Vincristine

Vincristine is an antineoplastic agent belonging to the pharmacological class of vinca alkaloids.

The FDA has approved Vincristine to treat acute leukaemia, malignant lymphoma, Hodgkin's disease, erythraemia, and panmyelosis.

Vincristine is poorly absorbed from the gastrointestinal tract, exhibits limited distribution across the blood-brain barrier, undergoes extensive protein binding, is primarily metabolized in the liver, and is excreted mainly through bile into faeces, with a secondary elimination route through urine.

The most common side effects of Vincristine are hair loss, peripheral neuropathy (tingling and numbness of feet and hands), and constipation.

Vincristine is available in the form of an injectable solution.

The molecule is available in India, the United States, Canada, the United Kingdom, Australia, Germany, France, Japan, China, Brazil and South Africa.

Vincristine is an antineoplastic agent belonging to the pharmacological class of vinca alkaloids.

Vincristine works by inhibiting microtubule formation in the mitotic spindle, arresting dividing cells at metaphase. Marqibo, a liposome-encapsulated vincristine sulfate, exhibits this mechanism. Non-liposomal vincristine sulfate, binding to tubulin, alters the tubulin polymerization equilibrium, resulting in a modified microtubule structure and function. It stabilizes the spindle apparatus, preventing chromosome segregation, inducing metaphase arrest, and inhibiting mitosis. Additionally, Vincristine may interfere with various cellular processes, including amino acid, cyclic AMP, glutathione metabolism, calmodulin-dependent Ca2+-transport ATPase activity, cellular respiration, nucleic acid and lipid biosynthesis.

Injectable solutions: To be administered parenterally, as applicable.

As the physician recommends, take the medication with or without food. Dosage and frequency depend on the specific medical condition.

• Breast cancer
• Non-small cell lung cancer
• Pancreatic cancer
• Kidney cancer
• Blood cancer
• Multiple myeloma
• Lymphomas
• Bone cancer

Off-label: Idiopathic thrombocytopenic purpura, Kaposi sarcoma, bladder cancer

• Breast cancer: Vincristine, whether used alone or in combination with other treatments like chemotherapy, effectively treats breast cancer by halting cancer cell growth and preventing multiplication. It alleviates symptoms such as breast lumps, nipple discharge, and changes in breast texture, contributing to the management of the disease.

• Non-small cell lung cancer: Vincristine is effective for treating non-small cell lung cancer in both smokers and non-smokers and may be administered alone or with other medications. It is crucial to discuss the potential risks and benefits with your doctor. Abstain from alcohol during treatment and maintain hydration by consuming plenty of water.
• Pancreatic cancer: Vincristine controls pancreatic cancer, alleviating symptoms like appetite loss and unexplained weight loss. It inhibits chemicals promoting cancer growth, enhancing life expectancy and well-being. The pancreas plays a crucial role in digestion and blood sugar metabolism, producing natural insulin. This medicine effectively manages pancreatic cancer, contributing to an extended and healthier life.
• Kidney cancer: Vincristine effectively treats kidney cancer and related symptoms like blood in the urine, unexplained low back pain, weight loss, fatigue, and loss of appetite. It halts cancer growth, preventing the multiplication of cancer cells and thereby impeding its spread to unaffected areas.
• Blood cancer: Vincristine effectively treats blood cancer, known as leukaemia, a condition affecting the blood-forming tissues, reducing the body's infection-fighting ability. It kills or halts the growth of cancer cells and prevents their multiplication. It's a potent and highly toxic medicine, requiring a discussion of risks and benefits with your doctor. During treatment, avoid alcohol and ensure adequate hydration by drinking plenty of water.
• Multiple myeloma: If individuals have multiple myeloma, their bodies are destroying bone faster than it's being replaced, leading to weak and painful bones prone to breaking. Vincristine, prescribed along with other cancer treatments like chemotherapy, is crucial for treatment, improving survival rates. It kills cancerous cells, preventing further growth and spread. Following doctors' instructions is vital for optimal benefits. Calcium and Vitamin D3 supplements may be prescribed if blood calcium levels are low.
• Lymphomas: Vincristine limits the growth of lymphomas and cancers affecting infection-fighting cells. It impedes cancer growth by blocking essential chemicals.
• Bone cancer: Vincristine treats bone cancer in children and young adults. It may be combined with other treatments like chemotherapy. This medication eliminates cancer cells, stops their multiplication, and spreads to unaffected areas.

