

Sensitivity Reactions

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

Other Warnings and 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

Neurotoxicity

Major and dose-limiting adverse effect;131 204 215 a 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 conventional vincristine therapy is continued.131

Most frequent manifestation is peripheral (mixed sensorimotor) neuropathy; occurs in nearly every patient receiving conventional vincristine.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 of conventional vincristine 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 with conventional vincristine is given.a

Cranial nerve palsies may account for headaches and jaw pain.a Jaw pain usually occurs within 24 hours after the first and/or second dose of conventional vincristine and rarely recurs.a Pain in other areas (e.g., pharyngeal, parotid gland, bone, back, limb) and myalgia have been reported with conventional or liposomal vincristine and may be severe.131 204 215

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 in patients receiving conventional vincristine.131

Peripheral neuritis (both mononeuritis and polyneuritis) and neuralgia also occur frequently in patients receiving conventional vincristine.a

Autonomic toxicity (e.g., severe constipation or obstipation, abdominal cramps, bowel obstruction, colonic pseudo-obstruction) may occur;204 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;131 204 a routine prevention regimen (e.g., laxatives, enemas) is recommended.131 204 Constipation usually persists <7 days with once-weekly conventional vincristine 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 in patients receiving conventional vincristine.a Whenever possible, discontinue other drugs causing urinary retention during the first few days after administration of conventional vincristine, particularly in geriatric patients.131

Other autonomic effects include orthostatic hypotension, abnormal Valsalva response, defective sweating, and myoclonic jerks.204 a

CNS effects (e.g., altered consciousness, depression, agitation, insomnia, hallucinations, seizures [often with hypertension], progressive encephalopathy, respiratory difficulties, coma) have occurred.204 a Seizures followed by coma have been reported in several pediatric patients receiving conventional vincristine.131

Neurotoxic effects may be additive with those of other neurotoxic agents and spinal cord irradiation.204 a Use with caution and monitor dosage and toxicity, particularly in patients receiving other neurotoxic drugs or in those with preexisting neuromuscular disease.131 204

Tumor Lysis Syndrome

Tumor lysis syndrome may occur following rapid lysis of malignant cells.204 a The risk of tumor lysis syndrome is increased in patients with non-Hodgkin’s lymphomas or leukemia;a closely monitor such patients and initiate appropriate precautions.204 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

Hematologic Effects

Anemia, leukopenia, and thrombocytopenia have been reported.131 204 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.131 204

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

CNS Leukemia

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

Respiratory Effects

Acute shortness of breath and bronchospasm, which can be severe or life threatening, have occurred;131 reported most frequently when mitomycin was administered concomitantly with conventional vincristine.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 conventional vincristine; do not readminister to these patients.131

Cardiovascular Effects

Hypertension131 and hypotension131 204 reported. CAD131 and MI124 127 128 130 131 have occurred in patients receiving conventional 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 Cardiac arrest has occurred in patients receiving liposomal vincristine.204

Otic Effects

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.)

Dermatologic Effects

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

Fatigue

Severe fatigue reported in patients receiving liposomal vincristine.204

Hepatic Effects

Hepatic veno-occlusive disease, sometimes fatal, reported in patients receiving conventional vincristine, particularly in pediatric patients receiving combination chemotherapy.131

Hepatotoxicity, sometimes fatal, and elevated AST concentrations reported in patients receiving liposomal vincristine.204

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.131 204 Avoid pregnancy during therapy.131 204 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.131 204

Radiation Therapy

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

Effects on Fertility

Animal data indicate vincristine may impair male fertility.204 Gonadal dysfunction reported in postpubertal males and females who received combination chemotherapy that included conventional vincristine.204 a

Specific Populations

Pregnancy

Category D.131 204 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether vincristine or its metabolites are distributed into milk.131 204 Discontinue nursing or the drug.131 204

Pediatric Use

Safety and efficacy of liposomal vincristine in pediatric patients not established.204

Geriatric Use

Use with caution due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in this age group.204

Hepatic Impairment

Use with caution and reduce dosage of conventional vincristine in patients with obstructive jaundice or other substantial hepatic impairment.a (See Hepatic Impairment under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Common Adverse Effects

Conventional vincristine: 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

Liposomal vincristine: Febrile neutropenia, neutropenia, anemia, thrombocytopenia, infections (e.g., pneumonia, septic shock, staphylococcal bacteremia), nausea, diarrhea, decreased appetite, insomnia, peripheral or motor neuropathy, constipation, ileus or colonic pseudo-obstruction, asthenia, respiratory distress or failure, fever, fatigue, pain, abdominal pain, elevated AST concentrations, hypotension, mental status changes, cardiac arrest, renal and urinary disorders, musculoskeletal and connective tissue disorders.204

Interactions for Vincristine Sulfate

No formal drug interaction studies conducted with liposomal vincristine; consider drugs known to interact with conventional vincristine to also interact with the liposomal formulation.204

Metabolized by CYP microsomal enzymes, including CYP3A.131

Substrate of P-gp.204

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A: Possible inhibition of vincristine metabolism; 131 avoid concomitant use.204 218

