VA Class:AN900
Vincristine sulfate, a naturally occurring vinca alkaloid, is an antineoplastic agent.135, 140
Vincristine sulfate is commercially available in 2 types of formulations: conventional vincristine sulfate and liposomal vincristine sulfate.131, 204 The efficacy and safety of vincristine for each indication is based on research and clinical experience using a specific formulation.204
Conventional vincristine is used as a 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 Various drugs have been used for combination chemotherapy of childhood and adult ALL,136, 141, 142, 143, 144, 145 and comparative efficacy of these regimens is continually being evaluated.141, 142, 143, 144, 145 Additional therapy (e.g., intrathecal administration of methotrexate with or without intrathecal cytarabine and hydrocortisone, with or without systemic methotrexate and leucovorin rescue and/or cranial radiation in children; intrathecal methotrexate given alone or in conjunction with cranial radiation or high-dose systemic methotrexate and leucovorin rescue in adults) is needed for prophylaxis of CNS involvement (meningeal leukemia) in patients with ALL.136, 141, 142, 143, 144, 145 Once remission has been attained, patients generally receive consolidation-intensification therapy and maintenance therapy.141, 143, 144, 145 Other regimens are preferred in certain subsets of patients with ALL (e.g., B-cell ALL, T-cell ALL, Philadelphia chromosome-positive ALL).141, 142, 144 Certain patients with a poor prognosis or with a poor response to initial treatment may be candidates for hematopoietic stem cell transplantation.136, 141, 142, 143, 144, 145, 203 Specialized references and experts should be consulted for additional information.
Although conventional vincristine used with a corticosteroid such as prednisone results in high remission induction rates in children with ALL, addition of an asparaginase preparation and/or an anthracycline (e.g., daunorubicin) can improve both the rate and duration of remission and therefore such 3- or 4-drug regimens generally are preferred.136, 141, 143 (For additional information on the asparaginase component of ALL regimens, see Asparaginase [Erwinia chrysanthemi] 10:00.) The use of intensive induction regimens with 4 or more drugs, including conventional vincristine, an asparaginase preparation, a corticosteroid (e.g., prednisone), and an anthracycline (e.g., daunorubicin), with or without cyclophosphamide, may improve the rate of event-free survival but is associated with greater toxicity.136, 141, 143 An induction regimen containing 4 or more drugs does not appear to be necessary to achieve favorable outcomes in patients at low or standard risk of treatment failure provided adequate intensification therapy is provided following achievement of remission.141, 203 Therefore, some clinicians reserve such regimens for patients with high-risk childhood ALL.136, 141, 143 However, other clinicians have elected to use a 4- or 5-drug induction regimen for all patients with childhood ALL regardless of presenting features.141 Maintenance therapy (e.g., methotrexate and mercaptopurine with or without pulses of conventional vincristine and prednisone) is administered for about 2-3 years.136, 141, 143
Induction regimens for adult ALL typically include conventional vincristine, prednisone, and an anthracycline; some regimens also add other drugs, such as an asparaginase preparation or cyclophosphamide.142
Liposomal vincristine is used for the 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 at least 2 prior therapies.204, 205 The drug has been designated an orphan drug by FDA for use in this condition.214 The accelerated approval of liposomal vincristine for this indication is based on overall response rate; continued approval for this indication may be contingent on verification and description of clinical benefit (e.g., overall survival) of liposomal vincristine in confirmatory studies.204, 215
The current indication for liposomal vincristine is based principally on the results of an open-label, noncomparative, phase 2 study in 65 adults with Ph- relapsed or refractory ALL.204, 205 Patients were enrolled if they were in second or greater relapse or if their disease had relapsed or was refractory following at least 2 prior therapies.204, 205 Patients enrolled in the study also were required to have achieved complete remission (defined as a leukemia-free interval lasting at least 90 days) after at least one prior therapy.204, 205 In this study, patients received liposomal vincristine sulfate at a dosage of 2.25 mg/m2 of vincristine sulfate by IV infusion over 60 minutes on days 1, 8, 15, and 22 of each 28-day cycle; concomitant therapy with systemic corticosteroids or hydroxyurea was not permitted beyond day 5 or 14, respectively, of the first cycle.204, 205 The primary measure of efficacy was complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) according to the International Working Group (IWG) response criteria.205, 215 The median age of patients was 31 years; 85% of the patients had precursor B-cell ALL (pre-B-ALL), 15% had precursor T-cell ALL (pre-T-ALL), 48% had undergone hematopoietic stem cell transplantation prior to study entry, and 80% of the patients had residual neuropathy at baseline following prior therapy with conventional vincristine.204, 205 Approximately one-half of patients had received 3 or more prior therapies for their disease; all of the enrolled patients received prior therapy with conventional vincristine and 45% were refractory to their most recent therapy prior to study entry.204, 205 Overall, CR or CRi was reported in 15.4% of patients; 4.6% of patients achieved CR.204 At the time of analysis, the median duration of response from initial CR or CRi to date of documented relapse, death, or subsequent chemotherapy or stem-cell transplantation was 56 days.204
Conventional vincristine is used 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. (See Uses: Leukemias, in Cytarabine 10:00.)
Conventional vincristine is used as a component of various chemotherapeutic regimens for the treatment of Hodgkin's disease.131, 136, 139 Various drugs have been used for combination chemotherapy, and comparative efficacy of these regimens is continually being evaluated.139 Conventional vincristine is used in combination with bleomycin, etoposide, doxorubicin, cyclophosphamide, procarbazine and prednisone (in the increased-dose BEACOPP regimen) for the treatment of early or advanced Hodgkin's disease.136, 139 Conventional vincristine also is 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 the treatment of Hodgkin's disease.136, 139
Conventional vincristine is used as a component of combination chemotherapeutic regimens for the treatment of non-Hodgkin's lymphomas,131, 136 and the comparative efficacy of various regimens is continually being evaluated. Conventional vincristine generally is used with cyclophosphamide and prednisone with or without doxorubicin (i.e., CHOP or CVP regimen); rituximab usually is administered with these regimens.210
Conventional vincristine is used as a component of various chemotherapeutic regimens for the treatment of neuroblastoma.136
Conventional vincristine is used as a component of combination chemotherapeutic regimens for the treatment of childhood rhabdomyosarcoma; conventional vincristine is commonly used with dactinomycin, with or without cyclophosphamide, as an adjunct to surgery and/or radiation therapy.136, 211
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 in children with Wilms' tumor. Conventional vincristine is generally used with dactinomycin (with or without doxorubicin) or in combination with doxorubicin, cyclophosphamide, and etoposide for the treatment of Wilms' tumor.136, 212
Conventional vincristine is used for the palliative treatment of various primary brain tumors†.136 Various regimens that typically include conventional 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 See Uses: Brain Tumors in Lomustine 10:00 for further discussion.
