A Comprehensive Monograph on Vincristine (DB00541): Pharmacology, Clinical Utility, and Risk Management

1.0 Executive Summary

Vincristine is a complex, naturally occurring antineoplastic agent belonging to the vinca alkaloid class of chemotherapeutics. Isolated from the Madagascar periwinkle plant, Catharanthus roseus, it has been a cornerstone of cancer treatment for over half a century.[1] Its primary mechanism of action involves the disruption of microtubule dynamics, leading to cell cycle arrest in the mitotic phase and subsequent apoptosis of rapidly dividing cancer cells.[4] Vincristine demonstrates a broad spectrum of clinical activity, proving indispensable in combination chemotherapy regimens for a variety of hematologic malignancies—including acute lymphocytic leukemia (ALL) and Hodgkin and non-Hodgkin lymphomas—as well as numerous pediatric solid tumors such as Wilms' tumor, neuroblastoma, and rhabdomyosarcoma.[1]

A defining characteristic that establishes Vincristine's unique therapeutic niche is its relative lack of significant bone marrow suppression at standard doses, a property that allows it to be combined effectively with more myelosuppressive agents.[1] However, the clinical utility of Vincristine is fundamentally constrained by its significant and cumulative dose-limiting toxicity: a severe peripheral neuropathy that can manifest with sensory, motor, and autonomic dysfunction.[4] The management of patients receiving Vincristine is therefore a delicate balance between maximizing its potent anticancer effects and mitigating its debilitating neurotoxicity. Compounding these challenges is a critical and absolute safety mandate: Vincristine is for intravenous administration only. Inadvertent intrathecal injection is almost uniformly fatal, necessitating stringent, system-wide safety protocols to prevent this catastrophic medical error.[9]

2.0 Drug Identification and Formulation

2.1 Chemical Identity and Origin

Vincristine is a natural alkaloid isolated from the leaves of the Madagascar periwinkle, Catharanthus roseus (formerly Vinca rosea Linn).[2] It is classified as a small molecule antineoplastic agent and is one of the principal vinca alkaloids used in clinical oncology.[1] Structurally, it is a complex dimeric compound composed of two multi-ringed units, vindoline and catharanthine.[1]

The drug is known by several synonyms and chemical names, including Leurocristine, 22-Oxovincaleukoblastine, and the common abbreviations LCR (Leurocristine) and VCR.[1] Its chemical formula is

C46​H56​N4​O10​.[13] In clinical practice, it is administered as the sulfate salt, vincristine sulfate (

C46​H56​N4​O10​⋅H2​SO4​), which appears as a white to off-white powder that is freely soluble in water.[3]

2.2 Commercial Formulations and Brand Names

Vincristine is available in several formulations, reflecting efforts to optimize its delivery and manage its toxicity profile.

2.2.1 Standard Formulation

The conventional formulation is Vincristine Sulfate for Injection, USP. It is a sterile, preservative-free solution intended for intravenous use only, typically supplied in single-use vials containing 1 mg of vincristine sulfate in 1 mL of solution.[3]

2.2.2 Liposomal Formulation

A significant advancement in Vincristine delivery technology is the development of a liposomal formulation, marketed as Marqibo (vincristine sulfate liposome injection).[1] This formulation encapsulates vincristine sulfate within sphingomyelin/cholesterol liposomes.[14] The design of this carrier system directly addresses the primary clinical limitation of conventional Vincristine: its dose-limiting neurotoxicity.

The rationale behind this advanced formulation is rooted in pharmacokinetic engineering. By encapsulating the drug, the liposome alters its distribution and release characteristics. Pharmacokinetic studies comparing liposomal vincristine (VSLI) to conventional vincristine sulfate injection (VSI) in humans have demonstrated that VSLI results in a significantly increased maximum plasma concentration (Cmax​) and a much larger area under the plasma concentration-time curve (AUC) for total Vincristine. Concurrently, it produces a markedly lower Cmax​ and AUC for free, unbound Vincristine.[14] This suggests that the liposomal carrier effectively sequesters the drug in the circulation, prolonging its half-life and allowing for gradual release. The hypothesis is that the acute, severe toxicities associated with Vincristine are driven by high peak concentrations of the free drug. By minimizing this peak free-drug exposure, Marqibo may allow for the administration of higher effective doses of Vincristine, potentially enhancing antitumor activity while mitigating some of the most severe toxicities, thereby widening the therapeutic window.[14]

2.2.3 Global Brand Names

Vincristine is marketed globally under a multitude of brand names. In the United States, common brand names have included Oncovin and Vincasar PFS.[13] Although the brand name Oncovin (originally marketed by Eli Lilly) has been officially taken off the market in some regions, the name remains pervasive in clinical literature and practice protocols.[16]

Internationally, the drug is available under numerous other names, reflecting its widespread global use. These include, but are not limited to: Alcrist, Biocrist, Biocrystin, Cellcristin, Citomid, Crivosin, Farmistin, Fauldvincri, Kyocristine, Micristin, Onkocristin, Pericristine, Tecnocris, Unicristin, Vinces, Vincosid, Vincran, Vincrex, Vincrifil, Vincrin, Vincrisin, Vincrisol, Vinlon, and Vintec.[18]

3.0 Clinical Pharmacology

3.1 Pharmacodynamics (Mechanism of Action)

The antitumor activity of Vincristine is primarily due to its interaction with microtubules, which are essential components of the cellular cytoskeleton and the mitotic spindle.[4]

3.1.1 Primary Molecular Target and Effect

Vincristine functions as a potent antimicrotubule agent. Its primary molecular target is tubulin, the dimeric protein subunit that polymerizes to form microtubules. Specifically, it binds to the beta-tubulin subunit at the plus ends of microtubules.[1] This binding has a dual effect: it inhibits the polymerization of tubulin dimers, thereby preventing the elongation and formation of new microtubules, and it can also induce the depolymerization or "destabilization" of existing microtubules.[4] This disruption of microtubule dynamics is the core of its cytotoxic action.

