Vincristine

Vincristine is a vinca alkaloid derived from the periwinkle plant (Catharanthus roseus). It is a critical component of many curative regimens for pediatric and hematologic malignancies.

Mechanism of Action

Microtubule Disruption:

• Binds to tubulin, preventing microtubule formation
• Disrupts mitotic spindle assembly
• Arrests cells in metaphase (M-phase specific)
• Prevents cell division

Additional Effects:

• Inhibits axonal transport in neurons (causes neuropathy)
• Affects rapidly dividing cells preferentially

Pharmacokinetics

• Distribution: rapid and extensive — more than 90% of the dose is distributed from blood into tissues within 15–30 minutes after intravenous injection. Vincristine does not cross the blood-brain barrier significantly, accounting for its lack of CNS activity and the catastrophic nature of intrathecal administration.
• Volume of distribution: very large (reflects tight tissue binding); >90% redistributed from blood within minutes of IV administration.
• Protein binding: approximately 75% bound to plasma proteins; also binds extensively to platelets and erythrocytes.
• Metabolism: primarily CYP3A4 and CYP3A5 in the liver; minor contributions from CYP2C19. Subject to significant drug interactions with CYP3A4 inhibitors (which markedly increase exposure and neurotoxicity risk) and inducers (which may reduce efficacy).
• Half-life: triphasic elimination — initial phase approximately 5 minutes; middle phase approximately 2.3 hours; terminal phase approximately 85 hours (range 19–155 hours in humans).
• Clearance: data limited; elimination is primarily non-renal.
• Excretion: approximately 80% excreted in feces (biliary route); 10–20% in urine.

Vincristine is a key component of curative regimens:

Acute Lymphoblastic Leukemia (ALL):

• Essential in induction, consolidation, and maintenance
• Part of multi-drug protocols achieving >90% cure rate in children
• Critical for CNS prophylaxis regimens

Lymphomas:

• CHOP regimen for non-Hodgkin lymphoma
• ABVD regimen for Hodgkin lymphoma
• R-CHOP for B-cell lymphomas

Pediatric Solid Tumors:

• Wilms tumor
• Neuroblastoma
• Rhabdomyosarcoma
• Ewing sarcoma
• Medulloblastoma

• Acute lymphoblastic leukemia (ALL)
• Acute myeloid leukemia (AML)
• Hodgkin and non-Hodgkin lymphoma
• Multiple myeloma
• Wilms tumor
• Neuroblastoma
• Rhabdomyosarcoma
• Ewing sarcoma
• Brain tumors (pediatric)

Almost always used in combination chemotherapy regimens.

Absolute:

• INTRATHECAL ADMINISTRATION (FATAL - for IV use only)
• Hypersensitivity to vincristine or vinca alkaloids
• Demyelinating Charcot-Marie-Tooth syndrome
• Patients receiving concurrent radiation therapy through liver ports

Relative:

• Pre-existing severe neurotoxicity
• Severe hepatic impairment
• Pregnancy and breastfeeding

WARNING: FATAL IF GIVEN INTRATHECALLY. FOR INTRAVENOUS USE ONLY. Syringes should be labeled: “FOR INTRAVENOUS USE ONLY - FATAL IF GIVEN BY OTHER ROUTES”

Dose-Limiting Toxicity:

• Peripheral Neuropathy: Progressive, dose-related, may be irreversible

Neurotoxicity (Very Common):

• Peripheral neuropathy (tingling, numbness in hands/feet)
• Loss of deep tendon reflexes
• Foot drop, wrist drop
• Jaw pain
• Constipation (neurogenic) - can progress to paralytic ileus
• Urinary retention
• Orthostatic hypotension
• Cranial nerve palsies (rare)

Common:

• Alopecia (common, reversible)
• Mild myelosuppression (less than other vinca alkaloids)
• Nausea, vomiting (mild)
• Abdominal cramping
• Weight loss
• Diarrhea

Serious:

• Severe constipation/paralytic ileus
• Syndrome of inappropriate ADH secretion (SIADH)
• Severe neurotoxicity (may require dose reduction or discontinuation)
• Extravasation: Vesicant - causes severe tissue necrosis
• Hepatotoxicity (if hepatic dysfunction)

Rare:

• Seizures
• Cortical blindness (reversible)
• Optic atrophy
• Vocal cord paralysis
• Hypertension

Adult Dosing:

• Typical: 1.4 mg/m² IV (maximum 2 mg per dose in many protocols)
• Usually given weekly
• Dose capping controversial (some cap at 2 mg, others don’t)

Pediatric Dosing:

• <10 kg or <1 m²: Often dosed at 0.05 mg/kg (not capped)
• ≥10 kg: 1.4-2 mg/m² (capping varies by protocol)

Dose Modifications:

• Reduce dose for significant neuropathy:
  • Grade 2: Consider 50% dose reduction
  • Grade 3-4: Hold until improvement
• Hepatic impairment:
  • Bilirubin 1.5-3 mg/dL: 50% dose
  • Bilirubin >3 mg/dL: 25% dose or hold

Administration:

• INTRAVENOUS ONLY - NEVER INTRATHECAL
• IV push over 1 minute OR short infusion
• Through free-flowing IV or central line
• Follow with saline flush

CYP3A4 Inhibitors:

• Increase vincristine levels and toxicity
• Azole antifungals, macrolides, protease inhibitors
• Grapefruit juice
• Use caution, monitor for toxicity

CYP3A4 Inducers:

• Decrease vincristine levels
• Phenytoin, rifampin, St. John’s wort

Other:

• L-asparaginase: Give vincristine 12-24 hours before asparaginase (reduces hepatic clearance)
• Itraconazole: Severe neurotoxicity reported
• Mitomycin C: Increased risk of pulmonary toxicity

CRITICAL SAFETY:

• FOR INTRAVENOUS USE ONLY
• FATAL IF GIVEN INTRATHECALLY
• Dispense in overwrap labeled “DO NOT REMOVE UNTIL MOMENT OF INJECTION”
• Diluted syringes must be labeled “FOR IV USE ONLY - FATAL IF GIVEN BY OTHER ROUTES”
• Never remove syringe from protective overwrap until immediately before administration
• Multiple fatal intrathecal administrations have occurred - strict protocols required

Neuropathy Management:

• Assess neurological status before each dose
• Use standardized neuropathy grading
• Prophylactic bowel regimen (stool softeners, laxatives)
• Encourage high-fiber diet, adequate hydration
• Reduce dose or hold for progressive neuropathy
• Neuropathy may worsen after discontinuation before improving

Constipation Prevention:

• Start prophylactic stool softeners and stimulant laxatives
• Monitor bowel movements
• Treat constipation aggressively
• Paralytic ileus is medical emergency

Extravasation:

• Vesicant - causes severe tissue damage
• Administer through secure IV or central line
• Monitor site continuously
• If extravasation:
  • Stop infusion immediately
  • Aspirate residual drug
  • Do NOT apply pressure
  • Apply moderate heat (not cold) - controversial
  • Consider hyaluronidase injection
  • Plastic surgery consultation for severe cases

Pregnancy:

• Teratogenic
• Effective contraception required
• Avoid during first trimester if possible

Handling:

• Cytotoxic - protective equipment required
• Follow institutional chemotherapy handling protocols

Store at 2-8°C. Protect from light. Do not freeze. Retain in carton until time of use.

24-36 months depending on formulation. Do not use after expiry date.

Prescription required. Hospital/oncology use only. Must be administered by trained oncology professionals following strict safety protocols to prevent intrathecal administration. Dispensed in protective overwrap with clear labeling.