Conventional vincristine is used in combination chemotherapy for the palliative treatment of AIDS-related Kaposi's sarcoma†.136, 146, 147, 148, 149, 181 Combination chemotherapy that includes a vinca alkaloid (vinblastine or conventional vincristine), conventional doxorubicin, and bleomycin has previously been a preferred regimen for the disease,136, 146, 148, 149 but many clinicians currently consider a liposomal anthracycline (doxorubicin or daunorubicin) the first-line therapy of choice for advanced AIDS-related Kaposi's sarcoma (see Uses: AIDS-related Kaposi's Sarcoma in Doxorubicin 10:00 for overview and further discussion of therapy; also see Daunorubicin 10:00).136, 146, 184, 190, 191
Combination chemotherapy with conventional antineoplastic agents (e.g., bleomycin, conventional doxorubicin, etoposide, vinblastine, conventional vincristine) usually has been used for more advanced disease (e.g., extensive mucocutaneous disease, lymphedema, symptomatic visceral disease).146, 148, 149, 186 However, the results of several randomized, multicenter trials indicate that patients receiving a liposomal anthracycline for the treatment of advanced AIDS-related Kaposi's sarcoma experience similar or higher response rates with a more favorable toxic effects profile than those receiving combination therapy with conventional chemotherapeutic agents.146, 184, 190, 191
Conventional vincristine also has been used alone for the palliative treatment of AIDS-related Kaposi's sarcoma.120, 121, 146 In one study in patients with AIDS-related Kaposi's sarcoma who received a conventional vincristine dosage of 2 mg weekly for 2-5 weeks and then every 2 weeks thereafter as tolerated, partial or minor response was observed in about 61 or 39% of evaluable patients, respectively.121, 149
Conventional vincristine is used in combination with cyclophosphamide and doxorubicin (CAV) for the treatment of extensive-stage small cell lung cancer†.136, 187 Survival outcomes are similar in patients with extensive-stage small cell lung cancer receiving CAV or cisplatin/etoposide.187 Conventional vincristine also has been used in combination with cyclophosphamide and etoposide for the treatment of extensive-stage small cell lung cancer†.213 Combination chemotherapy regimens have produced response rates of 70-85% and complete response rates of 20-30% in patients with extensive-stage disease; however, comparative efficacy is continually being evaluated.187 Because the current prognosis for small cell lung carcinoma is unsatisfactory regardless of stage and despite considerable diagnostic and therapeutic advances, all patients with this cancer are candidates for inclusion in clinical trials at the time of diagnosis.187
Conventional vincristine also is used as a component of combination chemotherapy for the treatment of osteosarcoma† (including Ewing's sarcoma†), multiple myeloma†, and choriocarcinoma†.136 Combination chemotherapy with conventional vincristine, cyclophosphamide, and prednisone, with or without doxorubicin, is used in the treatment of chronic lymphocytic leukemia (CLL)†.136 Combination chemotherapy with conventional vincristine, cisplatin, and fluorouracil is used in the treatment of hepatoblastoma†.136 Conventional vincristine combined with cyclophosphamide and dacarbazine is used for the treatment of pheochromocytoma†.136
Conventional vincristine has been used in the treatment of immune thrombocytopenic purpura†.197 IV injections of the drug have also been used 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
Reconstitution and Administration
Vincristine sulfate is commercially available in 2 types of formulations: conventional vincristine sulfate and liposomal vincristine sulfate (Marqibo®).131, 204 The properties of vincristine may differ according to formulation, and the dosage and preparation for vincristine sulfate are specific to formulation.204 The manufacturer's instructions for the specific formulation should be consulted to ensure that the correct preparation procedure is followed.204
Conventional and liposomal vincristine formulations are for IV use only and should be administered by individuals experienced in the administration of the drug.131, 204 Conventional and liposomal vincristine sulfate must not be given by other routes (e.g., IM, subcutaneously, intrathecally). 131, 204 Intrathecal administration of vincristine usually results in death. 131, 204 When dispensed, the infusion bag or syringe holding the individual dose prepared for administration to the patient must be labeled with the statement “For intravenous use only. Fatal if given by other routes.”131, 206 The syringe must be enclosed 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
In addition to use of the labels and overwrap, other protective measures to prevent inadvertent intrathecal administration of conventional or liposomal vincristine or other vinca alkaloids include: administration of the diluted drug in small-volume IV bags (i.e., minibags), preparing the medication at the time of administration, attaching a unique filter, dispensing the vinca alkaloid separately from all other medications, dispensing the vinca alkaloid 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 of the drug, and administering the vinca alkaloid in a separate room from rooms where other medications are administered.200, 209, 219
Management of patients mistakenly receiving intrathecal conventional or liposomal vincristine is a medical emergency.131 Unfortunately, the prognosis to date generally has been poor despite immediate efforts at removing spinal fluid and flushing with lactated Ringer's injection as well as other solutions, with such efforts failing to prevent ascending paralysis and death in almost all cases.131 In one case, progression of paralysis was stopped in an adult patient when the following treatment was initiated immediately after inadvertent intrathecal injection of conventional vincristine.131 Such 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 per 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
Conventional Vincristine Sulfate
Extra fluid should not be added to the vial containing conventional vincristine sulfate prior to removal of the dose.131 Conventional vincristine sulfate injection should be withdrawn from the vial into an accurate dry syringe, and the dose should be measured carefully.131 Extra fluid should not be added to the vial in an attempt to empty it completely.131
Preparation of the conventional vincristine dose as a diluted solution in a minibag is recommended as a protective measure 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 The larger volume of the diluted conventional vincristine solution and incompatible packaging make it less likely that the IV conventional vincristine dose will be confused with a drug that is intended for intrathecal use.199, 209, 219 For preparation in a minibag, the dose of conventional vincristine sulfate should be diluted with an appropriate volume of 0.9% sodium chloride injection to a final concentration of 0.0015-0.08 mg/mL.131 If the drug is prepared in a minibag or diluted in a 30-mL syringe, the dose should be administered by IV injection over 5-10 minutes in adults; in children, the dose should be administered at a slower rate.198 The Oncology Nursing Society (ONS) recommends that if a vesicant drug such as vincristine is administered by short infusion into a peripheral vein, an IV pump not be used in order to decrease pressure applied on the veins.201, 202
Conventional vincristine also has been diluted in a large volume of IV solution and 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 Specialized references should be consulted for specific information on slow IV infusion of conventional vincristine.