3.1.2 Cell Cycle Specificity and Consequence

Because microtubule function is most critical during cell division, Vincristine is considered a cell cycle phase-specific agent. Its effects are most pronounced during the M-phase (mitosis) and, to a lesser extent, the S-phase (DNA synthesis) of the cell cycle.[4]

By preventing the proper assembly of the mitotic spindle, Vincristine-treated cells are unable to align and segregate their chromosomes correctly during mitosis. This leads to a cellular arrest in the metaphase stage of the cell cycle.[4] Prolonged metaphase arrest activates the spindle assembly checkpoint, a cellular surveillance mechanism that monitors the proper attachment of chromosomes to the spindle. When the checkpoint fails to be satisfied due to the dysfunctional spindle, it triggers a cascade of events leading to programmed cell death, or apoptosis.[5] This apoptotic pathway has been shown to involve the induction of the tumor suppressor protein p53 and the phosphorylation and subsequent inactivation of the anti-apoptotic protein BCL-2.[5]

3.1.3 Secondary Mechanisms

While microtubule disruption is the principal mechanism, evidence suggests that Vincristine may also interfere with other cellular pathways. These include the metabolism of amino acids, cyclic AMP, and glutathione; the activity of calmodulin-dependent Ca2+-transport ATPase; cellular respiration; and the biosynthesis of nucleic acids and lipids.[1] However, the clinical significance of these secondary effects relative to its primary antimitotic action is less well-defined.

3.2 Pharmacokinetics

The pharmacokinetic profile of Vincristine is characterized by rapid tissue distribution, extensive hepatic metabolism, and a long terminal half-life, all of which contribute to its efficacy and significant inter-individual variability in toxicity.

3.2.1 Absorption and Distribution

Due to erratic and unpredictable absorption from the gastrointestinal tract, Vincristine must be administered exclusively by the intravenous route.[4] Following IV injection, it is cleared very rapidly from the bloodstream and distributed extensively into body tissues. Over 90% of the drug is removed from the blood within 15 to 30 minutes.[1] This is reflected in its large volume of distribution (Vd), which is approximately 8.4 L/kg in adults, indicating widespread tissue uptake and binding.[20] Vincristine is approximately 75% bound to plasma proteins, primarily albumin, and also binds avidly to blood cells, particularly platelets.[1]

A critical pharmacokinetic feature is its poor penetration of the blood-brain barrier. This limits its efficacy against cancer cells within the central nervous system (CNS), meaning that CNS leukemia requires treatment with other agents that can achieve adequate cerebrospinal fluid concentrations.[4]

3.2.2 Metabolism and Excretion

Vincristine undergoes extensive metabolism in the liver. This biotransformation is primarily mediated by isoenzymes of the cytochrome P450 (CYP) 3A subfamily, with both CYP3A4 and CYP3A5 playing significant roles.[1] In vitro studies have shown that CYP3A5 is particularly efficient at converting Vincristine to its major metabolite, M1, a finding with significant pharmacogenomic implications for drug toxicity.[5]

The liver is the main organ of excretion. Approximately 80% of an administered dose is eliminated in the feces, largely through biliary excretion.[1] This process is mediated by efflux transporters such as P-glycoprotein (P-gp, encoded by the

ABCB1 gene) and Multidrug Resistance-Associated Protein 2 (MRP2, encoded by ABCC2) located on the apical side of hepatocytes.[5] A smaller fraction of the dose, around 10-20%, is excreted in the urine.[1]

3.2.3 Half-Life and Clinical Implications

The serum decay of Vincristine follows a triphasic pattern after a rapid IV injection. The initial distribution half-life (t1/2α​) is very short, at approximately 5 minutes. This is followed by an intermediate phase (t1/2β​) of about 2.3 hours. The most clinically significant phase is the long terminal elimination half-life (t1/2γ​), which averages 85 hours but exhibits a very wide range in humans, from 19 to 155 hours.[1]

This extremely long terminal half-life is a direct consequence of the drug's extensive tissue binding. Although the binding is not irreversible, the slow release of the drug from tissue reservoirs back into circulation for elimination results in a prolonged presence in the body. This pharmacokinetic property is a key contributor to the cumulative nature of Vincristine's toxicity, particularly neurotoxicity. With weekly dosing, the body may not fully clear the drug before the next dose is administered, leading to a gradual buildup of drug effect and an increased risk of adverse events over the course of treatment. The combination of a large Vd, long terminal half-life, and metabolism by the highly variable CYP3A enzymes creates a scenario ripe for significant inter-patient variability in drug exposure and, consequently, in both therapeutic response and toxicity.[4]