• Vincristine is indicated for the treatment of neuroblastoma, rhabdomyosarcoma, Wilms' tumour, Hodgkin lymphoma, non-Hodgkin lymphomas, and acute lymphocytic leukaemia (ALL). 
• It is also indicated during the Relapsed acute lymphoblastic leukaemia (ALL) with Philadelphia chromosome negativity (Ph-) may benefit from liposomal vincristine treatment.

Parenterally: Vincristine can only be given parenterally by intravenous (IV) infusion; a central line or a more prominent peripheral vein is usually used to reduce the risk of extravasation. The medication is diluted in an appropriate IV solution before injection. Because there is a possibility of lethal neurotoxicity, intrathecally given, Vincristine should never be used. Caution should be taken when choosing the injection site to prevent any potential tissue damage. Close monitoring is necessary during the infusion to control any side effects and ensure the safe and efficient administration of Vincristine.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Injectable solutions: 1mg/mL

Vincristine is available in the form of Injectable solutions.

Dose Adjustment in Adult Patients:

Acute Leukemia

Phase of induction: 1.4 mg/m2 on days 1, 8, 15, and 22

Phase of consolidation: 1.4 mg/m2 on days 8, 15, and 22

Maintenance phase: 1.4 mg/m2 q3months for 2.5

Combination Treatment

cancers

While taking Vincristine, follow the vital dietary guidelines and precautions. Consume antioxidant-rich foods like berries, spinach, kidney beans, and dark chocolate, emphasizing a high-fibre diet. Opt for small, frequent meals to support a faster recovery. Avoid smoking and alcohol. Additionally, avoid high-fat and cholesterol-rich diets to enhance the overall effectiveness of the treatment.

The dietary restriction should be individualized as per patient requirements.

• Hypersensitivity: Anyone who has previously experienced hypersensitivity to Vincristine or any of the other components of Vincristine.

• Patients with demyelinating disorders, such as Charcot-Marie-Tooth syndrome.
• Intrathecal administration of Vincristine.

• If extravasation occurs, discontinue dosing immediately and introduce any remaining dose into another vein to minimize tissue injury.
• Neurologic toxicity: Monitor patients for peripheral motor, sensory, central, and autonomic neuropathy. Consider treatment with Vincristine for patients with preexisting severe neuropathy only after a careful risk-benefit assessment.
• Myelosuppression: Check blood counts before each Vincristine dose.
• Neutropenia, thrombocytopenia, or anaemia may occur; consider dose reduction or interruption, along with supportive care measures.
• Tumour lysis syndrome: Anticipate, monitor, and manage symptoms of tumour lysis syndrome.
• Constipation, bowel obstruction, and/or paralytic ileus: Implement a prophylactic bowel regimen to prevent constipation, bowel obstruction, and/or paralytic ileus.
• Fatigue: Severe fatigue can occur as a side effect.
• Hepatic toxicity: Regularly monitor liver function and modify or interrupt dosing accordingly.
• Embryofetal toxicity: Vincristine can cause fetal harm, so women should be advised of the potential risk to the fetus.

It is unsafe to consume Vincristine with alcohol.

It is not recommended for use during breastfeeding.

It is not recommended for use during pregnancy.

Consume an antioxidant-rich diet, avoid smoking/alcohol.

