Vincristine

L01C - Plant alkaloids and other natural products ATC L01CA02 Small molecule approved 1963 Parenteral Natural product Black-box warning

JFDA label: VINCRISTINE INJ 1 MG

⚠ Black-Box Warning

Experienced physician:
Extravasation:
Not for intrathecal use:

Mechanism of Action

Vincristine 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.

Indications

Approved

Acute lymphocytic leukemia
Hodgkin lymphoma
Neuroblastoma
Non-Hodgkin lymphomas
Rhabdomyosarcoma
Wilms tumor

Off-label

Central nervous system tumors (low grade gliomas, medulloblastoma)
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
Ewing sarcoma
Gestational trophoblastic tumors (high-risk)
Multiple myeloma
Ovarian germ cell tumors
Primary CNS lymphoma
Retinoblastoma (Children)
Small cell lung cancer
Thymoma, advanced

Class profile

mechanismClass	Plant alkaloid (vinca alkaloid)
targetMolecule	Beta-tubulin (prevents polymerization)
targetPathway	Mitotic spindle assembly
generation	1st generation vinca
primaryTumors	ALL,Lymphoma,Neuroblastoma,Wilms tumor,Rhabdomyosarcoma
resistanceMechanisms	MDR1/P-gp efflux,Altered beta-tubulin (TUBB mutations),Beta-III tubulin overexpression
source	NCCN/OncoKB/Goodman&Gilman13ed

Contraindications

Source: Lexicomp

Patients with the demyelinating form of Charcot-Marie-Tooth syndrome Documentation of allergenic cross-reactivity for drugs in this class is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (6)

Not Known Edema · hypertension · hypotension · ischemic heart disease · myocardial infarction · phlebitis

Nervous system disorders (17)

Not Known 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 · neuralgia (common) · neurotoxicity (dose-related) · paralysis · paresthesia · parotid pain · peripheral neuropathy (common) · seizure · sensorimotor neuropathy · sensory disturbance · vertigo

Hepatobiliary disorders (1)

Not Known Hepatic sinusoidal obstruction syndrome (formerly known as hepatic veno-occlusive disease)

Renal and urinary disorders (4)

Not Known Bladder dysfunction (atony) · dysuria · Polyuria · urinary retention

Blood and lymphatic system disorders (5)

Not Known Anemia (mild) · hemolytic uremic syndrome · leukopenia (mild) · thrombocytopenia (mild) · thrombotic thrombocytopenic purpura

Metabolism and nutrition disorders (3)

Not Known Hyperuricemia · uric acid nephropathy (acute) · weight loss

Gastrointestinal disorders (12)

Not Known Abdominal cramps · abdominal pain · anorexia · constipation (common) · diarrhea · intestinal necrosis · intestinal perforation · nausea · oral mucosa ulcer · paralytic ileus · sore throat · vomiting

Skin and subcutaneous tissue disorders (2)

Not Known Alopecia (common) · skin rash

Musculoskeletal and connective tissue disorders (7)

Not Known Amyotrophy · back pain · foot-drop · jaw pain · limb pain · myalgia · ostealgia

Eye disorders (3)

Not Known Cortical blindness (transient) · nystagmus · optic atrophy with blindness

Ear and labyrinth disorders (1)

Not Known Deafness

General disorders and administration site conditions (3)

Not Known Fever · Local irritation (if infiltrated) · tissue necrosis (if infiltrated)

Respiratory, thoracic and mediastinal disorders (2)

Not Known Bronchospasm · dyspnea

Dosing

Source: Lexicomp

Note: Doses may be capped at a maximum of 2 mg/dose. Dosing and frequency may vary by protocol and/or treatment phase. 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). Dosing in the manufacturer’s labeling: IV: 1.4 mg/m2/dose; frequency may vary based on protocol 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 (off-label use): IV: Low-grade gliomas (eg, supratentorial grade 2 astrocytoma, oligodendroglioma, or oligoastrocytoma): 1.4 mg/m2 (maximum dose: 2 mg) on days 8 and 29 of an 8-week treatment cycle (in combination with procarbazine and lomustine) for 6 cycles (Buckner 2016; Shaw 2012) Medulloblastoma: Adults ≤21 years of age: 1.5 mg/m2 (maximum dose: 2 mg) weekly for a maximum of 8 doses (in combination with radiation, cisplatin, and either lomustine or cyclophosphamide) (Packer 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) Chronic lymphocytic leukemia/small lymphocytic leukemia (with Richter transformation) (off-label use): IV: 2 mg (flat dose) days 4 and 11 of courses 1, 3, 5, and 7 (in combination with cyclophosphamide, mesna, doxorubicin, and dexamethasone [± rituximab]) and alternates with even courses 2, 4, 6, and 8 (methotrexate, leucovorin, and cytarabine) (Thomas 2006; Tsimberidou 2003) or 1.4 mg/m2/dose (maximum dose: 2 mg) on day 1 of a 21-da

(For additional information see "Vincristine (conventional): Pediatric drug information") 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). Dosing in the manufacturer’s labeling: IV: Children ≤10 kg: 0.05 mg/kg/dose once weekly Children >10 kg: 1.5 to 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 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) Medulloblastoma (off-label use): Children ≥3 years of age and Adolescents: IV: 1.5 mg/m2 (maximum dose: 2 mg) weekly for a maximum of 8 doses (in combination with radiation, cisplatin, and either lomustine or cyclophosphamide) (Packer 2006) 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 carboplat

Refer to adult dosing.