For rapid IV (“bolus”) injections, conventional vincristine sulfate injection must be administered through an intact, free-flowing IV needle or catheter.131 Care should be taken to ensure that the needle or catheter is securely within the vein to avoid extravasation.131 If leakage or swelling occurs, the injection should be discontinued immediately and the remainder of the dose given through another vein; local treatment of the area of leakage may minimize discomfort and the possibility of cellulitis.131 (See Cautions: Local Effects.) Conventional vincristine sulfate injection may be injected either directly into a vein or into the tubing of a running IV infusion; injection of the drug should be completed within 1 minute.131, 208
When conventional vincristine and asparaginase must be administered sequentially, the sequence of vincristine followed by asparaginase is recommended.131 (See Drug Interactions: Antineoplastic Agents.)
Liposomal vincristine sulfate (Marqibo®) is 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 of liposomal vincristine sulfate suspension requires 60-90 minutes of dedicated and uninterrupted time because extensive monitoring of temperature and time is required during the process.204 Deviations from temperature control, timing, and preparation procedures may affect encapsulation of vincristine sulfate into the liposomes.204 If deviations in the preparation process occur, the components of the kit should be discarded and a new kit should be used 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 For preparation of liposomal vincristine sulfate injection concentrate, equipment provided by the manufacturer (i.e., water bath or block heater, calibrated thermometer, electronic timer, tongs) must be used.204 Either the water bath or block heater (but not both) may be used to prepare liposomal vincristine sulfate injection concentrate.204 All steps required to mix and dilute the drug product should be performed inside the sterile area using strict aseptic technique since the injection does not contain any preservative or bacteriostatic agent.204 Each vial in the kit and the final diluted suspension for infusion should be inspected visually for particulate matter and discoloration prior to preparation and administration whenever solution and container permit; the vials and diluted suspension for infusion should not be used if foreign particles or precipitate is present.204
Liposomal vincristine is administered by IV infusion over 1 hour.204 Liposomal vincristine should not be admixed with any other drug and should not be administered using an inline filter.204 Care should be taken to ensure that the venous access line is secure and free-flowing to avoid extravasation.204 If extravasation is suspected, the infusion should be discontinued immediately and local treatments considered.204 (See Cautions: Local Effects.)
Water Bath Preparation Instructions
The water bath should be prepared and maintained outside the sterile area.204 The water in the bath should be maintained at a minimum depth of 8 cm and at a temperature of 63-67°C (measured by the calibrated thermometer) throughout the preparation process.204 The calibrated thermometer should remain in the water bath throughout the preparation process.204 All steps required to mix and dilute the drug product should be performed inside the sterile area using strict aseptic technique.204
For preparation of liposomal vincristine sulfate injection concentrate, a venting needle (or other suitable venting device) with a 0.2-µm filter should be inserted into the vial containing dibasic sodium phosphate solution with the point of the venting needle positioned well above the surface of the solution.204 A volume of 1 mL of sphingomyelin-cholesterol liposome suspension followed by 5 mL of vincristine sulfate solution should be injected into the vial.204 The venting needle should then be removed and the vial should be gently inverted 5 times to mix the 3 components; the vial should not be shaken.204 The neck of the vial containing the mixture of the 3 components should be fitted with the manufacturer-provided flotation ring, and then the vial should be placed in the water bath for 10 minutes; the temperature of the water bath and duration of flotation should be closely monitored using the calibrated thermometer and electronic timer.204 After 10 minutes, the vial should be removed from the water bath using tongs to prevent burns, and the flotation ring should be removed from the vial.204 The start time and temperature and the end time and temperature should be recorded on the liposomal vincristine sulfate injection concentrate overlabel immediately after the vial is placed into the water bath and upon removal, respectively.204 The vial exterior should be dried with a clean paper towel upon removal from the water bath, and then the overlabel should be affixed to the vial.204 The vial should be gently inverted another 5 times to mix the contents; the vial should not be shaken.204 The resultant liposomal vincristine sulfate injection concentrate contains vincristine sulfate 0.16 mg/mL and should be stored at room temperature (15-30°C) for no more than 12 hours.204 Liposomal vincristine sulfate injection concentrate should be allowed to come to room temperature (i.e., 15-30°C) over at least 30 minutes prior to dilution.204
For preparation of the final diluted IV infusion of liposomal vincristine sulfate, a volume equivalent to the volume of the appropriate dose of liposomal vincristine sulfate should be withdrawn from an infusion bag containing 100 mL of 5% dextrose or 0.9% sodium chloride injection and discarded; the appropriate dose of liposomal vincristine sulfate injection concentrate is then withdrawn from the vial and added to the infusion bag to yield a final volume of 100 mL.204 The infusion bag label supplied by the drug's manufacturer should be completed and affixed to the bag.204 Infusion of the diluted drug should be completed within 12 hours of initiation of preparation of liposomal vincristine sulfate injection.204
Block Heater Preparation Instructions
When a block heater is used for the preparation of liposomal vincristine sulfate injection concentrate, the block heater should be placed outside the sterile area.204, 221 All steps required to mix and dilute the drug product should be performed inside the sterile area using strict aseptic technique.204
For preparation of liposomal vincristine sulfate injection concentrate using a block heater, 3 heating blocks should be placed in the block heater with the block that will hold the vial containing the drug components placed between 2 blank blocks.204 The controller of the block heater should be set to 75°C and the temperature should be allowed to equilibrate to 73-77°C (measured by the calibrated thermometer) for 15 minutes.204 The temperature of the block heater should be maintained at 73-77°C throughout the preparation process.204 The calibrated thermometer should remain in the block heater throughout the preparation process.204
For preparation of liposomal vincristine sulfate injection concentrate, a venting needle (or other suitable venting device) with a 0.2-µm filter should be inserted into the vial containing dibasic sodium phosphate solution with the point of the venting needle well above the surface of the solution.204 A volume of 1 mL of sphingomyelin-cholesterol liposome suspension followed by 5 mL of vincristine sulfate solution should be injected into the vial.204 The venting needle should then be removed and the vial should be gently inverted 5 times to mix the 3 components; the vial should not be shaken.204 The vial containing the mixture of the 3 components should be placed in the block heater for 18 minutes; the temperature of the block heater and duration in the block heater should be closely monitored using the calibrated thermometer and electronic timer.204 After 18 minutes, the vial should be removed from the block heater using tongs to prevent burns.204 The start time and temperature and the end time and temperature should be recorded on the liposomal vincristine sulfate injection concentrate overlabel immediately after the vial is placed into the block heater and upon removal, respectively.204 The vial should be gently inverted another 5 times to mix the contents; the vial should not be shaken.204 The resultant liposomal vincristine sulfate injection concentrate contains vincristine sulfate 0.16 mg/mL and should be stored at room temperature (15-30°C) for no more than 12 hours.204 Liposomal vincristine sulfate injection concentrate should be allowed to come to room temperature (i.e., 15-30°C) over at least 30 minutes prior to dilution.204
For preparation of the final diluted IV infusion of liposomal vincristine sulfate, a volume equivalent to the volume of the appropriate dose of liposomal vincristine sulfate should be withdrawn from an infusion bag containing 100 mL of 5% dextrose or 0.9% sodium chloride injection and discarded; the appropriate dose of liposomal vincristine sulfate injection concentrate is then withdrawn from the vial and added to the infusion bag to yield a final volume of 100 mL.204 The infusion bag label supplied by the drug's manufacturer should be completed and affixed to the bag.204 Infusion of the diluted drug should be completed within 12 hours of initiation of preparation of liposomal vincristine sulfate injection.204
Conventional Vincristine Sulfate
Various conventional vincristine sulfate dosages have been used. Clinicians should consult published protocols for the dosage of conventional vincristine sulfate and other chemotherapeutic agents and the method and sequence of administration. The manufacturers of conventional vincristine sulfate recommend a usual adult dose of 1.4 mg/m2 and a usual pediatric dose of 1.5-2 mg/m2.131 For children weighing 10 kg or less, the manufacturers of conventional vincristine sulfate recommend that therapy be initiated at 0.05 mg/kg once weekly.131 Some clinicians recommend that adult doses not exceed 2 mg of conventional vincristine sulfate. Subsequent doses must be determined by the clinical and hematologic response and tolerance of the patient in order to obtain optimum therapeutic results with minimum adverse effects. Conventional vincristine is usually administered at weekly intervals.131 Small daily doses are not recommended because they produce severe toxicity with no added therapeutic benefit.