Table 1: Key Pharmacokinetic Parameters of Vincristine

Parameter	Value / Description	Source(s)
Administration Route	Intravenous (IV) only	4
Oral Bioavailability	Erratic and not clinically used	4
Volume of Distribution (Vd​)	~8.4 L/kg (Adults); indicates extensive tissue distribution	20
Plasma Protein Binding	~75%	1
Primary Metabolism	Hepatic, via CYP3A4 and CYP3A5 isoenzymes	1
Primary Excretion Route	Feces (~80%, via biliary excretion)	1
Secondary Excretion Route	Urine (~10-20%)	1
Initial Half-Life (t1/2α​)	~5 minutes	1
Middle Half-Life (t1/2β​)	~2.3 hours	1
Terminal Half-Life (t1/2γ​)	~85 hours (Range: 19-155 hours)	1

4.0 Clinical Efficacy and Therapeutic Indications

4.1 Approved and Common Indications

Vincristine is a versatile chemotherapeutic agent with a broad spectrum of activity against a range of malignancies. It is a fundamental component in the treatment of both hematologic cancers and solid tumors, particularly in the pediatric population.[1]

• Hematologic Malignancies: Vincristine is highly active in lymphoid malignancies. It is a cornerstone of therapy for Acute Lymphocytic Leukemia (ALL), where it is used in induction, consolidation, and maintenance phases of treatment.[1] The liposomal formulation, Marqibo, is specifically indicated for adults with Philadelphia chromosome-negative (Ph-) ALL in second or greater relapse or whose disease has progressed after two or more anti-leukemia therapies.[1] It is also used in regimens for Acute Myeloid Leukemia (AML), Hodgkin's Lymphoma, and various types of Non-Hodgkin Lymphomas.[1]
• Pediatric Solid Tumors: Vincristine is a critical drug in pediatric oncology. It is a standard component of treatment for Wilms' tumor (nephroblastoma), Neuroblastoma, and Rhabdomyosarcoma.[1]
• Other Malignancies: Its use extends to other cancers, including breast cancer, Kaposi's sarcoma, testicular cancer, and small cell lung cancer.[1]

4.2 Role in Combination Chemotherapy

A defining feature of Vincristine's clinical utility is its role as a component of multi-agent chemotherapy protocols, often referred to as polychemotherapy.[1] It is rarely used as a single agent. Its value in these combinations stems from two key properties.

First, and most importantly, Vincristine exhibits a relative lack of significant bone marrow suppression (myelosuppression) at its recommended therapeutic doses.[1] This "marrow-sparing" effect is in stark contrast to many other potent cytotoxic agents, such as alkylating agents (e.g., cyclophosphamide) and anthracyclines (e.g., doxorubicin). This property allows it to be combined with highly myelosuppressive drugs without causing prohibitively severe or overlapping hematologic toxicity.

Second, its primary dose-limiting toxicity—neurotoxicity—is mechanistically distinct from the primary toxicities of many of its common combination partners. For example, in the widely used CHOP regimen (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) for lymphoma, Vincristine's neurotoxicity does not overlap with the cardiotoxicity of doxorubicin or the hemorrhagic cystitis of cyclophosphamide. This allows for the combination of drugs with different toxicity profiles to maximize the antitumor effect while managing a broader, but less concentrated, range of side effects.[1]

4.3 Summary of Clinical Trial Evidence

The role of Vincristine as a backbone therapy is well-supported by numerous clinical trials, particularly in the context of combination regimens for aggressive cancers.

• Acute Lymphoblastic Leukemia (ALL): Clinical trials in ALL consistently feature Vincristine as a key agent in intensive, multi-drug protocols. In a Phase 1 trial for newly diagnosed high-risk pediatric ALL (NCT00866307), Vincristine was part of a complex regimen including pegaspargase, cyclophosphamide, cytarabine, daunorubicin, dexamethasone, doxorubicin, methotrexate, and prednisone.[30] Another trial for relapsed ALL in young patients (NCT01403415) combined Vincristine with temsirolimus, dexamethasone, and mitoxantrone.[30] The development of novel combinations continues, with a Phase 1/2 trial (NCT00440726) investigating the addition of the proteasome inhibitor bortezomib to a backbone of Vincristine, dexamethasone, pegaspargase, and doxorubicin for relapsed pediatric ALL.[32] Furthermore, the evolution of Vincristine formulations is evident in trial NCT00144963, which studied liposomal Vincristine in combination with dexamethasone for patients with relapsed or refractory ALL.[32]
• Neuroblastoma (NB): Vincristine is also integral to treatment protocols for high-risk neuroblastoma. For patients with resistant or relapsed disease, a Phase 1 trial (NCT00509353) explored the combination of Vincristine with irinotecan and targeted radionuclide therapy (131I-MIBG).[33] In the upfront setting for advanced neuroblastoma, Vincristine is included in intensive induction chemotherapy regimens, such as those studied in trials NCT00070200 and NCT00002740. These protocols combine Vincristine with agents like cyclophosphamide, topotecan, cisplatin, doxorubicin, and etoposide, often as a prelude to high-dose chemotherapy and autologous stem cell transplantation.[33]

