Mannitol + Vincristine

Usage

This combination is primarily used in specific chemotherapy regimens where Mannitol is administered to reduce the risk of Vincristine-induced side effects. Vincristine, a vinca alkaloid, is a critical component of various chemotherapy protocols for cancers like acute leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma, Wilms’ tumor, rhabdomyosarcoma, neuroblastoma, and other childhood cancers. Mannitol, an osmotic diuretic, is adjunctively used to prevent or mitigate Vincristine’s nephrotoxic and neurotoxic effects. Vincristine’s pharmacological classification is antineoplastic (specifically, a plant alkaloid and anti-mitotic agent), while Mannitol is classified as an osmotic diuretic.

Vincristine’s mechanism of action involves binding to tubulin, a protein crucial for microtubule formation in cells. This binding inhibits microtubule assembly and dynamics, disrupting mitosis (cell division) and ultimately leading to cell death. Mannitol increases osmotic pressure in the glomerular filtrate, promoting diuresis. This increased diuresis helps to flush out Vincristine from the kidneys, reducing the risk of kidney damage, as well as potentially minimizing neurotoxicity.

Alternate Names

Vincristine: Often abbreviated VCR. A liposomal formulation is marketed under the brand name Marqibo.

Mannitol: Osmitrol, Resectisol

How It Works

Vincristine:

• Pharmacodynamics: Vincristine’s primary effect is cell cycle-specific cytotoxicity, predominantly affecting the M phase (mitosis). By interfering with microtubule function, it disrupts cell division. Its main toxicity manifests as neurotoxicity (peripheral neuropathy) and myelosuppression (bone marrow suppression), which can lead to leukopenia, neutropenia, thrombocytopenia, and anemia. It can also cause gastrointestinal issues like constipation.

• Pharmacokinetics: Administered intravenously. Metabolized primarily in the liver by CYP3A4. Excreted predominantly in bile and feces, with minimal renal excretion.

• Mode of Action: Binds to tubulin dimers, preventing polymerization into microtubules. This disrupts spindle formation during mitosis, arresting cell division and leading to apoptosis (programmed cell death).

Mannitol:

• Pharmacodynamics: Increases the osmolarity of plasma and glomerular filtrate, leading to increased water excretion by the kidneys. Can decrease intracranial and intraocular pressure.

• Pharmacokinetics: Administered intravenously. Not metabolized. Excreted primarily unchanged by the kidneys through glomerular filtration.

Dosage

Dosage regimens vary depending on the specific cancer being treated, patient age, and other factors. The following is a general guideline and should not be used as a replacement for physician-determined dosages. Mannitol is given as an adjunct to Vincristine, not as a combined drug.

Standard Dosage

Adults:

• Vincristine: Typically 1.4 mg/m² intravenously weekly. Maximum single dose typically 2 mg.

• Mannitol: Dosages vary depending on the indication, usually administered before, during, or after Vincristine.

Children:

• Vincristine: Dosage usually based on body surface area (BSA) - typically 1.5-2 mg/m² intravenously weekly. Maximum single dose usually 2 mg.

• Mannitol: Dosages based on body weight or BSA; specific dosing is determined by the treating physician.

Special Cases:

Dosage adjustments should be made by a physician based on the individual patient’s kidney and liver function, age, and overall health condition.

Clinical Use Cases

The Mannitol + Vincristine combination is not specifically indicated for these cases. Mannitol may be used in some cases, such as intubation or surgical procedures, and Vincristine may be indicated for patients undergoing mechanical ventilation or receiving ICU care if these patients are being treated for cancers. However, the combination of drugs would be based on each individual patient’s situation, rather than a standard treatment plan.

Dosage Adjustments

Dosage must be adjusted by a physician based on patient-specific factors, including renal/hepatic dysfunction, comorbidities, and other medications.

Side Effects

Common Side Effects (Vincristine):

• Peripheral neuropathy (numbness, tingling, pain in hands and feet)
• Constipation
• Hair loss
• Nausea and vomiting
• Jaw pain

Rare but Serious Side Effects (Vincristine):

• Severe peripheral neuropathy
• Paralytic ileus
• Hyponatremia (low sodium)
• Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Common Side Effects (Mannitol):

• Fluid and electrolyte imbalances
• Headache
• Dizziness
• Nausea and vomiting

Rare but Serious Side Effects (Mannitol):

• Pulmonary edema
• Heart failure
• Seizures

Contraindications

Vincristine: Contraindicated in patients with demyelinating Charcot-Marie-Tooth syndrome.

Mannitol: Contraindicated in anuria, severe pulmonary edema, active intracranial bleeding, and severe dehydration.

Drug Interactions

Vincristine: Interacts with numerous drugs, including itraconazole, digoxin, and phenytoin.

Mannitol: Can enhance the excretion of lithium.

Pregnancy and Breastfeeding

Vincristine: Contraindicated in pregnancy and breastfeeding.

Mannitol: Consult a physician regarding use during pregnancy and breastfeeding.

Drug Profile Summary

Refer to above sections for summaries.

Popular Combinations

Vincristine is often used in combination chemotherapy regimens, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) for non-Hodgkin’s lymphoma, and MOPP (mechlorethamine, vincristine, procarbazine, prednisone) for Hodgkin’s disease.

Precautions

Refer to above sections for precautions.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Mannitol + Vincristine?

A: Mannitol and Vincristine are not administered as a combined dose. The dosing of each medication is determined independently based on patient factors and the intended therapeutic effect.

Q2: How does Mannitol help reduce Vincristine side effects?

A: Mannitol’s osmotic diuretic action promotes increased urinary excretion of Vincristine, minimizing nephrotoxicity and potentially mitigating neurotoxic effects.

Q3: What are the most significant side effects to watch for with Vincristine?

A: Peripheral neuropathy, constipation, myelosuppression, and SIADH.

Q4: How is Vincristine metabolized and eliminated?

A: Primarily metabolized in the liver via CYP3A4 and excreted through bile and feces.

Q5: Can Vincristine be given intrathecally?

A: No, intrathecal administration of Vincristine is contraindicated as it can cause fatal neurotoxicity.

Q6: What are the key monitoring parameters for patients receiving Vincristine and Mannitol?

A: Monitor for neurotoxicity (clinical assessment), complete blood count (CBC) for myelosuppression, serum electrolytes (sodium, potassium, uric acid), liver function tests, and creatinine clearance. Monitor the infusion site closely for extravasation during Vincristine administration.

Q7: What should be done in case of Vincristine extravasation?

A: Stop the infusion immediately, aspirate any remaining drug, and administer hyaluronidase locally. Apply warm compresses to the area.

Q8: Are there any specific drug interactions of concern with Vincristine?

A: Yes, Vincristine interacts with numerous drugs metabolized by CYP3A4, including itraconazole and some antiepileptic medications. Concomitant use can increase the risk of Vincristine toxicity.

Q9: Can Vincristine be used during pregnancy or breastfeeding?

A: No, Vincristine is contraindicated during pregnancy and breastfeeding due to its potential for teratogenic effects and unknown risks to infants.

Q10: What is the role of Mannitol in the treatment of cancer?

A: Mannitol itself is not an anti-cancer drug. It is used adjunctively with certain chemotherapy agents, such as Vincristine, to mitigate specific side effects like nephrotoxicity.