For the 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 at least 2 prior therapies, the recommended adult dosage of liposomal vincristine sulfate is 2.25 mg/m2 of vincristine sulfate administered IV over 1 hour once weekly.204
Dosage Modification for Toxicity
Careful monitoring for neurologic toxicity including clinical evaluation (e.g., history, physical examination) is advised, and dosage reduction may be necessary, particularly in patients with preexisting neuromuscular disease or in patients receiving other agents with neurotoxic potential.131, 204 Adverse neurologic effects, such as neuritic pain or constipation, may lessen or disappear when the dosage of conventional vincristine is reduced.131
If grade 3 peripheral neuropathy (severe symptoms resulting in interference with self-care activities of daily living) occurs in patients receiving liposomal vincristine, therapy with the drug should be withheld.204 If grade 3 peripheral neuropathy persists or worsens despite interruption of therapy, liposomal vincristine therapy should be discontinued.204 If peripheral neuropathy improves to grade 2 or less, liposomal vincristine therapy may be resumed at a reduced vincristine sulfate dosage (i.e., 2.25 mg/m2 reduced to 2 mg/m2).204
If persistent grade 2 peripheral neuropathy (moderate symptoms resulting in interference with instrumental activities of daily living) occurs in patients receiving liposomal vincristine, therapy with the drug should be withheld.204 If grade 2 peripheral neuropathy worsens to grade 3 or 4 despite interruption of therapy, liposomal vincristine therapy should be discontinued.204 If the toxicity improves, liposomal vincristine therapy may be resumed at a reduced vincristine sulfate dosage (i.e., 2.25 mg/m2 reduced to 2 mg/m2).204
If the patient has persistent grade 2 peripheral neuropathy at a reduced dosage of 2 mg/m2, liposomal vincristine therapy should be withheld again for up to 7 days.204 If grade 2 peripheral neuropathy worsens despite interruption of therapy, liposomal vincristine therapy should be discontinued.204 If the toxicity improves to grade 1, liposomal vincristine therapy may be resumed at a further reduced vincristine sulfate dosage (i.e., 2 mg/m2 reduced to 1.825 mg/m2).204 If the patient has persistent grade 2 peripheral neuropathy at a dosage of 1.825 mg/m2, liposomal vincristine therapy should be withheld again for up to 7 days.204 If grade 2 peripheral neuropathy worsens despite interruption of therapy, liposomal vincristine therapy should be discontinued.204 If the toxicity improves to grade 1, liposomal vincristine therapy may be resumed at a further reduced vincristine sulfate dosage (i.e., 1.825 mg/m2 reduced to 1.5 mg/m2).204
Complete blood cell (CBC) counts should be performed before the administration of each dose of conventional or liposomal vincristine.131, 204
Following administration of conventional vincristine, a decrease in leukocyte count or platelet count may occur, particularly in patients for whom previous therapy or disease has reduced bone marrow function.131 In patients with leukopenia or infectious complications, withholding of the next dose of conventional vincristine should be considered.131 Leukopenia may lessen or disappear when the dosage of conventional vincristine is reduced.131
If grade 3 or 4 neutropenia, thrombocytopenia, or anemia occurs in patients receiving liposomal vincristine, dosage reduction or temporary interruption of liposomal vincristine therapy and supportive care measures should be considered.204
If hepatotoxicity occurs in patients receiving liposomal vincristine, dosage reduction or temporary interruption of liposomal vincristine therapy should be considered.204
Conventional vincristine therapy should be discontinued in patients who develop progressive dyspnea.131
If fatigue occurs in patients receiving liposomal vincristine, dosage reduction, temporary interruption, or discontinuance of liposomal vincristine therapy should be considered.204
A 50% reduction in conventional vincristine dose is recommended for patients with a direct serum bilirubin concentration exceeding 3 mg/dL or other evidence of clinically important hepatic impairment.131
The manufacturer makes no specific recommendations regarding dosage of liposomal vincristine in patients with hepatic impairment.204 (See Pharmacokinetics.)