Table 2: Summary of Representative Clinical Trials for Vincristine

ClinicalTrials.gov ID	Malignancy	Patient Population	Phase	Purpose	Key Combination Agents	Source(s)
NCT01403415	Relapsed ALL / Non-Hodgkin Lymphoma	Pediatric / Young Adult	1	Treatment	Temsirolimus, Dexamethasone, Mitoxantrone, Pegaspargase	30
NCT00866307	High-Risk ALL	Pediatric / Young Adult	1	Treatment	Pegaspargase, Cyclophosphamide, Cytarabine, Doxorubicin, Methotrexate	30
NCT00440726	Relapsed Pediatric ALL	Pediatric	1 / 2	Treatment	Bortezomib, Cytarabine, Doxorubicin, Pegaspargase, Dexamethasone	32
NCT00144963	Relapsed / Refractory ALL	Adult / Pediatric	1 / 2	Treatment	Liposomal Vincristine, Dexamethasone	32
NCT00509353	Resistant / Relapsed Neuroblastoma	Pediatric	1	Treatment	Irinotecan, 131I-MIBG Therapy	33
NCT00070200	Advanced Neuroblastoma	Pediatric	1	Treatment	Cyclophosphamide, Topotecan, Doxorubicin, Etoposide	33

5.0 Adverse Drug Reactions and Toxicity Profile

The therapeutic use of Vincristine is intrinsically linked to the management of its significant and predictable toxicity profile. While its marrow-sparing nature is a clinical advantage, its effects on the nervous system are profound and constitute its primary limitation.

Table 3: Comprehensive Profile of Adverse Effects by System Organ Class and Frequency

System Organ Class	Frequency	Adverse Reaction	Source(s)
Nervous System	Very Common (>10%)	Peripheral Neuropathy (sensory and motor), Constipation (autonomic neuropathy)	4
	Common (1-10%)	Headache, Jaw pain, Ataxia, Loss of deep tendon reflexes, Paresthesia	4
	Uncommon (0.1-1%)	Seizures (often with hypertension), Cranial nerve palsies (e.g., vocal cord paralysis, ptosis)	4
	Rare (<0.1%)	Paralytic ileus, Transient or permanent cortical blindness, Optic atrophy	4
Skin and Subcutaneous Tissue	Very Common (>10%)	Alopecia (hair loss)	6
	Common (1-10%)	Rash	21
General Disorders & Administration Site Conditions	Common (1-10%)	Injection site reaction (pain, redness, swelling); Vesicant - risk of tissue necrosis with extravasation	21
Blood and Lymphatic System	Uncommon (0.1-1%) to Rare (<0.1%)	Leukopenia, Anemia, Thrombocytopenia (generally mild and transient)	3
Gastrointestinal	Common (1-10%)	Nausea, Vomiting (usually mild to moderate), Abdominal pain/cramps, Anorexia, Weight loss	6
	Uncommon (0.1-1%)	Diarrhea, Oral ulceration (stomatitis)	21
	Rare (<0.1%)	Intestinal necrosis and/or perforation	6
Endocrine	Rare (<0.1%)	Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion	12
Pulmonary	Rare (<0.1%)	Acute bronchospasm and dyspnea (especially with mitomycin-C)	3
Cardiovascular	Rare (<0.1%)	Hypertension, Hypotension, Coronary artery disease/myocardial infarction (causality uncertain)	21
Hypersensitivity	Rare (<0.1%)	Allergic reactions (rash, edema, anaphylaxis)	4

5.1 Vincristine-Induced Peripheral Neuropathy (VIPN): The Dose-Limiting Toxicity

Neurotoxicity is the most common, most troublesome, and definitively dose-limiting adverse effect of Vincristine therapy.[4] This toxicity is directly related to the dose, is cumulative with repeated administrations, and develops in nearly all patients to some extent over a course of treatment.[4] The pathophysiology is a direct extension of the drug's primary mechanism of action; the disruption of microtubule structures within neuronal axons impairs essential axonal transport, leading to a "dying-back" axonopathy, neurofibrillary degeneration, and subsequent nerve dysfunction.[36] While VIPN is often reversible upon cessation of the drug, recovery can be very slow, taking several months, and in some cases, the damage can be permanent and disabling.[4]

The clinical manifestations of VIPN are diverse and typically follow a predictable sequence:

• Peripheral Sensory Neuropathy: This is usually the earliest manifestation. It presents as a progressive, symmetric, "glove-and-stocking" paresthesia, with symptoms of numbness, tingling, burning sensations, and neuropathic pain beginning in the distal extremities (fingers and toes) and ascending proximally with continued treatment.[7]
• Peripheral Motor Neuropathy: As treatment continues, motor deficits emerge. An early sign is the depression or loss of deep tendon reflexes, most notably the Achilles tendon reflex. This can progress to distal muscle weakness, leading to difficulties with fine motor tasks (e.g., buttoning clothes), foot drop, wrist drop, and an unsteady, ataxic, or "slapping" gait.[3] In pediatric patients, motor neuropathy can be the predominant feature, sometimes manifesting as pain in the extremities and a refusal to walk.[12]
• Autonomic Neuropathy: This is a very common component of VIPN. Its most frequent symptom is constipation, which can be severe and accompanied by colicky abdominal pain. In serious cases, it can progress to paralytic ileus, mimicking a surgical abdomen.[4] Other autonomic effects include urinary retention due to bladder atony, orthostatic hypotension, and lack of sweating.[4]
• Cranial Neuropathy: The cranial nerves can also be affected. A characteristic symptom is jaw pain, which can be severe and may occur within hours of the first dose.[4] Other manifestations include hoarseness or a weak voice due to vocal cord paresis or paralysis, as well as ocular motor nerve palsies resulting in ptosis (drooping eyelids), strabismus, and diplopia (double vision).[4]
• Central Nervous System (CNS) Toxicity: Although Vincristine poorly penetrates the CNS, central effects have been reported. These include seizures, which are frequently associated with hypertension, as well as headache, dizziness, confusion, and mental depression.[4] In rare and catastrophic cases, Vincristine has been associated with transient or permanent cortical blindness and optic atrophy.[35]

Risk for developing severe VIPN is increased in elderly patients, those with pre-existing neuromuscular disease (e.g., Charcot-Marie-Tooth syndrome), and those with specific genetic polymorphisms, particularly in the CYP3A5 gene.[4]

5.2 Gastrointestinal Effects

Gastrointestinal side effects are common, primarily driven by the drug's impact on the autonomic nervous system.

