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VinCRIStine

Pronunciation

Pronunciation

(vin KRIS teen)

Index Terms

  • Conventional Vincristine
  • Leurocristine Sulfate
  • Oncovin
  • Vincristine (Conventional)
  • Vincristine Sulfate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous, as sulfate:

Vincasar PFS: 1 mg/mL (1 mL, 2 mL)

Solution, Intravenous, as sulfate [preservative free]:

Generic: 1 mg/mL (1 mL, 2 mL)

Brand Names: U.S.

  • Vincasar PFS

Pharmacologic Category

  • Antineoplastic Agent, Antimicrotubular
  • Antineoplastic Agent, Vinca Alkaloid

Pharmacology

Binds to tubulin and inhibits microtubule formation, therefore, arresting the cell at metaphase by disrupting the formation of the mitotic spindle; it is specific for the M and S phases. Vincristine may also interfere with nucleic acid and protein synthesis by blocking glutamic acid utilization.

Distribution

Rapidly removed from bloodstream and tightly bound to tissues; penetrates blood-brain barrier poorly

Metabolism

Extensively hepatic, via CYP3A4

Excretion

Feces (~80%); urine (10% to 20%; <1% as unchanged drug)

Clearance: In pediatric patients, correlation with diagnosis has been reported; clearance in patients with ALL and non-Hodgkin lymphoma higher than Wilms’ tumor (Gidding 1999):

Infants: Vincristine clearance is lower compared to children; more closely related to body weight than to body surface area (Crom 1994)

Children and Adolescents 2 to 18 years: Reported means: 357 to 482 mL/minute/m2; some suggest faster clearance in children <10 years of age than in adolescents (Crom 1994); however, more recent data does not support this finding nor a dosage reduction in adolescent patients (Frost 2003; Gidding 1999)

Half-Life Elimination

Terminal: 85 hours (range: 19-155 hours)

Use: Labeled Indications

Treatment of acute lymphocytic leukemia (ALL), Hodgkin lymphoma, non-Hodgkin lymphomas, Wilms' tumor, neuroblastoma, rhabdomyosarcoma

Use: Unlabeled

Treatment of central nervous system tumors, chronic lymphocytic leukemia (CLL), Ewing’s sarcoma, gestational trophoblastic tumors (high-risk), multiple myeloma, ovarian germ cell tumors, retinoblastoma, small cell lung cancer (SCLC); thymoma (advanced)

Contraindications

Patients with the demyelinating form of Charcot-Marie-Tooth syndrome

Dosing: Adult

Note: Doses may be capped at a maximum of 2 mg/dose. Dosing and frequency may vary by protocol and/or treatment phase; refer to specific protocol. In order to prevent inadvertent intrathecal administration, the World Health Organization (WHO) and the Institute for Safe Medication Practices (ISMP) strongly recommend dispensing vincristine in a minibag (NOT a syringe).

Doses in the manufacturer’s U.S. labeling: IV: 1.4 mg/m2/dose; frequency may vary based on protocol

Additional dosing in combination therapy; indication-specific and/or off-label dosing:

Acute lymphocytic leukemia (ALL): IV:

Hyper-CVAD regimen: 2 mg/dose days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, followed by maintenance treatment (if needed) of 2 mg monthly for 2 years (Kantarjian, 2004)

CALBG 8811 regimen: Induction phase: 2 mg/dose days 1, 8, 15, and 22 (4-week treatment cycle); Early intensification phase: 2 mg/dose days 15, and 22 (4-week treatment cycle, repeat once); Late intensification phase: 2 mg/dose days 1, 8, 15 (8-week treatment cycle); Maintenance phase: 2 mg/dose day 1 every 4 weeks until 24 months from diagnosis (Larson, 1995)

Central nervous system tumors: IV: PCV regimen: 1.4 mg/m2/dose (maximum dose: 2 mg) on days 8 and 29 of a 6-week treatment cycle for a total of 6 cycles (van de Bent, 2006) or 1.4 mg/m2/dose (no maximum dose) on days 8 and 29 of a 6-week treatment cycle for up to 4 cycles (Cairncross, 2006)

Hodgkin lymphoma: IV:

BEACOPP regimen: 1.4 mg/m2/dose (maximum dose: 2 mg) on day 8 of a 21-day treatment cycle (Diehl, 2003)

Stanford-V regimen: 1.4 mg/m2/dose (maximum dose: 2 mg) in weeks 2, 4, 6, 8, 10, and 12 (Horning, 2000; Horning, 2002)