In general, adverse reactions to vincristine are dose related and reversible.131
The incidence of adverse effects associated with liposomal vincristine is based principally on clinical trial data for 83 patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory acute lymphocytic (lymphoblastic) leukemia (ALL) who received the drug at the recommended dosage.204 The most common adverse effects, each occurring in more than 30% of patients, included constipation, nausea, fever, fatigue, peripheral neuropathy, febrile neutropenia, diarrhea, anemia, decreased appetite, and insomnia.204 All patients receiving the drug experienced adverse effects; 96% of patients experienced grade 3 or greater adverse effects, and 76% experienced serious adverse effects, most commonly febrile neutropenia (21%), fever (13%), hypotension (7%), respiratory distress (6%), and cardiac arrest (6%).204 Dose reduction, delay, or omission occurred in 53% of patients, and 28% of patients discontinued therapy because of adverse events, including peripheral neuropathy (10%), leukemia-related effects (7%), and tumor lysis syndrome (2%).204
The major and dose-limiting adverse effect of conventional and liposomal vincristine is neurotoxicity, the severity of which may vary greatly among patients. 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 with conventional vincristine is continued.131 The most frequent neurotoxic manifestation is peripheral (mixed sensorimotor) neuropathy, which occurs in nearly every patient receiving conventional vincristine. In clinical trials in patients with ALL, peripheral neuropathy occurred in 39% of patients receiving liposomal vincristine and was grade 3 or greater in 17% of patients receiving the drug.204 The earliest and most consistent indication of peripheral neuropathy is asymptomatic depression of the Achilles reflex. Loss of other deep tendon reflexes occurs in most patients after 3 or more weekly doses of conventional vincristine, and peripheral paresthesias, especially numbness, pain, and tingling, are common. If prolonged or high-dose conventional vincristine therapy is given, wrist drop, foot drop, cranial nerve palsy, atrophy, cramps, ataxia, slapping gait, and difficulty in walking or inability to walk may occur. 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 conventional vincristine and rarely recurs. Pain in other areas, including pharyngeal, parotid gland, bone, back, or limb pain as well as myalgia, has been reported in patients receiving 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, while those involving extrinsic eye muscles may cause ptosis, double vision, and optic and extraocular neuropathy. 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. Grade 3 or greater asthenia and muscle weakness have been reported during clinical trials in 5 and 1%, respectively, of patients with ALL receiving liposomal vincristine.204
Vincristine also produces autonomic and CNS toxicity, although less frequently than peripheral neuropathy. Autonomic effects commonly include severe constipation or obstipation, abdominal cramps, bowel obstruction, and colonic pseudo-obstruction. Adynamic ileus, which mimics “surgical abdomen,” is particularly likely to occur in young children. In clinical trials in patients with ALL, grade 3 or greater constipation occurred in 5% of patients receiving liposomal vincristine and grade 3 or greater ileus and colonic pseudo-obstruction occurred in 6% of patients receiving the drug.204 Constipation may take the form of upper-colon impaction, and a flat abdominal film may be used to facilitate diagnosis so the clinician is not misled by presentation of colicky abdominal pain coupled with an empty rectum.131 Constipation may be treated with high enemas and laxatives.131, 204 A routine regimen (e.g., laxatives, enemas) to prevent constipation is recommended for patients receiving conventional or liposomal vincristine.131, 204 When conventional vincristine is administered in single weekly doses, constipation usually persists less than 7 days;131 abdominal cramps and adynamic ileus in children usually also disappear in 1 week or less. Urinary tract disturbances including bladder atony, incontinence, urinary retention, nocturia, oliguria, dysuria, and polyuria also have been reported in patients receiving conventional vincristine. Whenever possible, other drugs known to cause urinary retention should be discontinued during the first few days following administration of conventional vincristine, particularly in geriatric patients.131 Other autonomic effects of vincristine include orthostatic hypotension, abnormal Valsalva response, defective sweating, and myoclonic jerks. CNS effects including episodes of altered consciousness and mental changes such as depression, agitation, insomnia, and hallucinations have been reported. Seizures (frequently accompanied by hypertension), progressive encephalopathy, respiratory difficulties, and coma also have occurred. Seizures followed by coma have been reported in several pediatric patients receiving conventional vincristine.131
Neurotoxic effects of conventional or liposomal vincristine may be additive with those of other neurotoxic agents and spinal cord irradiation. Geriatric patients and those with underlying neurologic disease may be more susceptible than other patients to the neurotoxic effects of conventional or liposomal vincristine. No antidote to the neurotoxic effects of vincristine has been found to date. Most experts reduce the dose or discontinue the drug if depression of reflexes, paresthesia, and/or motor weakness develop. Sensory loss, paresthesia, difficulty in walking, slapping gait, loss of deep tendon reflexes, and/or muscle wasting may persist during conventional vincristine therapy.131 Generalized sensorimotor dysfunction may become increasingly severe with continued therapy with conventional vincristine.131 Recovery from neurotoxicity usually begins with the discontinuance of conventional vincristine. Paresthesia is the most readily reversible, followed by motor and sensory impairment. Although these symptoms resolve by about the sixth week following discontinuance of conventional vincristine therapy in most patients, some patients may experience neuromuscular problems for prolonged periods.131 Depressed deep tendon reflexes return slowly, if at all, and some patients experience minor neurologic symptoms up to several months after conventional vincristine has been discontinued.
Acute shortness of breath and bronchospasm, which can be severe or life threatening, have occurred following administration of vinca alkaloids (e.g., vincristine), being reported most frequently when mitomycin was used 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 a dose of mitomycin.131 Progressive dyspnea, which may require chronic therapy, can occur in patients receiving conventional vincristine; the drug should not be readministered to these patients.131 In clinical trials in patients with ALL, respiratory distress or failure has been reported in 6 or 5%, respectively, of patients receiving liposomal vincristine.204
Alopecia is reported to occur in 20-70% of patients who receive conventional vincristine. Alopecia is reversible when conventional vincristine is discontinued. Regrowth of hair may occur even when conventional vincristine is continued in therapeutic doses.131 Rash has occurred occasionally in patients receiving conventional vincristine.