• Constipation: This is a hallmark adverse effect of Vincristine and a direct result of autonomic neuropathy affecting gut motility.[4] It can be severe and is often accompanied by abdominal cramps.[34] Due to its high frequency and potential for complications like upper colon impaction or paralytic ileus, prophylactic management with a routine bowel regimen (e.g., stool softeners, laxatives) is recommended for all patients receiving Vincristine.[4]
• Nausea and Vomiting: Vincristine is considered to have low to moderate emetogenic potential. Nausea and vomiting can occur but are generally not severe and are usually well-controlled with standard antiemetic medications.[21]
• Other GI Effects: Less common but notable GI effects include anorexia, weight loss, diarrhea, and oral ulcerations (stomatitis or mucositis).[6] In rare and severe instances, intestinal necrosis and/or perforation have been reported.[6]

5.3 Hematologic Effects (Myelosuppression)

A defining and clinically advantageous feature of Vincristine is its relative lack of significant myelosuppression when used at standard therapeutic doses.[1] While many potent chemotherapeutic agents cause severe dose-limiting suppression of bone marrow function, Vincristine is notably "marrow-sparing." Although mild and transient decreases in white blood cell count (leukopenia), platelet count (thrombocytopenia), and red blood cell count (anemia) can occur, they are typically rare and of short duration (less than 7 days).[3] This favorable hematologic profile is a primary reason for its inclusion in combination chemotherapy regimens, as it can be administered alongside more myelosuppressive drugs without contributing significantly to cumulative hematologic toxicity.[1]

5.4 Other Systemic Side Effects

• Dermatologic: Alopecia (hair loss) is a very common and expected side effect, affecting a majority of patients, though it is typically reversible after treatment completion.[6]
• Injection Site Reactions: Vincristine is a potent vesicant. Accidental leakage of the drug outside the vein during administration (extravasation) can cause severe local reactions, including pain, inflammation, and tissue necrosis.[10] Meticulous intravenous administration technique is therefore essential.
• Endocrine and Metabolic: The Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion has been convincingly established as a potential adverse effect, leading to water retention and hyponatremia (low sodium levels).[12] Acute elevation of serum uric acid can also occur, particularly during the rapid cell lysis that follows induction therapy for leukemia.[9]
• Pulmonary: Acute shortness of breath and severe bronchospasm have been reported. These reactions are rare but have been encountered most frequently when Vincristine is used in combination with mitomycin-C.[3]
• Cardiovascular: Both hypertension and hypotension have been reported.[21] While coronary artery disease and myocardial infarction have been associated with chemotherapy combinations that include Vincristine, a direct causal link has not been firmly established.[21]

6.0 Dosing, Administration, and Safety Protocols

6.1 Dosing Regimens

The dosing of Vincristine requires careful calculation and consideration of patient-specific factors to balance efficacy and toxicity.

• Standard Dosing: Dosing is calculated based on body surface area (BSA). The typical adult dose is 1.4 mg/m², administered intravenously, usually on a weekly basis.[11] The standard pediatric dose is slightly higher, at 1.5 to 2.0 mg/m², also given weekly.[6]
• Dose Capping: A critical safety practice in adult oncology is the application of a maximum single dose cap, which is almost universally set at 2 mg. This means that even if a patient's BSA calculation results in a dose greater than 2 mg, the administered dose is capped at 2 mg. This practice is a direct measure to mitigate the risk of severe, unacceptable neurotoxicity at higher doses.[12]
• Pediatric Dosing Considerations: For infants and very small children (e.g., <10 kg or BSA <0.6 m²), standard BSA-based dosing can be inaccurate. In these populations, dosing is often based on body weight (e.g., an initial dose of 0.05 mg/kg weekly) or utilizes specialized BSA-banded dosing tables. These tables are designed to provide more uniform drug exposure across the pediatric age range and are the subject of ongoing clinical research, such as the PEPN22P1 study (NCT05359237).[6]
• Dose Adjustments:
• Hepatic Impairment: Since Vincristine is primarily cleared by the liver, dose modification is required in patients with hepatic dysfunction. A 50% dose reduction is recommended for patients with a direct serum bilirubin level greater than 3 mg/dL.[6]
• Neurotoxicity: The development of moderate to severe neurotoxicity is the most common reason for dose modification. Doses are frequently reduced, delayed, or discontinued entirely based on the severity of a patient's neurologic symptoms.[3]
• Renal Impairment: No dose adjustment is generally necessary for patients with renal impairment, as the kidneys play a minor role in Vincristine elimination.[6]

6.2 Administration Guidelines and Extravasation Management

Vincristine administration must be performed with extreme care by personnel experienced in handling cytotoxic agents.[9]