Non-Hodgkin lymphoma: IV:

Burkitt lymphoma:

CODOX-M/IVAC: Cycles 1 and 3 (CODOX-M): 1.5 mg/m2 (no maximum dose) days 1 and 8 of cycle 1 and days 1, 8, and 15 of cycle 3 (Magrath, 1996) or 1.5 mg/m2 (maximum dose: 2 mg) days 1 and 8 of cycles 1 and 3 (Mead 2002; Mead 2008); CODOX-M is in combination with cyclophosphamide, doxorubicin, methotrexate, and CNS prophylaxis and alternates with IVAC (etoposide, ifosfamide, mesna, cytarabine, and CNS prophylaxis) for a total of 4 cycles

Hyper-CVAD: 2 mg (flat dose) days 4 and 11 of courses 1, 3, 5, and 7 (in combination with cyclophosphamide, doxorubicin, and dexamethasone) and alternates with even courses 2, 4, 6, and 8 (methotrexate and cytarabine) (Thomas, 2006)

Follicular lymphoma: CVP regimen: 1.4 mg/m2/dose (maximum dose: 2 mg) on day 1 of a 21-day treatment cycle (in combination with cyclophosphamide and prednisone) for 8 cycles (Marcus, 2005)

Large B-cell lymphoma:

CHOP regimen: 1.4 mg/m2/dose (maximum dose: 2 mg) on day 1 of a 21-day treatment cycle for 8 cycles (Coiffier, 2002)

EPOCH regimen: 0.4 mg/m2/day continuous infusion for 4 days (over 96 hours) (total 1.6 mg/m2/cycle; dose not usually capped) of a 21-day treatment cycle (Wilson, 2002)

Ewing’s sarcoma (off-label use): IV: VAC/IE regimen: VAC: 2 mg/m2 (maximum dose: 2 mg) on day 1 of a 21-day treatment cycle (in combination with doxorubicin and cyclophosphamide), alternates with IE (ifosfamide and etoposide) for a total of 17 cycles (Grier, 2003)

Gestational trophoblastic tumors, high-risk (off-label use): IV: EMA/CO regimen: 1 mg/m2 on day 8 of 2-week treatment cycle (in combination with etoposide methotrexate, dactinomycin, and cyclophosphamide), continue for at least 2 treatment cycles after a normal hCG level (Escobar, 2003)

Multiple myeloma (off-label use): IV:

DVD regimen: 1.4 mg/m2/dose (maximum dose: 2 mg) on day 1 of a 28-day treatment cycle (Rifkin, 2006)

VAD regimen: 0.4 mg/day continuous infusion for 4 days (over 96 hours) (total 1.6 mg/cycle) of a 28-day treatment cycle (Rifkin, 2006)

Ovarian cancer (off-label use): IV: VAC regimen: 1.5 mg/m2/dose (maximum dose: 2 mg) weekly for 8-12 weeks (Slayton, 1985)

Small cell lung cancer (off-label use): IV: CAV regimen: 1.4 mg/m2/dose day 1 of a 21-day treatment cycle (Hong, 1989) or 2 mg/dose on day 1 of a 21-day treatment cycle (von Pawel, 1999)

Thymoma, advanced (off-label use): IV: ADOC regimen: 0.6 mg/m2 on day 3 every 3 weeks (in combination with cisplatin, doxorubicin, and cyclophosphamide) (Fornasiero, 1991)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Doses may be capped at a maximum of 2 mg/dose. Dosing and frequency may vary by protocol and/or treatment phase; refer to specific protocol. In order to prevent inadvertent intrathecal administration, the World Health Organization (WHO) and the Institute for Safe Medication Practices (ISMP) strongly recommend dispensing vincristine in a minibag (NOT in a syringe).

Doses in the manufacturer’s U.S. labeling: IV:

Children ≤10 kg: 0.05 mg/kg/dose once weekly

Children >10 kg: 1.5-2 mg/m2/dose; frequency may vary based on protocol

Additional dosing in combination therapy; indication-specific and/or off-label dosing:

Acute lymphocytic lymphoma (ALL): IV: Induction phase: 1.5 mg/m2/dose days 0, 7, 14, and 21; Consolidation phase: 1.5 mg/m2/dose days 0, 28, and 56; Delayed intensification phase: 1.5 mg/m2/dose days 0, 7, and 14; Maintenance phase: 1.5 mg/m2/dose days 0, 28, and 56 (Bostrom, 2003) or Induction phase: 1.5 mg/m2/dose days 0, 7, 14, and 21; Consolidation phase: 1.5 mg/m2/dose days 0, 28, and 56; Interim maintenance phases: 1.5 mg/m2/dose days 0 and 28; Delayed intensification phase: 1.5 mg/m2/dose days 0, 7, and 14; Maintenance phase: 1.5 mg/m2/dose every 4 weeks (Avramis, 2002)

Burkitt lymphoma and B-cell ALL: IV: 1.5 mg/m2 (maximum dose: 2 mg) on days 4 and 11 of initial phase cycle (initial phase is in combination with cyclophosphamide, doxorubicin, and CNS prophylaxis; alternates with secondary phase) for a total of 4 cycles of each phase (Bowman, 1996) or 1.5 mg/m2 (maximum dose: 2 mg) on day 1 of cycle AA (in combination with dexamethasone, ifosfamide, methotrexate, cytarabine, etoposide and CNS prophylaxis) and on day 1 of cycle BB (in combination with dexamethasone, cyclophosphamide, methotrexate, doxorubicin, and CNS prophylaxis) (Reiter, 1999)

Ewing's sarcoma (off-label use): IV: 2 mg/m2/dose (maximum dose: 2 mg) on day 1 of a 21-day cycle, administer either every cycle or during odd-numbered cycles (Grier, 2003) or 0.67 mg/m2/day continuous infusion days 1, 2, and 3 (total 2 mg/m2/cycle; maximum dose/cycle: 2 mg) during cycles 1, 2, 3, and 6 (Kolb, 2003)

Hodgkin lymphoma: IV: BEACOPP regimen: 2 mg/m2/dose (maximum dose: 2 mg) on day 7 of a 21-day treatment cycle (Kelly, 2002)

Neuroblastoma: IV:

CE-CAdO regimen: 1.5 mg/m2 (maximum dose: 2 mg) days 1 and 5 every 21 days for 2 cycles (Rubie, 1998) or 0.05 mg/kg days 1 and 5 for 2 cycles (Rubie, 2001)

CAV-P/VP regimen (off-label dosing): 0.033 mg/kg/day continuous infusion days 1, 2, and 3, then 1.5 mg/m2 bolus day 9 of courses 1, 2, 4, and 6 (Kushner, 1994)

Retinoblastoma (off-label use): IV:

Children: 0.05 mg/kg on day 1 every 21 days (in combination with carboplatin) for 8 cycles (Rodriguez-Galindo, 2003)

or

Children ≤36 months: 0.05 mg/kg on day 0 every 28 days (in combination with carboplatin and etoposide) for 6 cycles (Freidman, 2000)

or

Children >36 months: 1.5 mg/m2 (maximum dose: 2 mg) on day 0 every 28 days (in combination with carboplatin and etoposide) for 6 cycles (Friedman, 2000)

Rhabdomyosarcoma: IV:

VA regimen: 1.5 mg/m2/dose (maximum dose: 2 mg) weeks 1-8, weeks 13-20, and weeks 25-32 (Crist, 2001)

VAC regimen: 1.5 mg/m2/dose (maximum dose: 2 mg) weeks 0-12, week 16, weeks 20-25; Continuation therapy: Weeks 29-34, and weeks 38-43 (Crist, 2001)

Wilms' tumor: IV:

Children <1 year: 0.75 mg/m2/dose weekly for 10-11 weeks, then every 3 weeks for 15 additional weeks (total 25-26 weeks) (Pritchard, 1995)

Children ≥1 year: 1.5 mg/m2/dose weekly for 10-11 weeks, then every 3 weeks for 15 additional weeks (total 25-26 weeks) (Pritchard, 1995)

or

Children ≤30 kg: 0.05 mg/kg/dose (maximum dose: 2 mg) weeks 1, 2, 4, 5, 6, 7, 8, 10, and 11, followed by 0.067 mg/kg/dose (maximum dose: 2 mg) weeks 12, 13, 18, and 24 (Green, 2007)

Children >30 kg: 1.5 mg/m2/dose (maximum dose: 2 mg) weeks 1, 2, 4, 5, 6, 7, 8, 10, and 11, followed by 2 mg/m2/dose (maximum dose: 2 mg) weeks 12, 13, 18, and 24 (Green, 2007)

Dosing: Renal Impairment

No dosage adjustment necessary (Kintzel, 1995).