Potent inducers of CYP3A: Possible increased vincristine metabolism; avoid concomitant use.204

Drugs Affecting or Affected by P-glycoprotein Transport

Potent inhibitors or inducers of P-gp: Possible altered pharmacokinetics or pharmacodynamics of vincristine; avoid concomitant use.204

Specific Drugs

Drug

Interaction

Comments

Anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin)

Potent CYP3A inducers (e.g., carbamazepine, phenobarbital, phenytoin): Potential increased metabolism of vincristine204

Phenytoin: Decreased phenytoin concentrations and increased seizure activity reported with combination chemotherapy regimens that included conventional vincristine, possibly as a result of decreased absorption and/or increased metabolism of phenytoin131 204

Potent CYP3A inducers: Avoid concomitant use204

Antifungals, azoles (e.g., itraconazole, ketoconazole, posaconazole, voriconazole)

Possible increased plasma concentrations of vincristine; serious adverse effects (e.g., peripheral, autonomic, and cranial neuropathy; seizures; hyponatremia or SIADH; paralytic ileus or other GI toxicity)195 216 217 218 and earlier onset and/or increased severity of adverse neuromuscular effects reported131

Avoid concomitant use;204 218 use concomitantly only when no alternative antifungal options exist, and monitor frequently for toxicity216 217 218

Antimycobacterials, rifamycins (e.g., rifabutin, rifampin, rifapentine)

Potential increased metabolism of vincristine204

Avoid concomitant use204

Antiretroviral agents, HIV protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)

Potential impaired metabolism of vincristine204

Avoid concomitant use204

Asparaginase

Possible reduction in hepatic clearance of vincristine131

When used concomitantly, administer conventional vincristine 12–24 hours before administration of asparaginase to minimize toxicity; do not administer asparaginase before vincristine administration131

Dexamethasone

Potential increased metabolism of vincristine204

Avoid concomitant use204

Macrolides (clarithromycin, telithromycin)

Potential impaired metabolism of vincristine131 204

Avoid concomitant use204

Mitomycin

Potential increased risk of serious adverse respiratory effects with concomitant use, particularly in preexisting pulmonary dysfunction131

Reactions may occur up to 2 weeks after mitomycin dose131 (see Respiratory Effects under Cautions)

Nefazodone

Potential impaired metabolism of vincristine131 204

Avoid concomitant use204

Ototoxic drugs (e.g., platinum-containing antineoplastic agents)

Potential additive ototoxic effect131

Varying degrees of permanent or temporary hearing impairment associated with eighth cranial nerve damage reported in patients receiving vinca alkaloids; use concomitantly with other potentially ototoxic drugs with extreme caution131

St. John’s wort (Hypericum perforatum)

Potential increased metabolism of vincristine204

Avoid concomitant use204

Vincristine Sulfate Pharmacokinetics

Absorption

Bioavailability

Conventional vincristine: Following rapid IV injection, peak serum concentrations occur immediately100 101 102 104 and drug is rapidly cleared from serum.100 101 102 103 104 AUC is greater following continuous IV infusion compared with rapid IV injection.101

Liposomal vincristine: Peak concentrations reflect liposome-encapsulated drug that may not be immediately bioavailable.204 AUC is increased relative to that of conventional vincristine because of slower clearance of liposomal vincristine.204

Distribution

Extent

Conventional vincristine: Distribution of vincristine and its metabolites not fully characterized; following IV administration, the drug is rapidly and widely distributed.100 101 102 103 104

Conventional vincristine: Following rapid IV injection, rapidly and extensively distributed into bile.103

Conventional vincristine: Following rapid IV injection, vincristine and its metabolites (and/or decomposition products) cross the blood-brain barrier poorly, generally do not appear in the CSF in cytotoxic concentrations.102

Not known whether conventional or liposomal vincristine and its metabolites are distributed into milk.131 204

Elimination

Metabolism

Not clearly determined; apparently extensively metabolized, probably in the liver by CYP microsomal enzymes, including CYP3A,131 but extent of metabolism is not clear because vincristine also apparently undergoes decomposition in vivo.100 103

Elimination Route

Conventional vincristine: Vincristine and its metabolites (and/or decomposition products) are excreted principally in feces via biliary elimination (30% within 24 hours and 70% within 72 hours) and to lesser extent in urine (about 10% within 24 hours).100 103 104

Liposomal vincristine: Extent of urinary excretion (<8% within 96 hours) is similar to that of conventional vincristine.204

Half-life

Conventional vincristine: 19–155 hours.131

Clearance of liposomal vincristine is slower than that of conventional vincristine (345 versus 11,340 mL/hour).204

Special Populations

In patients with hepatic impairment, metabolism of vincristine may be decreased.102 103 131 Only small amounts of vincristine are removed by hemodialysis.131

Liposomal vincristine: In patients with melanoma and moderate hepatic impairment (Child-Pugh class B) secondary to liver metastases, dose-adjusted peak plasma concentrations and systemic exposure207 similar to those in patients with ALL and normal hepatic function.204