No dosage adjustment necessary (Kintzel 1995).

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 to 3 mg/dL or transaminases 2 to 3 times ULN or alkaline phosphatase increased: Administer 50% of dose. Superfin 2007: Serum bilirubin 1.5 to 3 mg/dL: Administer 50% of dose. Serum bilirubin >3 mg/dL: Avoid use.

Warnings & Precautions

Source: Lexicomp

Extravasation

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.

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.

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 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

Avoid eye contamination. Other warnings/precautions:

Not for intrathecal administration

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.

Pregnancy & Lactation

Pregnancy

FDA category D Teratogenic

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.

Lactation

It is not known if vincristine is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, the decision to discontinue vincristine or to discontinue breastfeeding should take into account the benefits of treatment to the mother.

Monitoring

Efficacy	Tumour response (RECIST criteria, tumour markers, imaging); progression-free survival; performance status (ECOG/Karnofsky)
Toxicity	CBC with differential (nadir timing depends on agent); LFTs; renal function; ECG (QT for relevant agents); echocardiogram for cardiotoxic agents (anthracyclines, trastuzumab); cumulative dose tracking for dose-limited toxicities
Clinical pearl	Treatment response is assessed after 2–3 cycles. Grade 3–4 toxicities typically require dose reduction or interruption per protocol-defined criteria.
Counseling	Attend all scheduled blood tests and imaging appointments. Report fever > 38°C (risk of neutropaenic sepsis — medical emergency), unusual bleeding, or new pain immediately.

Chemistry & Properties

Formula	C46H56N4O10
Molecular weight	824.97 g/mol
IUPAC name	methyl (1R,9R,10S,11R,12R,19R)-11-acetyloxy-12-ethyl-4-[(13S,15S,17S)-17-ethyl-17-hydroxy-13-methoxycarbonyl-1,11-diazatetracyclo[13.3.1.04,12.05,10]nonadeca-4(12),5,7,9-tetraen-13-yl]-8-formyl-10-hydroxy-5-methoxy-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate
CAS	57-22-7
PubChem CID	5978
InChIKey	`OGWKCGZFUXNPDA-XQKSVPLYSA-N`
logP	3.52 (XLogP 2.8)
Polar surface area	171.17 Å²
H-bond acceptors / donors	12 / 3
Drug-likeness (QED)	0.13
Lipinski violations	2

SMILES

CC[C@]1(O)C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C=O)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No (logBB -1.03)

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2B6	Inhibitor	—
CYP2C19	Substrate	—
CYP2C8	Inhibitor	—
CYP3A4	Inhibitor	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MATE1 (Inhibitor)MDR1 (Inhibitor)MRP (Inhibitor)MRP1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)MRP7 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT3 (Inhibitor)OCTN2 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MDR1 (Substrate)MRP (Substrate)MRP1 (Substrate)MRP2 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Adalimumab	major
Amprenavir	major
Atazanavir	major
Bacillus calmette-guerin substrain tice live antigen	major
Baricitinib	major
Boceprevir	major
Ceritinib	major
Certolizumab pegol	major
Cladribine	major
Clarithromycin	major
Clozapine	major
Cobicistat	major
Conivaptan	major
Deferiprone	major
Delavirdine	major
Erythromycin	major
Etanercept	major
Fingolimod	major
Fosamprenavir	major
Golimumab	major
Idelalisib	major
Indinavir	major
Infliximab	major
Itraconazole	major
Ketoconazole	major
Leflunomide	major
Lomitapide	major
Lonafarnib	major
Measles virus vaccine live attenuated	major
Mipomersen	major
Mumps virus strain B level jeryl lynn live antigen	major
Natalizumab	major
Nefazodone	major
Nelfinavir	major
Ozanimod	major
Pexidartinib	major
Posaconazole	major
Ritonavir	major
Rotavirus vaccine	major
Rubella virus vaccine	major

Showing 40 of 100+.

Registered Products (6)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Cytocine-C	Vial 1 mg/ml	1 vial	Greenland Drug Store	—
Pharmacristine	Injection 1 mg/ml	1 ml	Khuson Drug Store	—
VINCRISTINE INJ	Injection 1 mg/1 ml	5 vial pack varies	Khoury Drug Store	—
VINCRISTINE INJ	Injection 1 mg/1 ml	2 ml pack varies	Khoury Drug Store	—
Vincristine Sulphate	Vial 1 mg/1 ml	5 vial	Petra Drug Store	—
Vincristine Sulphate	Vial 2 mg/2 ml	5 vial	Petra Drug Store	—