Dosing: Hepatic Impairment

The manufacturer’s labeling recommends the following adjustment: Serum bilirubin >3 mg/dL: Administer 50% of normal dose.

The following adjustments have also been recommended:

Floyd, 2006: Serum bilirubin 1.5-3 mg/dL or transaminases 2-3 times ULN or alkaline phosphatase increased: Administer 50% of dose.

Superfin, 2007:

Serum bilirubin 1.5-3 mg/dL: Administer 50% of dose.

Serum bilirubin >3 mg/dL: Avoid use.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Dose should be capped at a maximum of 2 mg due to neurotoxicity concerns (Griggs, 2012)

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Solutions for IV infusion may be mixed in NS or D5W. Note: In order to prevent inadvertent intrathecal administration the World Health Organization (WHO) and the Institute for Safe Medication Practices (ISMP) strongly recommend dispensing vincristine in a minibag (NOT in a syringe). Vincristine should NOT be prepared during the preparation of any intrathecal medications. If dispensing vincristine in a syringe, affix an auxiliary label stating “For intravenous use only - fatal if given by other routes” to the syringe, and the syringe must also be packaged in the manufacturer-provided overwrap which bears the statement "Do not remove covering until the moment of injection. For intravenous use only. Fatal if given intrathecally."

Administration

For IV administration only. FATAL IF GIVEN INTRATHECALLY.

In order to prevent inadvertent intrathecal administration, the World Health Organization (WHO) and the Institute for Safe Medication Practices (ISMP) strongly recommend dispensing vincristine in a minibag (NOT in a syringe). Vincristine should NOT be delivered to the patient at the same time with any medications intended for central nervous system administration.

IV: Preferred administration is as a short 5- to 10-minute infusion in a 25 to 50 mL minibag. If administration via minibag is not possible, may also be administered as a slow (1-minute) push. Some protocols utilize a 24-hour continuous infusion.

Vesicant; ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); initiate hyaluronidase antidote; remove needle/cannula; apply dry warm compresses for 20 minutes 4 times a day for 1 to 2 days; elevate (Perez Fidalgo, 2012). Remaining portion of the vincristine dose should be infused through a separate vein.

Hyaluronidase: If needle/cannula still in place, administer 1 to 6 mL hyaluronidase (150 units/mL) into the existing IV line; the usual dose is 1 mL hyaluronidase for each 1 mL of extravasated drug (Perez Fidalgo, 2012; Schulmeister, 2011). If needle/cannula was removed, inject 1 to 6 mL (150 units/mL) subcutaneously in a clockwise manner using 1 mL for each 1 mL of drug extravasated (Schulmeister, 2011) or administer 1 mL (150 units/mL) as 5 separate 0.2 mL injections (using a 25-gauge needle) subcutaneously into the extravasation site (Polovich, 2009).

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Stable in D5W, LR, NS.

Y-site administration: Incompatible with cefepime, furosemide, idarubicin, sodium bicarbonate.

Storage

Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light.

IV solution: Diluted in 25 to 50 mL NS or D5W, stable for 7 days under refrigeration, or 2 days at room temperature. In ambulatory pumps, solution is stable for 7 days at room temperature. After preparation, keep vincristine in a location away from the separate storage location recommended for intrathecal medications.

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosphenytoin: May decrease the serum concentration of VinCRIStine. VinCRIStine may decrease the serum concentration of Fosphenytoin. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Itraconazole: May enhance the adverse/toxic effect of VinCRIStine. Itraconazole may increase the serum concentration of VinCRIStine. Consider therapy modification

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

Lopinavir: May increase the serum concentration of VinCRIStine. Management: Monitor closely for signs and symptoms of vincristine toxicity; consider temporary interruption of lopinavir/ritonavir antiviral therapy if patients develop significant toxicity with concurrent use. Consider therapy modification

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Macrolide Antibiotics: May increase the serum concentration of Antineoplastic Agents (Vinca Alkaloids). Macrolides may also increase the distribution of Vinca Alkaloids into certain cells and/or tissues. Management: Consider an alternative to using a macrolide antibiotic when possible in order to avoid the potential for increased vinca alkaloid toxicity. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

MitoMYcin (Systemic): Antineoplastic Agents (Vinca Alkaloids) may enhance the adverse/toxic effect of MitoMYcin (Systemic). Specifically, the risk of pulmonary toxicity may be increased. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