Stability

Storage

Parenteral

Conventional Vincristine Injection

2–8°C;131 store vial in upright position131 and protect from light.a

Doses of 0.5, 1, 2, or 3 mg of vincristine sulfate diluted in 25 or 50 mL of 0.9% sodium chloride injection in small-volume IV bags (i.e., minibags) or in 20 mL of 0.9% sodium chloride injection in a 30-mL syringe remained stable when stored for 7 days at 4°C followed by 2 days at 23°C.199

Liposomal Vincristine Injection

Kit containing vincristine sulfate solution, sphingomyelin-cholesterol liposome suspension, and dibasic sodium phosphate solution: 2–8°C; do not freeze.204

Liposomal vincristine sulfate injection concentrate: 15–30°C for ≤12 hours.204 Complete infusion of final diluted drug suspension within 12 hours of initiation of liposomal vincristine sulfate preparation.204

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Manufacturers state that vincristine sulfate injection should not be diluted in solutions that alter pH outside range of 3.5–5.5 and do not recommend mixing with solutions other than 0.9% sodium chloride injection or 5% dextrose injection.131

Solution Compatibility (for Conventional Vincristine)208

Compatible

Dextrose 5% in water

Ringer’s injection, lactated

Sodium chloride 0.9%

Solution Compatibility (for Liposomal Vincristine)204

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Drug Compatibility
Admixture Compatibility (for Conventional Vincristine)208

Compatible

Bleomycin sulfate

Cytarabine

Doxorubicin HCl

Doxorubicin HCl with etoposide phosphate

Doxorubicin HCl with ondansetron HCl

Fluorouracil

Methotrexate sodium

Variable

Doxorubicin HCl with etoposide

Y-Site Compatibility (for Conventional Vincristine)208

Compatible

Allopurinol sodium

Amifostine

Amphotericin B cholesteryl sulfate complex

Anidulafungin

Aztreonam

Bleomycin sulfate

Caspofungin acetate

Cisplatin

Cladribine

Cyclophosphamide

Doxorubicin HCl

Doxorubicin HCl liposome injection

Droperidol

Etoposide phosphate

Filgrastim

Fludarabine phosphate

Fluorouracil

Gemcitabine HCl

Granisetron HCl

Heparin sodium

Leucovorin calcium

Linezolid

Melphalan HCl

Methotrexate sodium

Metoclopramide HCl

Mitomycin

Ondansetron HCl

Oxaliplatin

Paclitaxel

Pemetrexed disodium

Piperacillin sodium–tazobactam sodium

Sargramostim

Teniposide

Thiotepa

Topotecan HCl

Vinblastine sulfate

Vinorelbine tartrate

Incompatible

Furosemide

Idarubicin HCl

Sodium bicarbonate

Actions

  • 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

Advice to Patients

  • Importance of advising patients and/or their parents or guardians of adverse effects and associated manifestations.a

  • Risk of extravasation;131 204 importance of informing clinician if burning or local irritation occurs during or after infusion.204

  • Risk of neurologic toxicity (e.g., peripheral neuropathy) or fatigue.131 204 Importance of not driving or engaging in hazardous activities (e.g., operating hazardous machinery) if such symptoms occur.204 Importance of informing clinician of new or worsening manifestations of peripheral neuropathy (e.g., tingling, numbness, pain, burning sensation or weakness in hands or feet).204

  • Risk of constipation.131 204 Importance of informing clinician if signs and symptoms of constipation (e.g., infrequent bowel movements, abdominal pain, bloating, diarrhea, nausea, vomiting) occur.204 Importance of a routine prevention regimen (e.g., proper diet, adequate fluid intake, laxatives).204

  • Risk of hair loss; reversible when the drug is discontinued.a Regrowth of hair may occur even when vincristine is continued in therapeutic doses.a

  • Risk of fever, productive cough, or loss of appetite.204

  • Importance of avoiding contact of vincristine with eyes;131 importance of informing clinician if eye irritation continues after washing affected eye(s) following contact.a

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.a

  • Risk of fetal harm.131 204 Necessity of advising women of childbearing potential that they should use an effective method of contraception while receiving vincristine.204

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.a

  • Importance of informing patients of other important precautionary information.a (See Cautions.)

Preparations

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

vinCRIStine Sulfate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV use only

1 mg/mL (1 and 2 mg)*

vinCRIStine Sulfate Injection

vinCRIStine Sulfate Liposomal

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Kit, for suspension, for injection, for IV infusion only

1 Vial, Injection, Vincristine Sulfate 5 mg/5 mL (for preparation of liposome-encapsulated vincristine sulfate suspension, 0.16 mg [of vincristine sulfate] per mL [5 mg]),

1 Vial, For injectable suspension, Sphingomyelin/Cholesterol Liposome 103 mg/mL (Sphingomyelin 73.5 mg/mL and Cholesterol 29.5 mg/mL)

1 Vial, Injection, Sodium Phosphate, Dibasic 355 mg/25mL

Marqibo (available with flotation ring, vial overlabel, and infusion bag label)

Spectrum

AHFS DI Essentials™. © Copyright 2018, Selected Revisions October 15, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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