• Intravenous Administration: The drug must be administered through a secure, freely flowing intravenous line. It is recommended that the solution be injected over a period of about 1 minute or as a short infusion (e.g., 5-10 minutes) into the tubing of a running IV line.[10]
• Extravasation Management: Vincristine is a potent vesicant, and extravasation (leakage into surrounding tissue) can cause severe pain, inflammation, and local tissue necrosis. If extravasation is suspected (e.g., swelling, pain, or burning at the injection site), the infusion must be stopped immediately. Any remaining portion of the dose should be administered through a new, secure IV line in another vein. Local treatment of the affected area is recommended to minimize damage. This typically involves the local injection of hyaluronidase to help disperse the drug, followed by the application of moderate heat to the site.[10]

6.3 Black Box Warning: Risk of Fatal Intrathecal Administration

Vincristine carries one of the most serious black box warnings in all of medicine, related to the route of administration.

• The Critical Warning: The drug is intended FOR INTRAVENOUS USE ONLY. Inadvertent administration directly into the cerebrospinal fluid (the intrathecal route) is a catastrophic medical error that is almost uniformly FATAL, leading to an ascending paralysis and massive, irreversible neurological injury.[6]
• Mandatory Safety Protocols: This devastating potential for error has led to the implementation of stringent, system-wide safety protocols mandated by regulatory agencies like the FDA and adopted by healthcare institutions worldwide. The goal of these protocols is to create multiple layers of protection to make this error as difficult to commit as possible. This is a prime example of human factors engineering applied to medication safety. The error often occurs because other chemotherapy agents commonly used in the same patient populations, such as methotrexate and cytarabine, are routinely administered intrathecally.[17] To prevent a mix-up, the following measures are required:

1. Dilution in Minibags: Instead of preparing the dose in a standard syringe, which could be mistaken for a syringe intended for intrathecal use, conventional Vincristine should be diluted in a small-volume IV infusion bag (a "minibag"). This makes it physically incompatible with the equipment used for a lumbar puncture.[10]
2. Explicit Warning Labels: All preparations containing Vincristine, whether in a minibag or (if unavoidable) a syringe, must be packaged in a distinct overwrap and be prominently labeled with a clear, unambiguous warning, such as: "WARNING: FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.".[9]

These protocols represent a shift from simply warning practitioners of a danger to actively redesigning the medication use system to build in physical and procedural barriers that prevent the error from occurring.

7.0 Drug Interactions and Contraindications

7.1 Absolute Contraindications

The use of Vincristine is absolutely contraindicated in the following situations:

• Intrathecal Administration: As detailed previously, this route is fatal and is an absolute contraindication.[10]
• Charcot-Marie-Tooth (CMT) Syndrome: Patients with the demyelinating form of CMT, a hereditary motor and sensory neuropathy, must not be given Vincristine. These individuals have an underlying nerve vulnerability and are at extremely high risk of developing profound, severe, and potentially irreversible neurotoxicity.[3]
• Hypersensitivity: Patients with a known history of a clinically significant hypersensitivity reaction to Vincristine or any of its formulation components should not receive the drug.[35]

7.2 Clinically Significant Drug-Drug Interactions

Vincristine is susceptible to a large number of clinically significant drug-drug interactions, with over 400 documented.[42] The most important of these are pharmacokinetic interactions involving its primary metabolic pathway, the CYP3A enzyme system, and its transport by the P-glycoprotein (P-gp/ABCB1) efflux pump.[5]

Table 4: Clinically Significant Drug-Drug Interactions with Vincristine

Interacting Drug/Class	Mechanism of Interaction	Clinical Consequence	Management Recommendation	Source(s)
Potent CYP3A4/P-gp Inhibitors (e.g., Azole antifungals like itraconazole, voriconazole; Macrolide antibiotics like clarithromycin; Protease inhibitors like ritonavir)	Inhibition of CYP3A4-mediated metabolism and/or P-gp-mediated efflux	Increased plasma concentration of Vincristine, leading to a higher risk of earlier onset and more severe neurotoxicity and myelosuppression	Avoid concomitant use if possible. If unavoidable, consider a significant Vincristine dose reduction and monitor the patient extremely closely for signs of toxicity.	23
CYP3A4 Inducers (e.g., Anticonvulsants like carbamazepine, phenytoin; Apalutamide; St. John's Wort)	Induction of CYP3A4-mediated metabolism	Decreased plasma concentration of Vincristine, leading to a potential loss of therapeutic efficacy	Monitor for clinical response. Dose increases of Vincristine may be necessary. Avoid St. John's Wort.	1
L-asparaginase	Pharmacodynamic/Pharmacokinetic; L-asparaginase may reduce hepatic clearance of Vincristine	Increased risk of Vincristine toxicity, particularly neurotoxicity	Administer Vincristine 12 to 24 hours before the administration of L-asparaginase to allow for Vincristine clearance prior to the enzyme's effect on the liver.	4
Mitomycin-C	Pharmacodynamic (mechanism not fully elucidated)	Increased risk of acute pulmonary toxicity (severe bronchospasm, dyspnea)	Monitor pulmonary function closely. Do not re-administer Vincristine if a severe reaction occurs.	3
Other Neurotoxic Agents (e.g., Cisplatin, Bortezomib, high-dose Methotrexate)	Additive Pharmacodynamic Effect	Increased risk and severity of peripheral neuropathy	Use with caution and perform frequent, careful neurologic monitoring.	1
Grapefruit Juice	Inhibition of intestinal CYP3A4	Increased oral bioavailability (not relevant for IV Vincristine) and potentially systemic CYP3A4 inhibition, leading to increased Vincristine levels	Patients should be advised to avoid consuming grapefruit or grapefruit juice during Vincristine therapy.	1