NIFEdipine: May increase the serum concentration of VinCRIStine. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Phenytoin: May decrease the serum concentration of VinCRIStine. VinCRIStine may decrease the serum concentration of Phenytoin. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Posaconazole: May enhance the adverse/toxic effect of Antineoplastic Agents (Vinca Alkaloids). Posaconazole may increase the serum concentration of Antineoplastic Agents (Vinca Alkaloids). Management: Avoid the concomitant use of posaconazole and vinca alkaloids when possible. If combined, monitor for increased vinca alkaloid toxicities (eg, neurotoxicity, gastrointestinal toxicity). Consider therapy modification

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Ritonavir: May increase the serum concentration of VinCRIStine. Management: Monitor closely for signs and symptoms of vincristine toxicity; consider temporary interruption of ritonavir antiviral therapy if patients develop significant toxicity with concurrent use. Consider therapy modification

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Teniposide: May enhance the neurotoxic effect of VinCRIStine. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Voriconazole: May enhance the adverse/toxic effect of Antineoplastic Agents (Vinca Alkaloids). Voriconazole may increase the serum concentration of Antineoplastic Agents (Vinca Alkaloids). Consider therapy modification

Adverse Reactions

Frequency not defined.

Cardiovascular: Edema, hepatic veno-occlusive disease (SOS; hepatic sinusoidal obstruction syndrome), hypertension, hypotension, ischemic heart disease, myocardial infarction, phlebitis

Central nervous system: Abnormal gait, ataxia, coma, cranial nerve dysfunction (auditory impairment, extraocular muscle impairment, laryngeal muscle impairment, motor dysfunction, paralysis, paresis, vestibular damage, vocal cord paralysis), decreased deep tendon reflex, dizziness, headache, neurotoxicity (dose-related), neuropathic pain (common), paralysis, paresthesia, parotid pain, peripheral neuropathy (common), seizure, sensorimotor neuropathy, sensory loss, vertigo

Dermatologic: Alopecia (common), skin rash

Endocrine & metabolic: Hyperuricemia, uric acid nephropathy (acute), weight loss

Gastrointestinal: Abdominal cramps, abdominal pain, anorexia, constipation (common), diarrhea, intestinal necrosis, intestinal perforation, nausea, oral mucosa ulcer, paralytic ileus, sore throat, vomiting

Genitourinary: Bladder atony, dysuria, urinary retention

Hematologic & oncologic: Anemia (mild), hemolytic uremic syndrome, leukopenia (mild), thrombocytopenia (mild), thrombotic thrombocytopenic purpura

Local: Local irritation (if infiltrated)

Neuromuscular & skeletal: Amyotrophy, back pain, foot-drop, jaw pain, limb pain, myalgia, ostealgia

Ophthalmic: Cortical blindness (transient), nystagmus, optic atrophy with blindness

Otic: Deafness

Renal: Polyuria

Respiratory: Bronchospasm, dyspnea

Miscellaneous: Fever, tissue necrosis (if infiltrated)

<1% (Limited to important or life-threatening): Anaphylaxis, hypersensitivity reaction, SIADH (syndrome of inappropriate antidiuretic hormone secretion)

ALERT: U.S. Boxed Warning

Experienced physician:

Vincristine should be administered by individuals experienced in the administration of the drug.

Extravasation:

It is extremely important that the intravenous (IV) needle or catheter be properly positioned before any vincristine is injected. Leakage into surrounding tissue during IV administration may cause considerable irritation. If extravasation occurs, discontinue the injection immediately and then introduce any remaining portion of the dose into another vein. Local injection of hyaluronidase and the application of moderate heat to the area of leakage will help disperse the drug and are thought to minimize discomfort and the possibility of cellulitis.

Not for intrathecal use:

For IV use only. Fatal if given by other routes. The intrathecal administration of vincristine usually results in death.

Syringes containing this product should be labeled, using the auxiliary sticker provided, to state, “For intravenous use only. Fatal if given by other routes.” Extemporaneously prepared syringes containing this product must be packaged in an overwrap that is labeled, “Do not remove covering until moment of injection. For intravenous use only. Fatal if given by other routes".

Treatment of patients following intrathecal administration of vincristine has included immediate removal of spinal fluid and flushing with Ringer's lactate solution, as well as other solutions, and has not prevented ascending paralysis and death. In one case, progressive paralysis in an adult was arrested by the following treatment initiated immediately after the intrathecal injection:

As much spinal fluid was removed as could be safely done through lumbar access.

