Etoposide
Medicine Type :
Allopathy
Allopathy
Prescription Type:
Prescription Required
Prescription Required
Approval :
DCGI (Drugs Controller General of India)
DCGI (Drugs Controller General of India)
Schedule
Schedule H
Schedule H
Pharmacological Class:
Topoisomerase II Inhibitors, Therapy Class:
Antineoplastic agent, Approved Countries
India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.
Etoposide is an antineoplastic agent belonging to the pharmacological class of topoisomerase II inhibitors.
Etoposide is FDA-approved for the treatment of testicular and small-cell lung tumours.
Etoposide is primarily absorbed through the gastrointestinal tract, and roughly 50% of the drug is orally. Although it rapidly distributes through the body, it poorly penetrates the blood-brain barrier. The CYP3A4 enzyme system primarily metabolizes the drug. It's eliminated in urine and faeces, constituting 35% removal.
The most common side effects of Etoposide include low blood platelets, vomiting, nausea, hair loss, and anaemia (low number of red blood cells).
Etoposide is available as capsules, injectable solution and powder for injection.
The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.
Etoposide is an antineoplastic agent belonging to the pharmacological class of topoisomerase II inhibitors.
Inhibiting DNA re-ligation is achieved by Etoposide through inhibiting DNA topoisomerase II. During the premitotic stage of cell division, this results in critical errors in DNA synthesis and may cause the cancer cell to undergo apoptosis. Etoposide is phase-specific and cell cycle-dependent, mainly affecting cell division's S and G2 phases. Etoposide's anti-tumour activity is caused by inhibition of the topoisomerase II alpha isoform. Though suppression of this target is not connected to the anti-tumour activity, the medication can also inhibit the beta isoform. Instead, it is related to the development of cancer.
The peak plasma time for this is within one hour after administration.
The peak plasma concentration is 4.7 mcg/mL at peak levels following administration of this medication.
Etoposide is available as capsules, injectable solution and powder for injection.
Capsules: Take them whole with water for oral capsules, usually on an empty stomach or as directed.
Injectable solution and powder for injection: To be administered by healthcare professionals through intravenous infusion after appropriate dilution.
- Small cell lung cancer
- Testicular cancer
- Official label use: Acute Myelomonoblastic Leukaemia (AML)
- In Small cell lung cancer: Etoposide effectively treats fast-growing small cell lung cancer, often triggered by smoking. Administered alone or in combination with other drugs, it targets rapidly dividing cancer cells, shrinking tumours and halting their spread. It's a potent yet toxic medicine. Patients undergoing treatment should abstain from alcohol and prioritize hydration by drinking plenty of water.
- Testicular cancer: In men, testicular cancer affects the testicles, responsible for male hormones and sperm production, situated in the scrotum. Etoposide stops cancer cell growth and multiplication, promoting tumour regression when incorporated into treatment. It impedes cancer cell proliferation and should never be self-administered, serving as a crucial component in combating this malignancy.
- Acute Myelomonoblastic Leukaemia (AML): In treating Acute Myelomonoblastic Leukemia (AML), Etoposide significantly benefits by targeting and inhibiting the rapid growth of abnormal white blood cells. Combined with other chemotherapy agents, it effectively impedes disease progression by targeting and inhibiting the rapid division of leukaemia cells, contributing to improved therapeutic outcomes and potentially enhancing survival rates for individuals with AML.
Etoposide is indicated for the treatment of the neoplasms listed below:
- Refractory Testicular Tumors: In patients with refractory testicular tumours who have previously undergone the necessary surgical, chemotherapeutic, and radiotherapeutic treatments, Etoposide is prescribed with other approved chemotherapeutic agents.
- Small Cell Lung Cancer: The first line of treatment for individuals with small cell lung cancer is Etoposide for Injection and/or Capsules when combined with other approved chemotherapeutic agents.
Orally: Patients orally administer Etoposide capsules by swallowing them whole with water, typically on an empty stomach. It's crucial to strictly adhere to the prescribed schedule and avoid chewing or breaking the capsules unless directed by the healthcare provider for optimal therapeutic benefits.
Parenterally: Etoposide is administered parenterally, typically through intravenous infusion, as an injectable solution or powder for injection, ensuring proper dilution and compatibility with infusion solutions before administration. It's crucial to follow appropriate aseptic techniques during preparation and administration to reduce the risk of infection.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
- Capsule: 50mg
- Injectable solution: 20mg/mL
- Powder for injection: 100mg
Etoposide is available as capsules, injectable solution and powder for injection.
Dose Adjustment in Adult Patients:
Testicular Cancer IV: 50–100 mg/m³/day on days 1–5, OR
100 mg/m2/day IV on days 1, 3, and 5
Take it every three to four weeks.