The adverse reactions related to Vincristine can be categorized as

•Common Adverse Effects: Alopecia

•Less Common Adverse Effects: Nausea, vomiting, constipation, abdominal cramps, neurotoxicity (tingling, numbness, and weakness in the extremities).

•Rare Adverse Effects: Neurological effects (seizures, hallucinations), jaw pain, difficulty swallowing, paralytic ileus, severe allergic reactions.

The clinically relevant drug interactions of Vincristine are briefly summarized here.

Absorption of verapamil and digoxin (tablets) decreased when using antineoplastic regimens. Elevated serum etoposide levels when using Vincristine. More significant toxicity when ganciclovir is administered along with, before, or right after Vincristine. Vincristine metabolism is decreased when using miconazole. Increased toxicity when using nifedipine, voriconazole, posaconazole, itraconazole, and isoniazid. Reduced immunological response when vaccinations are taken at the same time. Higher myelotoxicity when zidovudine is used. Tamoxifen increases the risk of problems related to thromboembolism. Ototoxic medications (e.g., platinum-containing antineoplastic treatments) carry an increased risk of ototoxicity. Possibility of an earlier start time and/or more severe side effects when using macrolides. The potential rise in vincristine levels when using aprepitant. Potential reduction in antiepileptic levels with Vincristine; track antiepileptic levels in serum; assess chemotherapeutic efficacy.

Mitomycin C increases the chance of bronchospasm, which could be fatal. Decreased vincristine clearance and elevated asparaginase toxicity; minimize toxicity by giving Vincristine 12-24 hr before L-asparaginase administration.

The common side effects of Vincristine include:

• Hair loss
• Constipation
• Peripheral neuropathy (hand and foot tingling and numbness)
• Headache
• Mouth ulcers or irritation
• Stomach cramps
• Feeling tired or weak
• Muscle, joint, bone, or back pain

• Pregnancy

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

The administration of Vincristine to a pregnant woman may result in fetal harm based on the mechanism of action and findings from nonclinical trials. However, there is not enough information available on the use of vincristine sulfate in pregnant women to assess the possibility of a drug-associated risk.

Before starting treatment, find out whether any females who are capable of bearing children are pregnant.

Contraception

Females: Encourage women who are capable of becoming pregnant to use reliable contraception both during and for six months following the final dosage;

Males: Men with female partners who may get pregnant should use effective contraception during therapy and for three months following the last dose, according to genotoxicity studies.

Infertility

Treatment may decrease fertility, according to research in humans and animals; gonadal dysfunction has been described in post-pubertal individuals, both male and female, who received multi-agent chemotherapy.

Age, dosage, and agent-specific factors determine how much testicular or ovarian function is impaired; some patients may recover, but not all patients do; in animals, the adverse impacts on male reproductive organs were not reversible during a period of recovery.

Animal data

In animal reproduction studies, intravenous treatment during organogenesis in pregnant rats resulted in unfavorable developmental outcomes such as altered growth, structural abnormalities, and increased embryo-fetal mortality. Inform expectant mothers of any possible fetal risk.

• Nursing Mothers

Whether this medication is eliminated in human milk is unknown. The amount of the drug to the mother should be taken into consideration when deciding whether to stop breastfeeding or stop taking it altogether because many pharmaceuticals are excreted in human milk and because nursing infants may have severe adverse responses.

• Pediatric Use

As per FDA, safety and effectiveness of Vincristine in pediatric patients have not been established.

• Geriatric use

The safety and effectiveness of Vincristine in elderly individuals have not been established. Caution should be exercised while selecting the dose for elderly patients, considering the higher likelihood of decreased renal, hepatic, or cardiac function and the presence of concomitant disease or other drug therapy.

Dose Adjustment in Renal Impairment Patients:

Renal impairment: No need to adjust dosage

Dose Adjustment in Hepatic Impairment Patients:

Hepatic impairment: If direct bilirubin is more than 3 mg/dL (51 umol/L), lower the dosage by 50%.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Vincristine.