The subarachnoid space was flushed with Ringer's lactate solution infused continuously through a catheter in a cerebral lateral ventricle at the rate of 150 mL/h. The fluid was removed through a lumbar access.

As soon as fresh frozen plasma became available, the fresh frozen plasma, 25 mL, diluted in 1 L of Ringer's lactate solution was infused through the cerebral ventricular catheter at the rate of 75 mL/h with removal through the lumbar access. The rate of infusion was adjusted to maintain a protein level in the spinal fluid of 150 mg/dL.

Glutamic acid 10 g was given IV over 24 hours followed by 500 mg 3 times daily by mouth for 1 month or until neurological dysfunction stabilized. The role of glutamic acid in this treatment is not certain and may not be essential.

Warnings/Precautions

Concerns related to adverse effects:

• Gastrointestinal effects: Constipation, paralytic ileus, intestinal necrosis and/or perforation may occur; constipation may present as upper colon impaction with an empty rectum (may require flat film of abdomen for diagnosis); generally responds to high enemas and laxatives. All patients should be on a prophylactic bowel management regimen.

• Extravasation: [US Boxed Warning]: Vincristine is a vesicant; ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation. Individuals administering should be experienced in vincristine administration. Extravasation may cause significant irritation. If extravasation occurs, discontinue immediately and initiate appropriate extravasation management, including local injection of hyaluronidase and moderate heat application to the affected area. Use a separate vein to complete administration.

• Neurotoxicity: Alterations in mental status such as depression, confusion, or insomnia may occur; neurologic effects are dose-limiting (may require dosage reduction) and may be additive with those of other neurotoxic agents and spinal cord irradiation. Use with caution in patients with pre-existing neuromuscular disease and/or with concomitant neurotoxic agents.

• Respiratory effects: Acute shortness of breath and severe bronchospasm have been reported with vinca alkaloids, usually when used in combination with mitomycin. Onset may be several minutes to hours after vincristine administration and up to 2 weeks after mitomycin. Progressive dyspnea may occur. Permanently discontinue vincristine if pulmonary dysfunction occurs.

• Uric acid nephropathy: Acute uric acid nephropathy has been reported with vincristine.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage modification required. May be associated with hepatic sinusoidal obstruction syndrome (SOS; formerly called veno-occlusive disease [VOD]), increased risk in children <3 years of age; use with caution in hepatobiliary dysfunction. Monitor for signs or symptoms of hepatic SOS, including bilirubin >1.4 mg/dL, unexplained weight gain, ascites, hepatomegaly, or unexplained right upper quadrant pain (Arndt, 2004).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]); avoid eye contamination.

Other warnings/precautions:

• Not for intrathecal administration: [US Boxed Warning]: For IV administration only; inadvertent intrathecal administration usually results in death. To prevent administration errors, the Institute for Safe Medication Practices (ISMP) Targeted Medication Safety Best Practices for Hospitals initiative and the World Health Organization strongly recommend dispensing vincristine diluted in a minibag (ISMP, 2014; WHO, 2007), if not dispensed in a minibag, affix an auxiliary label stating “For intravenous use only - fatal if given by other routes” and also place in an overwrap labeled “Do not remove covering until moment of injection.” Vincristine should NOT be prepared during the preparation of any intrathecal medications. After preparation, keep vincristine in a location away from the separate storage location recommended for intrathecal medications. Vincristine should NOT be delivered to the patient at the same time with any medications intended for central nervous system administration.

Monitoring Parameters

Serum electrolytes (sodium), hepatic function tests, CBC with differential, serum uric acid; monitor infusion site; neurologic examination, monitor for constipation/ileus and for signs/symptoms of peripheral neuropathy

Pregnancy Risk Factor

D

Pregnancy Considerations

Animal reproduction studies have demonstrated teratogenicity and fetal loss. May cause fetal harm if administered during pregnancy. Women of childbearing potential should avoid becoming pregnant during treatment.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, lack of appetite, abdominal cramps, weight loss, bone pain, joint pain, muscle pain, back pain, or hair loss. Have patient report immediately to prescriber signs of infection, signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), muscle weakness, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), severe injection site redness, burning, edema, pain or irritation, abnormal gait, shortness of breath, burning or numbness feeling, muscle weakness, severe constipation, severe abdominal pain, severe loss of strength and energy, change in balance, blindness, involuntary eye movements, throat pain, neck pain, jaw pain, vision changes, hearing impairment, hearing loss, seizures, bruising, bleeding, painful urination, polyuria, severe headache, dizziness, or passing out (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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