7.2.1 Interactions with CYP3A4/P-gp Inhibitors

Coadministration of Vincristine with potent inhibitors of CYP3A4 and/or P-gp is a major clinical concern. These inhibitors block the primary routes of Vincristine elimination, causing its plasma concentrations to rise significantly. This has been associated with severe, life-threatening toxicities, including paralytic ileus, profound myelosuppression, and severe neuropathy, occurring earlier and more frequently than expected.[49] Examples of potent inhibitors include azole antifungals (itraconazole, voriconazole, posaconazole), macrolide antibiotics (clarithromycin, erythromycin), HIV protease inhibitors (ritonavir), and other drugs like cyclosporine and amiodarone.[1] Concomitant use should be avoided whenever possible. If co-administration is medically necessary, a conservative approach with a preemptive reduction in the Vincristine dose and vigilant monitoring for toxicity is warranted.[49]

7.2.2 Interactions with CYP3A4 Inducers

Conversely, co-administration with strong inducers of CYP3A4 can accelerate the metabolism of Vincristine, leading to lower plasma concentrations and potentially compromising its anticancer efficacy.[5] Key inducers include certain anticonvulsants (carbamazepine, phenytoin), the anti-androgen apalutamide, and the herbal supplement St. John's Wort.[4] When these drugs are used concurrently, patients should be monitored closely for an adequate therapeutic response, and upward dose adjustments of Vincristine may be required.[4]

8.0 Comparative Analysis with Other Vinca Alkaloids

Vincristine belongs to a class of structurally related compounds, the vinca alkaloids, which also includes the clinically important agents Vinblastine and Vinorelbine. While they share a common core mechanism, their subtle structural differences lead to distinct clinical profiles, particularly regarding their dose-limiting toxicities. Understanding these differences is crucial for their appropriate clinical application.

8.1 Structural and Mechanistic Comparison

All three agents are dimeric alkaloids derived from Catharanthus roseus, composed of vindoline and catharanthine moieties.[1] The key structural difference between Vincristine and Vinblastine is a substitution on the vindoline nitrogen: Vincristine has a formyl group (-CHO), whereas Vinblastine has a methyl group (-CH3).[53] Vinorelbine is a semi-synthetic derivative of Vinblastine.[45]

Mechanistically, all three drugs bind to tubulin and arrest mitosis at the metaphase, and they possess roughly equivalent tubulin binding constants.[22] However, biophysical studies suggest that Vincristine has the highest overall affinity for inducing tubulin self-association into non-functional polymers, followed by Vinblastine, with Vinorelbine having the lowest affinity.[54] This difference in potency correlates well with their relative clinical doses: Vincristine is administered at the lowest doses, while Vinorelbine is used at the highest.[54]

8.2 Comparative Toxicity and Clinical Use

The most important clinical distinction among the vinca alkaloids lies in their differing dose-limiting toxicities. This divergence dictates their respective roles in chemotherapy.

• Vincristine: The dose-limiting toxicity is unequivocally neurotoxicity. Myelosuppression is characteristically mild and rarely clinically significant. This profile makes it an ideal agent for combination with myelosuppressive drugs in the treatment of leukemias, lymphomas, and various pediatric tumors.[12]
• Vinblastine: The dose-limiting toxicity is myelosuppression, primarily manifesting as leukopenia. While neurotoxicity can occur, it is significantly less frequent and severe than with Vincristine. This makes Vinblastine a key component in regimens where bone marrow suppression is a more manageable toxicity, such as in the treatment of testicular cancer and Hodgkin's lymphoma.[12]
• Vinorelbine: This semi-synthetic agent has an intermediate toxicity profile. Its dose-limiting toxicity is also myelosuppression (neutropenia), but it is generally considered less severe and of shorter duration than that caused by Vinblastine. Critically, Vinorelbine exhibits the least neurotoxic potential of the three. This improved safety profile is thought to be due to a greater selectivity for mitotic microtubules over the axonal microtubules that are implicated in neuropathy.[12] This makes Vinorelbine particularly useful in the treatment of non-small cell lung cancer and breast cancer, often in patients who may not tolerate the more severe toxicities of the other agents.

Table 5: Comparative Profile of Vincristine, Vinblastine, and Vinorelbine

Feature	Vincristine	Vinblastine	Vinorelbine
Primary Dose-Limiting Toxicity	Neurotoxicity	Myelosuppression	Myelosuppression (less severe than Vinblastine)
Severity of Neurotoxicity	High (+++)	Moderate (+)	Low (+/-)
Severity of Myelosuppression	Low (+/-)	High (+++)	Moderate (++)
Key Clinical Uses	Acute Lymphocytic Leukemia, Lymphomas, Pediatric Solid Tumors	Testicular Cancer, Hodgkin's Lymphoma	Non-Small Cell Lung Cancer, Breast Cancer
Relative Clinical Dose	Lowest	Intermediate	Highest
Structural Class	Natural Alkaloid	Natural Alkaloid	Semi-synthetic Derivative
Source(s):	12

