Usage
Etoposide is prescribed for the treatment of various types of cancer, including:
- Testicular cancer
- Small cell lung cancer
- Gestational trophoblastic neoplasia
- Ovarian Cancer
- Kaposi’s sarcoma
- Ewing sarcoma
- Acute myeloid leukemia
- Acute lymphocytic leukemia
- Germ cell tumor
It is classified as an antineoplastic agent, specifically a topoisomerase II inhibitor. Etoposide works by disrupting the function of topoisomerase II, an enzyme crucial for DNA replication and cell division. This leads to DNA strand breaks and ultimately prevents the proliferation of cancerous cells.
Alternate Names
Etoposide phosphate (a prodrug form) is sometimes used, and VP-16 is another name for etoposide. Brand names include VePesid, Toposar, and Etopophos.
How It Works
Pharmacodynamics: Etoposide exerts its antitumor effect primarily through the inhibition of topoisomerase II. This enzyme is essential for DNA replication and repair by creating transient breaks in the DNA double helix. Etoposide stabilizes the enzyme-DNA complex, preventing the re-ligation of these breaks. The resulting DNA damage triggers apoptosis (programmed cell death) in rapidly dividing cancer cells.
Pharmacokinetics:
- Absorption: Oral bioavailability is variable, ranging from 25-75%, with an average of about 50%. Oral absorption is dose-dependent and might be lower with higher doses. Food does not significantly affect absorption. Intravenous administration has 100% bioavailability.
- Metabolism: Etoposide is metabolized in the liver, primarily by CYP3A4 enzymes. It also has active and inactive metabolites.
- Elimination: Etoposide is eliminated through both renal and biliary (fecal) routes, with approximately 45-60% excreted in urine, mostly as unchanged drug. Biliary excretion contributes to up to 44% of fecal elimination. The elimination half-life is around 7 hours (range 3-12 hours) after intravenous administration, and approximately 6.8 hours after oral dosing.
Mode of Action: Etoposide forms a ternary complex with topoisomerase II and DNA, which prevents the re-ligation of DNA breaks. This DNA damage ultimately leads to cell cycle arrest and apoptosis.
Elimination Pathways: Primarily renal excretion (around 45-60%), with some biliary (fecal) excretion (up to 44%).
Dosage
Standard Dosage
Adults:
- Intravenous: 50-100 mg/m²/day for 5 days OR 100 mg/m²/day on days 1, 3, and 5. Repeat cycles every 3-4 weeks.
- Oral: 100-200 mg/m²/day for 5 days OR 200 mg/m²/day on days 1, 3, and 5. Repeat cycles every 3-4 weeks. The oral dose is generally twice the IV dose, rounded to the nearest 50 mg.
Children:
Dosage recommendations for children vary considerably depending on the specific cancer and treatment protocol. Generally, it is recommended to determine the dose according to local treatment protocol.
Special Cases:
- Elderly Patients: No specific dose adjustments are required unless renal impairment is present.
- Patients with Renal Impairment: For creatinine clearance between 15-50 mL/min, reduce the dose to 75% of the standard dose. For creatinine clearance below 15 mL/min, dose reduction to 50% or discontinuation is recommended.
- Patients with Hepatic Dysfunction: For bilirubin levels between 25-50 µmol/L, use 50% of the normal dose. For bilirubin >50-85 µmol/L, consider reducing the dose to 25%. If bilirubin is >85, etoposide is generally not recommended.
Clinical Use Cases
Dosing for specific clinical situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergencies is determined by the primary cancer treatment protocol and adjusted based on individual patient factors such as renal or hepatic function, concomitant medications, and tolerance to therapy.
Dosage Adjustments
Dose modifications should be based on myelosuppression (neutropenia, thrombocytopenia), hepatic or renal function, and concomitant medications.