Allergic reactions,126, 129, 131 including anaphylaxis,126, 131 rash,131 and edema,131 that were temporally related to conventional vincristine therapy have been reported in patients receiving the drug as part of combination chemotherapy regimens.126, 129, 131
Hematologic toxicity produced by vincristine is less than that produced by most other antineoplastic agents; therefore, the drug is useful in patients with pancytopenia or in combination regimens. Anemia, leukopenia, and thrombocytopenia have been reported.131, 204 Leukopenia usually persists less than 7 days when conventional vincristine is given in single weekly doses.131 In clinical trials in patients with ALL, grade 3 or greater anemia, neutropenia, and thrombocytopenia each have been reported in 17-18% of patients receiving liposomal vincristine, and grade 3 or greater febrile neutropenia has occurred in 31% of patients.204 An increase in the platelet count has been observed in some patients with thrombocytopenia after initiation of therapy with conventional vincristine before evidence of marrow remission is apparent.131
Vincristine is a tissue irritant and may cause phlebitis and necrosis. Extravasation results in pain and cellulitis. The manufacturers of conventional vincristine 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. The manufacturer of liposomal vincristine states that the infusion should be discontinued immediately if extravasation is suspected and local treatments should be considered.204
Hypertension131 and hypotension131, 204 have been reported in patients receiving vincristine. In clinical trials in patients with ALL, grade 3 or greater hypotension and cardiac arrest each have been reported in 6% of patients receiving liposomal vincristine.204 Coronary artery disease131 and myocardial infarction124, 127, 128, 130, 131 have occurred in patients receiving conventional vincristine in combination with other antineoplastic agents.124, 127, 128, 130, 131 Although a causal relationship has not been established,131 infarction was temporally related to administration of conventional vincristine in several patients, occurring within several hours after injection of the drug.127, 130 Some conventional vincristine-treated patients who developed myocardial infarction had previously received radiation therapy to the mediastinal area,127, 131 but infarction also has been reported in patients with no history of mediastinal radiation or risk factors associated with coronary artery disease.124, 128, 130
In addition to adverse GI effects of neurogenic origin associated with conventional or liposomal vincristine therapy (see Cautions: Nervous System Effects), local effects including nausea, vomiting, diarrhea, abdominal distention, stomatitis, and oral ulceration occur occasionally in patients receiving conventional vincristine. In clinical trials in patients with ALL, nausea, diarrhea and decreased appetite have been reported in 52, 37, and 33%, respectively, of patients receiving liposomal vincristine.204 Intestinal necrosis and/or perforation and anorexia also have been reported in patients receiving conventional vincristine.131
Eighth cranial nerve damage, which may be manifested by vestibular manifestations such as dizziness, nystagmus, and vertigo, and by auditory manifestations such as varying degrees of hearing impairment (including partial or total deafness) that may be temporary or permanent, has been reported in patients receiving vinca alkaloids.131 The manufacturers of conventional vincristine state that the drug should be used concomitantly with other potentially ototoxic drugs such as platinum-containing antineoplastic agents with extreme caution.131
A syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has occurred rarely in patients receiving conventional vincristine therapy.131 The syndrome may be associated with the neurotoxicity of the drug, possibly resulting from a direct effect on the hypothalamus. In these patients, hyponatremia associated with increased urinary sodium excretion occurs without evidence of renal or adrenal disease, hypotension, dehydration, azotemia, or clinical edema.131 Fluid restriction produces improvement in sodium balance and facilitates the safe use of repeated courses of conventional vincristine in patients who experience this syndrome.
Tumor lysis syndrome may occur following rapid lysis of malignant cells. The risk of tumor lysis syndrome is increased in patients with non-Hodgkin's lymphomas or leukemia. Such patients should be monitored closely and appropriate precautions should be taken.204 In some patients, uric acid nephropathy may result.131 These effects may be minimized by adequate hydration, alkalinization of the urine, and/or administration of allopurinol.
Hepatic veno-occlusive disease, sometimes fatal, has been reported in patients receiving conventional vincristine, particularly in pediatric patients receiving conventional vincristine in combination with other chemotherapy agents.131 Hepatotoxicity, sometimes fatal, also has occurred in patients receiving liposomal vincristine.204 Grade 3 or greater elevations in AST concentrations have been reported during clinical trials in 6-11% of patients receiving liposomal vincristine.204
Other occasionally occurring adverse effects of conventional vincristine include fever and, at high doses, weight loss. In clinical trials in patients with ALL, fever and fatigue have occurred in 43 and 41%, respectively, of patients receiving liposomal vincristine and were grade 3 or greater in 15 and 12%, respectively, of patients receiving the drug.204 In these clinical trials, grade 3 or greater infections (e.g., pneumonia, septic shock, staphylococcal bacteremia) occurred in 40% of patients receiving liposomal vincristine and grade 3 or greater pain and abdominal pain each occurred in 8% of patients.204
Precautions and Contraindications
Vincristine is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity. Vincristine must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents and should only be administered by individuals experienced in administration of the drug. (See Dosage and Administration: Reconstitution and Administration.) Patients and/or their parents or guardians should be advised of the possibility of adverse effects and associated manifestations.
Because of the hepatic metabolism and biliary excretion of vincristine, some clinicians recommend reduced doses in patients with obstructive jaundice or other hepatic impairment. Conventional and liposomal vincristine must be given with care, and dosage and toxicity monitored, particularly in patients receiving other neurotoxic drugs or those with preexisting neuromuscular disease.131, 204 Complete blood cell (CBC) counts should be performed before the administration of each dose of conventional or liposomal vincristine.131, 204 Serum concentrations of uric acid should be determined frequently during the first 3-4 weeks of therapy in patients receiving vincristine for the induction of remission in acute leukemia, and appropriate measures should be taken to prevent the occurrence of hyperuricemia related to the rapid lysis of leukemic cells.131 Because of the potential for hepatotoxicity, liver function tests should be monitored.204
The manufacturer states that conventional vincristine is contraindicated in patients with the demyelinating form of Charcot-Marie-Tooth syndrome.131 Conventional vincristine also should not be administered to patients while they are receiving radiation therapy through ports that include the liver.131 Liposomal vincristine is contraindicated in patients with demyelinating conditions including Charcot-Marie-Tooth syndrome.204 Liposomal vincristine also is contraindicated in patients with known hypersensitivity to the conventional or liposomal drug or to any ingredient in the formulation.204
Care must be taken to avoid contact of conventional vincristine sulfate solutions with the eye(s), as severe irritation or corneal ulceration (especially if the drug is administered under pressure) may result.131 If contact with the eye(s) occurs, the eye(s) should be washed immediately with copious amounts of water;131 patients should consult a clinician if ocular irritation persists.