9.0 Special Populations and Pharmacogenomics

9.1 Pediatric Use

Vincristine is a fundamental and indispensable drug in pediatric oncology, forming the backbone of curative regimens for many childhood cancers, including ALL, Wilms' tumor, and neuroblastoma.[2] While children generally tolerate the drug, they exhibit a unique susceptibility to certain toxicities. For instance, young children are particularly prone to developing paralytic ileus.[12] Dosing in infants and very young children requires special attention due to rapid changes in body size and organ function. To ensure safety and efficacy, dosing in this population is often guided by body weight rather than BSA, or by using validated BSA-banded dosing tables designed to achieve more consistent drug exposures.[11]

9.2 Geriatric Use

Elderly patients are generally more sensitive to the adverse effects of Vincristine, particularly its neurotoxicity.[4] They are also at an increased risk of developing severe constipation and urinary retention due to age-related changes in autonomic function and a higher prevalence of comorbid conditions.[4] Careful monitoring and consideration of dose capping and prophylactic measures are essential in this population.

9.3 Pharmacogenomics of Toxicity

The significant inter-individual variability observed in Vincristine-induced peripheral neuropathy (VIPN) has a strong genetic basis. Research in pharmacogenomics has provided a powerful mechanistic explanation for why some patients experience severe toxicity while others tolerate the drug well.

The most robust evidence points to genetic variations in the CYP3A5 gene, which encodes one of the key enzymes responsible for Vincristine metabolism.[5] A common single nucleotide polymorphism (SNP) in the

CYP3A5 gene (CYP3A53*) creates a cryptic splice site that results in a truncated, non-functional protein. Individuals who are homozygous for this variant allele (CYP3A53/3) are considered "non-expressers" and have no functional CYP3A5 enzyme. They must rely solely on the less efficient CYP3A4 enzyme for Vincristine metabolism. In contrast, individuals with at least one copy of the wild-type allele (CYP3A51*) are "expressers" and have a significantly higher capacity to metabolize the drug.[5]

This genetic difference has direct clinical consequences. The non-expresser genotype is highly prevalent in Caucasian populations, while the expresser genotype is much more common in individuals of African ancestry. This genetic distribution correlates precisely with clinical observations: studies have shown that Caucasian patients experience a significantly higher frequency and severity of VIPN, requiring more dose reductions and delays, compared to African-American patients.[27] This finding moves the understanding of this toxicity from a simple demographic observation to a biologically plausible, genetically driven phenomenon. It suggests that individuals with lower CYP3A5 activity have reduced clearance of Vincristine, leading to higher drug exposure and a greater risk of nerve damage.

While CYP3A5 is the most well-validated genetic marker, variants in other genes, such as the drug transporter gene ABCB1 (P-gp), have also been investigated for their role in Vincristine pharmacokinetics and resistance, though the clinical evidence is currently less definitive.[5] The strong association between

CYP3A5 genotype and VIPN risk opens the door for personalized medicine, where pre-treatment genotyping could be used to identify high-risk patients and guide dosing strategies to minimize toxicity.

10.0 Conclusions and Clinical Recommendations

Vincristine remains an essential and effective chemotherapeutic agent, whose value is firmly established in numerous curative-intent combination regimens for hematologic malignancies and pediatric solid tumors. Its enduring clinical utility is largely predicated on its unique toxicity profile, specifically its relative lack of myelosuppression, which allows for its integration with other cytotoxic drugs. However, its use is perpetually shadowed by its potent, cumulative, and dose-limiting neurotoxicity. The successful application of Vincristine in the clinic depends on a deep understanding of this therapeutic trade-off and a steadfast commitment to risk mitigation strategies.

Based on the comprehensive analysis of its pharmacology, clinical use, and safety profile, the following clinical recommendations are paramount:

1. Unyielding Adherence to Administration Safety Protocols: The prevention of accidental intrathecal administration is the single most critical safety priority. The mandatory use of minibag dilution for preparation and the prominent application of explicit warning labels—"FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES"—are non-negotiable standards of care that must be enforced through institutional policy and practice.
2. Vigilant and Proactive Neurological Monitoring: All patients receiving Vincristine must undergo regular, systematic clinical evaluation for the early signs and symptoms of peripheral neuropathy. This includes assessment of sensory changes (paresthesias), motor function (deep tendon reflexes, gait), and autonomic function (bowel habits). The timely detection of emerging neurotoxicity is essential for guiding dose modifications (reduction, delay, or discontinuation) to prevent irreversible nerve damage.
3. Systematic Management of Common Side Effects: Given the high frequency of autonomic neuropathy, a prophylactic bowel regimen to prevent severe constipation should be considered standard practice for all patients initiating Vincristine therapy.
4. Critical Assessment of Drug Interactions: Clinicians must maintain a high index of suspicion for drug-drug interactions. Particular caution is required with the co-administration of potent inhibitors or inducers of the CYP3A4 enzyme system. Concurrent use of potent inhibitors (e.g., many azole antifungals) should be avoided if possible, as they can dangerously increase Vincristine exposure and toxicity.
5. Advancing Toward Personalized Therapy: The strong evidence linking CYP3A5 genotype to the risk of severe neurotoxicity presents a clear opportunity for the future of Vincristine therapy. Further research and clinical validation are warranted to establish pharmacogenomic-guided dosing as a standard of care. Pre-treatment genotyping has the potential to identify high-risk patients, allowing for preemptive dose adjustments that could significantly improve the safety and therapeutic index of this vital anticancer drug.

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