Side Effects
Common Side Effects
- Myelosuppression (leukopenia, neutropenia, thrombocytopenia, anemia)
- Nausea and vomiting
- Alopecia (hair loss)
- Fatigue
- Mucositis (mouth sores)
- Diarrhea
- Loss of appetite
Rare but Serious Side Effects
- Anaphylaxis (severe allergic reaction)
- Secondary leukemia
- Hypotension (low blood pressure) with rapid IV administration
- Hepatotoxicity (liver damage)
- Peripheral neuropathy (nerve damage)
Long-Term Effects
- Infertility
- Increased risk of secondary malignancies
Adverse Drug Reactions (ADR)
- Severe myelosuppression
- Anaphylaxis
Contraindications
- Hypersensitivity to etoposide or any component of the formulation
- Severe myelosuppression
- Severe hepatic impairment
Drug Interactions
Etoposide interacts with numerous medications, including:
- CYP3A4 inducers (e.g., phenytoin, rifampin) decrease etoposide levels and efficacy.
- CYP3A4 inhibitors (e.g., ketoconazole, itraconazole) increase etoposide levels, potentially leading to increased toxicity.
- Cyclosporine increases etoposide exposure.
- Cisplatin decreases etoposide clearance.
- Anticoagulants (e.g., warfarin) may have altered effects due to etoposide-induced changes in clotting factors.
Pregnancy and Breastfeeding
Etoposide is contraindicated in pregnancy (Pregnancy Category D) due to its teratogenic effects. It should also be avoided during breastfeeding.
Drug Profile Summary
- Mechanism of Action: Topoisomerase II inhibitor
- Side Effects: Myelosuppression, nausea, vomiting, alopecia, fatigue, mucositis, diarrhea.
- Contraindications: Hypersensitivity, severe myelosuppression, severe hepatic impairment.
- Drug Interactions: CYP3A4 inducers/inhibitors, cyclosporine, cisplatin.
- Pregnancy & Breastfeeding: Contraindicated
- Dosage: See detailed section above.
- Monitoring Parameters: Complete blood count (CBC) with differential, renal function tests, liver function tests, blood pressure.
Popular Combinations
Etoposide is frequently used in combination chemotherapy regimens with other antineoplastic agents, including cisplatin, bleomycin, ifosfamide, and cyclophosphamide. The specific combination used will vary depending on the type of cancer being treated.
Precautions
- Administer IV infusions slowly over 30-60 minutes to avoid hypotension.
- Monitor closely for myelosuppression.
- Use caution in patients with renal or hepatic impairment.
- Patients should use effective contraception during and for several months after treatment.
- Avoid live vaccines during treatment.
- Avoid grapefruit and grapefruit juice during etoposide treatment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Etoposide?
A: The recommended dosage varies depending on the route of administration, the condition being treated, and patient-specific factors such as renal and hepatic function. See the detailed “Dosage” section above.
Q2: What are the most common side effects of Etoposide?
A: The most common side effects include myelosuppression (low blood cell counts), nausea, vomiting, hair loss, fatigue, and mouth sores.
Q3: How does Etoposide work?
A: Etoposide inhibits topoisomerase II, leading to DNA damage and ultimately cell death in rapidly dividing cancer cells.
Q4: Is Etoposide safe to use during pregnancy or breastfeeding?
A: No, etoposide is contraindicated during pregnancy and breastfeeding due to potential harm to the fetus or infant.
Q5: What are the key drug interactions with Etoposide?
A: Significant interactions can occur with drugs that affect CYP3A4 enzyme activity (inducers and inhibitors), as well as with cyclosporine and cisplatin.
Q6: What precautions should be taken when administering Etoposide intravenously?
A: IV infusions should be administered slowly over 30-60 minutes to minimize the risk of hypotension. The patient’s blood pressure should be monitored during and after the infusion.
Q7: How should Etoposide be handled?
A: Etoposide should be handled with care, using appropriate personal protective equipment such as gloves, due to its potential for skin reactions.
Q8: What should patients be advised regarding fertility when taking Etoposide?
A: Etoposide can cause infertility in both men and women. Patients should be counseled about fertility preservation options before starting treatment.
Q9: What blood tests should be monitored during Etoposide treatment?
A: Regular complete blood counts (CBC) with differential are essential to monitor for myelosuppression. Renal and liver function tests should also be monitored.