The manufacturer states that safety and efficacy of liposomal vincristine in pediatric patients have not been established.204
Vincristine should be used with caution in geriatric patients because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in this age group.204
Mutagenicity and Carcinogenicity
Genotoxicity has been demonstrated with conventional vincristine in some in vivo and in vitro studies;204 however, in vivo and in vitro tests have failed to demonstrate conclusively that vincristine is mutagenic.131 There was no evidence of carcinogenicity following intraperitoneal administration of conventional vincristine in rats and mice, but the study was limited.131 Patients receiving chemotherapy that included conventional vincristine and drugs known to be carcinogenic have developed secondary malignancies; however, the contribution of vincristine has not been determined.131 Formal carcinogenicity studies have not been conducted for conventional or liposomal vincristine.204
Pregnancy, Fertility, and Lactation
Vincristine can cause fetal toxicity when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite the possible risks to the fetus.131, 192, 193, 204 The drug can induce teratogenic and embryocidal effects in animals at doses that are not toxic to the pregnant animal.131 Dosages of conventional vincristine that caused resorption of 23-85% of fetuses in pregnant mice and hamsters produced fetal malformations that were present in surviving offspring.131 In 5 monkeys receiving single doses of conventional vincristine between days 27-34 of gestation, 3 fetuses were normal at term, while 2 had grossly evident malformations.131 Administration of liposomal vincristine to pregnant rats during organogenesis caused teratogenicity (skeletal and visceral malformations), decreased fetal weight, increased embryofetal deaths (resorptions, postimplantation losses), and decreased maternal body weight.204 Fetal malformations were observed in pregnant rats receiving liposomal vincristine at exposure levels that were approximately 20-40% of the human exposure at the recommended dosage.204 There are no adequate and controlled studies to date using conventional or liposomal vincristine in pregnant women, and the drugs should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.131, 192, 204 Women of childbearing potential should be advised to avoid becoming pregnant while receiving conventional or liposomal vincristine.131, 204 When conventional or liposomal vincristine is administered during pregnancy or the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.131, 204
Reproduction studies in animals using conventional vincristine have not been performed to date;131 however, an animal toxicology study indicates that liposomal vincristine may impair male fertility, which is consistent with literature on conventional vincristine.204 Azoospermia and increased plasma concentrations of follicle-stimulating hormone have occurred in males who received combination chemotherapy that included conventional vincristine and prednisone with cyclophosphamide or mechlorethamine and procarbazine, and amenorrhea has occurred in females receiving chemotherapy that included conventional vincristine. The manufacturers state that irreversible azoospermia or amenorrhea is less likely when chemotherapy that includes conventional vincristine is administered in prepubertal patients.131 Epididymal aspermia and testicular degeneration and atrophy have occurred in rats receiving liposomal vincristine.204
It is not known whether vincristine or its metabolites are distributed into milk.131, 204 Because of the potential for serious adverse effects in nursing infants, a decision should be made whether to discontinue nursing or conventional or liposomal vincristine, taking into account the importance of the drug to the woman.131, 204
Formal studies of drug interactions have not been conducted for liposomal vincristine; however, liposomal vincristine is expected to interact with drugs known to interact with conventional vincristine.204
Simultaneous administration of phenytoin (oral or IV) and combination chemotherapy containing conventional vincristine may reduce serum concentrations of phenytoin and increase seizure activity.131, 204 The mechanism of this interaction may involve reduced absorption of phenytoin and an increase in the rate of its metabolism and elimination.131 (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)
When conventional vincristine and asparaginase must be administered sequentially, the sequence of conventional vincristine followed by asparaginase is recommended.131 Conventional vincristine should be administered 12-24 hours preceding administration of asparaginase to minimize toxicity; administration of asparaginase first may reduce hepatic clearance of vincristine and increase the severity of adverse effects of the drug.131
Concomitant use of mitomycin and conventional vincristine may increase the risk of serious adverse respiratory effects, particularly in patients with preexisting pulmonary dysfunction.131 (See Cautions: Respiratory Effects.)
Drugs Affecting Hepatic Microsomal Enzymes
Metabolism of vinca alkaloids is mediated by the cytochrome P-450 (CYP) isoenzyme 3A, and the possibility exists that potent inhibitors of this isoenzyme may impair metabolism of vinca alkaloids.131 Concomitant use of azole antifungal agents (e.g., itraconazole, ketoconazole, posaconazole, voriconazole) and vincristine may increase plasma concentrations of vincristine and has resulted in serious adverse effects, including neuropathy (peripheral, autonomic, and cranial neuropathy), seizures, hyponatremia or syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and GI toxicity (including paralytic ileus);195, 216, 217, 218 earlier onset and/or increased severity of adverse neuromuscular effects has occurred.131 Therefore, concomitant use of vincristine with potent CYP3A inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole) should be avoided.204, 218 Azole antifungal agents should be used concomitantly with vincristine only in patients who have no alternative antifungal treatment options; if concomitant use cannot be avoided, patients should be monitored frequently for toxicity.216, 217, 218
Concomitant use of vincristine with potent CYP3A inducers (e.g., carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort [ Hypericum perforatum ]) should be avoided.204
Drugs Affecting or Affected by P-glycoprotein Transport
Vincristine is a P-glycoprotein (P-gp) substrate, and the possibility exists that potent inhibitors or inducers of P-gp may alter the pharmacokinetics or pharmacodynamics of vincristine.204 Concomitant use of vincristine with potent P-gp inhibitors or inducers should be avoided.204
Since varying degrees of permanent or temporary hearing impairment associated with eighth cranial nerve damage have been reported in patients receiving vinca alkaloids, vincristine should be used concomitantly with other potentially ototoxic drugs such as platinum-containing antineoplastic agents with extreme caution.131
Overdosage with vincristine produces adverse effects that are mainly extensions of common adverse effects. Doses 10 times the usual recommended doses of conventional vincristine sulfate have been lethal in children younger than 13 years of age, and severe manifestations of toxicity have been apparent following administration of 3-4 mg/m2 in this age group.131 Single doses of 3 mg/m2 of conventional vincristine sulfate can be expected to produce severe toxic manifestations in adults.131 Increased severity of adverse effects may be experienced by patients with hepatic impairment characterized by decreased biliary excretion.131 Grade 3 motor neuropathy and grade 4 grand mal seizure, elevated concentrations of AST, and hyperbilirubinemia occurred following administration of 2.4 mg/m2 of vincristine sulfate as the liposomal drug.204
Following vincristine overdosage, supportive and symptomatic treatment should be initiated. Treatment should include the prevention of adverse effects resulting from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (e.g., by restricting fluid intake and possibly by use of an appropriate diuretic); prophylactic administration of anticonvulsants; use of enemas to prevent ileus (in some cases, decompression of the GI tract may be necessary); monitoring of the cardiovascular system; and daily blood counts to monitor the hematologic system and guide transfusion requirements.131 Studies in mice and a few case reports have suggested that administration of leucovorin calcium may be of some value in the management of vincristine overdosage.131 A suggested regimen is to administer leucovorin calcium 100 mg IV every 3 hours for 24 hours and then every 6 hours for at least 48 hours.131 Treatment with leucovorin calcium does not preclude the need for the usual treatment measures.131 Because only small amounts of vincristine are removed by hemodialysis, removal of the drug by this method is not likely to be helpful following overdosage.131
In dogs pretreated with cholestyramine, fecal excretion of vincristine was increased; no published data are available regarding the use of cholestyramine as a possible antidote for vincristine overdosage in humans.131 No published data are available on the clinical outcome of oral ingestion of conventional vincristine.131 If oral ingestion of vincristine occurs, the stomach should be emptied immediately followed by oral administration of activated charcoal and a cathartic.131
Although the mechanism of action has not been fully elucidated, vincristine and other vinca alkaloids exert their cytotoxic effects by binding to tubulin, the protein subunit of the microtubules that form the mitotic spindle.135, 140 The formation of vincristine-tubulin complexes prevents the polymerization of the tubulin subunits into microtubules and induces depolymerization of microtubules resulting in inhibition of microtubule assembly and cellular metaphase arrest.135 In high concentrations, the drug also exerts complex effects on nucleic acid and protein synthesis. Vincristine exerts some immunosuppressive activity.