Signs and Symptoms

Severe toxicities, including motor neuropathy of Grade 3, grand mal seizures of Grade 4, increased aspartate aminotransferase, and hyperbilirubinemia of Grade 4, were observed when Vincristine was given at a dose of 2.4 mg/m2.

Management

There is no specific antidote; Supportive treatment is essential, focusing on preventing side effects related to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Measures include fluid restriction and the administration of loop diuretics. Anticonvulsants and enemas are employed to prevent ileus. Close monitoring of the cardiovascular system and daily assessment of blood counts guide transfusion requirements. Administration of Folinic acid, 100 mg intravenously every 3 hours for 24 hours, followed by every 6 hours for at least 48 hours, may be initiated. The utility of hemodialysis is unlikely.

Continuous observation and appropriate, timely medical interventions to address specific symptoms or complications are recommended.

Pharmacodynamics:

The vinca alkaloids, which consist of two multi-ringed units called vindoline and catharanthine, are structurally related substances. The vinca alkaloids were shown to have antitumor effects in 1959, which led to their clinical utility. Initially studied for their possible hypoglycemic effects, periwinkle plant (Catharanthus roseus) extracts were found to reduce marrow in rats and have antileukemic actions in vitro. Vincristine causes the microtubule to crystallize and causes mitotic arrest or cell death by binding to the microtubular proteins of the mitotic spindle. There is some immunosuppressive impact of Vincristine. It is believed that the vinca alkaloids are phase-specific to the cell cycle.

Pharmacokinetics:

• Absorption: The gastrointestinal absorption of the drug is limited, showing poor absorption from the digestive tract.
• Distribution: Significant distribution across the blood-brain barrier is not observed. Extensive binding to proteins occurs, with 44% bound to proteins. The volume of distribution (Vd) is approximately 8.4 L/kg.
• Metabolism: The primary site of metabolism for the drug is the liver.
• Excretion: The main excretion route is through bile into faeces, accounting for 70-80% of elimination as unchanged drugs and metabolites. Additionally, elimination occurs through urine, with an elimination half-life of 85 hours. Clearance is approximately 146 mL/min.

• Škubník J, Pavlíčková VS, Ruml T, Rimpelová S. Vincristine in Combination Therapy of Cancer: Emerging Trends in Clinics. Biology (Basel). 2021 Aug 31;10(9):849. doi: 10.3390/biology10090849. PMID: 34571726; PMCID: PMC8468923.
• Douer D. Efficacy and Safety of Vincristine Sulfate Liposome Injection in the Treatment of Adult Acute Lymphocytic Leukemia. Oncologist. 2016 Jul;21(7):840-7. doi: 10.1634/theoncologist.2015-0391. Epub 2016 Jun 21. PMID: 27328933; PMCID: PMC4943385.
• Nikpour F, Tayefi H, Mohammadnejad D, Akbarzadeh A. Adverse Effects of Vincristine Chemotherapy on Cell Changes in Seminiferous Tubules and Cetrorelix GnRH Antagonist Inhibitory Effects in Mice. Asian Pac J Cancer Prev. 2018 Mar 27;19(3):683-687. doi: 10.22034/APJCP.2018.19.3.683. PMID: 29580040; PMCID: PMC5980841.
• Broun GO, Blessing JA, Eddy GL, Adelson MD. A phase II trial of vincristine in advanced or recurrent endometrial carcinoma. A Gynecologic Oncology Group Study. Am J Clin Oncol. 1993 Feb;16(1):18-21. doi: 10.1097/00000421-199302000-00005. PMID: 8424397.

• https://www.ncbi.nlm.nih.gov/books/NBK557680/
• US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Depocyt® (Vincristine)
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/071868s032lbl.pdf
• KD Tripathi. [link]. Seventh Edition. New Delhi, India: Jaypee Brothers Medical Publishers; 2013: Page No 864-865