Cancer of the Small Cell Lungs
IV 35 mg/m²/day for four days, OR
IV 50 mg/m²/day for five days; repeat every 3–4 weeks
While taking Etoposide, follow dietary restrictions for optimal safety. Consume antioxidant-rich foods like berries and spinach, favouring a high-fibre diet with small, frequent meals for better recovery support. Avoid smoking, alcohol, and high-fat, cholesterol-rich foods to minimize potential interactions and adverse effects. Ensure a balanced diet and seek medical approval before using supplements or herbal products during treatment to maintain medication efficacy and safety.
The dietary restriction should be individualized as per patient requirements.
Hypersensitivity to Etoposide or teniposide present in the formulation.
- Etoposide therapy induces myelosuppression, leading to thrombocytopenia and neutropenia, potentially resulting in fatal infections and bleeding. Obtain complete blood counts before each cycle and more frequently as clinically needed. Consider withholding further treatment if platelet count drops below 50,000/mm³ or ANC falls below 500/mm³.
- Use with caution in cases of hepatic impairment.
- Administer the medication via slow infusion over at least 30-60 minutes to prevent hypotension. Watch closely for injection site reactions during administration.
- Avoid pregnancy during treatment due to potential risks.
- Etoposide may lead to oligospermia, azoospermia, and irreversible fertility loss. While sperm counts might normalize in some men post-therapy, it can cause genetic fetal abnormalities. Males with reproductive partners should use condoms during therapy and for at least four months post-treatment.
- In females, it can cause infertility and amenorrhea, potentially leading to premature menopause. The recovery of menses and ovulation depends on the age at treatment. Encourage females to use effective contraception during treatment and for at least six months after the final dose.
- Rare cases of acute leukaemia have been reported with etoposide treatment, and the risk of preleukemic or leukemic syndrome remains unclear when used alone or with other neoplastic agents.
- Prescribers must carefully weigh the benefits against the risks of therapy. If severe reactions occur, consider reducing the dose or discontinuing the medication and take appropriate corrective measures. Reinitiate therapy cautiously, being vigilant about the need for the drug and alert to potential recurrence of toxicity.
- Patients with low serum albumin may face heightened risks of etoposide-associated toxicities.
- Anaphylactic reactions presenting as chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension have been reported. Higher rates of anaphylactic-like responses have been observed in children receiving infusions at concentrations higher than recommended. The role of infusion concentration (or rate) in these reactions is uncertain. Symptomatic treatment is advised, immediately ceasing infusion and administering pressor agents, corticosteroids, antihistamines, or volume expanders per the physician's discretion.
- Reversible cases of acute renal failure have been reported with high-dose (2220 mg/m²) administration in hematopoietic stem cell transplantation with total body irradiation. The formulation includes dextran 40, associated with acute renal failure in high doses.
Alcohol Warning
It is unsafe to consume etoposide with alcohol.
Breast Feeding Warning
It is not recommended for use during breastfeeding.
Pregnancy Warning
It is not recommended for use during pregnancy.
Food Warning
Consume an antioxidant-rich diet, and avoid smoking/alcohol.
The adverse reactions related to Etoposide can be categorized as:
- Common Adverse Effects: Leukopenia, nausea, vomiting, thrombocytopenia, alopecia, anorexia, diarrhoea, and anaemia.
- Less Common Adverse Effects: Pancytopenia, stomatitis, hepatic toxicity, type 1 hypersensitivity, orthostatic hypotension, peripheral neuropathy
- Rare Adverse Effects: Severe myelosuppression, characterised by leucopaenia and thrombocytopaenia. Cardiotoxicity. Anaphylaxis.
The clinically relevant drug interactions of Etoposide are briefly summarized here.
Interaction with other cytotoxic medications. When administering drugs that block phosphatase activity, exercise caution. Etoposide clearance could be lowered by cyclosporin A. Comparing oral Etoposide with high-dose cyclosporin A at concentrations exceeding 2000 ng/mL has increased etoposide exposure by 80% while decreasing the body's overall clearance of Etoposide by 38%.
The common side effects of Etoposide include:
- Infection, especially in cases of low white blood cell counts
- Bruising, bleeding
- Anaemia, which may cause tiredness or may require blood transfusions
- Kidney damage, which may cause swelling, may require dialysis.
- Hearing loss, including ringing in the ears
- Diarrhea
- Liver damage
- Nausea, vomiting
- Stomatitis (Inflammation of the mouth), which may cause difficulty swallowing
- Confusion
- Hair loss
- Numbness, pain and tingling of the fingers, toes, arms and/or legs, loss of balance
- Pregnancy
Pregnancy Category D (FDA): Use in situations where there is no safer medication available and life is in danger. Evidence that human fetal risk exists.
If Etoposide is given to a pregnant woman, it may harm the fetus. In rats and mice, Etoposide has been demonstrated to be teratogenic.