Vincristine sulfate is unpredictably absorbed from the GI tract. Following rapid IV injection of a 2-mg dose of conventional vincristine sulfate in patients with normal renal and hepatic function, peak serum drug concentrations of approximately 0.19-0.89 µM occur immediately100, 101, 102, 104 and the drug is rapidly cleared from serum.100, 101, 102, 103, 104 The area under the serum vincristine concentration-time curve has been shown to be increased following continuous IV infusion of conventional vincristine compared with rapid IV injection of the drug when comparable doses are administered.101 Following IV infusion over 1 hour of a 2.25-mg/m2 dose of vincristine sulfate as the liposomal drug in patients with acute lymphocytic leukemia (ALL), peak concentrations of total vincristine sulfate average 1220 ng/mL and reflect liposome-encapsulated drug that may not be immediately bioavailable.204 Because clearance of the drug is slower following administration as liposomal vincristine, systemic exposure of the drug is increased relative to that of conventional vincristine.204
Distribution of vincristine and its metabolites (and/or decomposition products) into human body tissues and fluids has not been fully characterized, but the drug is rapidly and apparently widely distributed following IV administration of conventional vincristine.100, 101, 102, 103, 104 Drug that is distributed into tissues is tightly but reversibly bound.125, 131 Vincristine and its metabolites (and/or decomposition products) are rapidly and extensively distributed into bile, with peak biliary concentrations occurring within 2-4 hours after rapid IV injection of conventional vincristine.103 Vincristine and its metabolites (and/or decomposition products) cross the blood-brain barrier poorly following rapid IV injection of conventional vincristine and generally do not appear in the CSF in cytotoxic concentrations.102 It is not known whether vincristine and its metabolites are distributed into milk.
Following rapid IV injection of conventional vincristine, serum concentrations of the drug appear to decline in a triphasic manner.100, 101, 102, 131 The terminal elimination half-life of conventional vincristine has ranged from 19-155 hours.131 Clearance of the drug is slower following administration as a liposome-encapsulated formulation compared with administration as a conventional formulation (345 versus 11,340 mL/hour).204
The metabolic fate of vincristine has not been clearly determined; the drug appears to be extensively metabolized, probably in the liver by the cytochrome P-450 microsomal enzyme system, including CYP3A,131 but the extent of metabolism is not clear since the drug also apparently undergoes decomposition in vivo.100, 103 In patients with hepatic impairment, metabolism of vincristine may be decreased.131 Vincristine and its metabolites (and/or decomposition products) are excreted principally in feces via biliary elimination.100, 103 Following rapid IV injection of conventional vincristine in adults with normal renal and hepatic function, about 30% of a dose is excreted in feces within 24 hours and 70% within 72 hours;100 about 10% of a dose is excreted in urine within 24 hours,100, 104 with very little urinary excretion occurring thereafter.100 Following IV administration of liposomal vincristine, the extent of urinary excretion (less than 8% of the administered dose within 96 hours) is similar to that of conventional vincristine.204 The effects of hepatic impairment on the elimination of vincristine and its metabolites (and/or decomposition products) have not been established, but individuals with decreased hepatic function may have impaired elimination.102, 103 In a limited number of patients with melanoma and moderate hepatic impairment (Child-Pugh class B) secondary to liver metastases, dose-adjusted peak plasma concentrations and systemic exposure of liposomal vincristine207 were similar to those observed in patients with ALL and normal hepatic function.204
Only small amounts of vincristine are removed by hemodialysis.131
Vincristine sulfate, a naturally occurring vinca alkaloid, is an antimicrotubule antineoplastic agent.135, 140 Vincristine sulfate is the salt of a dimeric alkaloid isolated from Catharanthus roseus. Vincristine sulfate occurs as a white, off-white, or slightly yellow, hygroscopic, amorphous or crystalline powder and is freely soluble in water and slightly soluble in alcohol.131 Sulfuric acid,131 sodium hydroxide,131 acetic acid,194 and/or sodium acetate194 is added during the manufacture of conventional vincristine sulfate injection to adjust pH to 4-5131 or 3.5-5.5 depending on the preparation;194 the injection also contains mannitol.131, 194
Liposomal vincristine sulfate (Marqibo®) is 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 When prepared as directed, vincristine sulfate liposome injection is a sterile, preservative-free, white to off-white suspension of vincristine sulfate encapsulated in sphingomyelin-cholesterol liposomes.204 Each mL of vincristine sulfate liposome injection contains 0.16 mg of vincristine sulfate; more than 95% of the drug is encapsulated in liposomes.204 The liposomes are composed of sphingomyelin and cholesterol in a molar ratio of approximately 60:40; the mean liposome diameter is approximately 100 nm.204 Vincristine sulfate liposome injection also contains dibasic sodium phosphate, sodium citrate, citric acid, mannitol, sodium chloride, and ethanol.204
Conventional vincristine sulfate solutions are light-sensitive and must be protected from light. Conventional vincristine sulfate injection should be refrigerated at 2-8°C; the vials should be stored in an upright position.131
Commercially available liposomal vincristine sulfate (Marqibo®) kits containing single-use vials of vincristine sulfate solution, sphingomyelin-cholesterol liposome suspension, and dibasic sodium phosphate solution should be refrigerated at 2-8°C and should not be frozen.204 Once the 3 components have been admixed, the resultant liposomal vincristine sulfate injection concentrate may be stored at 15-30°C for up to 12 hours.204 Administration of the final diluted preparation of the drug should be completed within 12 hours of initiation of preparation of vincristine sulfate liposome injection.204
When preparing a diluted solution, the manufacturer states that conventional vincristine sulfate injection should be mixed only with 0.9% sodium chloride injection or 5% dextrose injection; the drug should not be diluted in solutions that raise or lower the pH outside the range of 3.5-5.5.131
Specialized references should be consulted for specific compatibility information. Doses of 0.5, 1, 2, or 3 mg of conventional vincristine sulfate diluted in 25 or 50 mL of 0.9% sodium chloride solution in small-volume IV bags (i.e., minibags) or in 20 mL of 0.9% sodium chloride solution in a 30-mL syringe remained stable when stored for 7 days at 4°C followed by 2 days at 23°C.199
Additional Information
For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV use only | 1 mg/mL (1 and 2 mg)* | Vincristine Sulfate Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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) |
Only references cited for selected revisions after 1984 are available electronically.
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