Rats that received higher doses of 1.2 and 3.6 mg/kg/day—roughly 1/7th and 1/2 of the human dose on a mg/m2 basis—experienced 90 and 100% embryonic resorptions. Maternal toxicity, embryotoxicity, and teratogenicity (skeletal abnormalities, encephalocele, exencephaly, and anophthalmia) were caused in rats by an intravenous (IV) etoposide dose of 0.4 mg/kg/day (roughly 1/20th of the human dose on a mg/m2 basis) during organogenesis. A single intraperitoneal injection of Etoposide at 1.0 mg/kg (1/16th of the human dose on a mg/m2 basis) on days 6, 7, or 8 of gestation resulted in embryotoxicity, cranial abnormalities, and significant skeletal malformations in mice. On day 7 of gestation, an I.P.dose of 1.5 mg/kg (roughly 1/10th of the human dose on a mg/m2 basis) resulted in a significant drop in the average fetal body weight as well as an increase in the incidence of fetal malformations and intrauterine death.
It should be advised to women who are capable of bearing children not to get pregnant. The patient should be informed of the possible risk to the fetus if this medication is taken during pregnancy or if the patient gets pregnant while taking it.
It is essential to understand that Etoposide may cause cancer in people. Rarely patients receiving Etoposide alone or in combination with other neoplastic agents have been reported to experience acute leukaemia, either with or without a preleukemic phase. It is unknown how likely it is that a leukemic or preleukemic syndrome will develop. Etoposide carcinogenicity studies have not been carried out on lab animals.
- Nursing Mothers
There is no information on the presence of Etoposide in human milk or how it affects the production of breastfed infant milk; mothers are advised not to breastfeed while receiving etoposide treatment due to the possibility of severe adverse reactions in nursing infants.
- Pediatric Use
As per FDA, the safety and efficacy of Etoposide in Pediatric patients have not been established.
However, when using this population, utmost caution should be taken.
Dose Adjustment in Pediatric Patients:
AML Induction (Off-label)
<3 years: 4 days of continuous IV infusion at 3.3 mg/kg/day
≥3 years: 4 days of continuous IV infusion at 100 mg/m²/day
- Geriatrics (> 65 years old)
Etoposide use in older people requires careful monitoring because of age-related vulnerabilities. Appropriate dosage adjustments and assessments are necessary to manage potential risks and ensure that Etoposide is suitable for treating specific cancers in older adults.
Dose Adjustment in Kidney Impairment Patients:
CrCl >50 mL/min: No need to change the dosage.
15–50 mL/min CrCl: 75% of the usual dosage
CrCl < 15 mL/min: Unknown; take into account additional dosage reductions.
Dose Adjustment in Hepatic Impairment Patients:
Hepatic Impairment: Not studied.
The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Etoposide.
Signs and Symptoms
Overconsumption of Etoposide could lead to myelosuppression, mucositis, and gastrointestinal toxicities.
Management
There is no specific antidote or treatment for overdosage of Etoposide, so treatment typically involves symptomatic and supportive measures, including close monitoring of hematological parameters and supportive care for myelosuppression. Gastric lavage or induced vomiting could be considered if the ingestion occurred within an hour, followed by the administration of activated charcoal to reduce further absorption of the drug from the gastrointestinal tract.
Consider therapeutic interventions for mucositis and gastrointestinal toxicity. Continuous monitoring of vital signs, haematological indices, and overall clinical status is critical.
Timely medical intervention plays a crucial role in managing Etoposide overdose, ensuring careful monitoring and proper care to address symptoms and prevent complications.
Pharmacodynamics
Etoposide is an epipodophyllotoxin, a semisynthetic derivative of podophyllotoxins, and an antineoplastic. It prevents DNA synthesis by inhibiting DNA topoisomerase II. Etoposide primarily affects the S and G2 phases and is phase-specific and cell cycle-dependent. There are two distinct dose-dependent reactions observed. Cells entering mitosis exhibit lysis at at least ten µg/mL concentrations. A low concentration of 0.3 to 10 µg/mL prevents cells from going into prophase. It does not affect the assembly of microtubules. The generation of free radicals or the induction of DNA strand breaks through interaction with DNA-topoisomerase II appear to be the main macromolecular effects of Etoposide.
Pharmacokinetics:
- Absorption: Around 50% of the medication is absorbed through the gastrointestinal tract upon oral administration. Plasma concentrations reach their peak approximately one-hour post-administration. The drug's bioavailability ranges between 25% to 75%.
- Distribution: Despite rapid distribution throughout the body, this medication demonstrates limited blood-brain barrier penetration. 94% to 98% of the drug binds to plasma proteins. The volume of distribution of this drug spans between 7 to 17 L/m², indicating its extent of distribution within the body.
- Metabolism: The drug undergoes metabolism primarily facilitated by the CYP3A4 enzyme system, impacting its breakdown and conversion within the body.
- Excretion: Elimination occurs with a terminal half-life ranging from 4 to 11 hours. About 35% of the drug is excreted through urine, while the remainder is eliminated via faeces. The clearance rate of this medication is about 13.4 mL/min.
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- https://www.ncbi.nlm.nih.gov/books/NBK557864/
Published on: 3 Jan 2024 2:28 AM GMT
