Etoposide (Etosid): FDA Approval, Licensing in Türkiye, and Reimbursement Status

• FDA Approval: Yes (first approval: 1983)
• Trade Names: Etosid®, Toposar®, Etopophos® (may vary by formulation)
• Active Ingredient: Etoposide
• Administration: Oral capsules and intravenous administration (IV injection)
• Class: Antineoplastic; topoisomerase II inhibitor
• Category: Chemotherapy agent
• Manufacturers: Bristol-Myers Squibb, Teva, and Fresenius Kabi (depending on formulation and market)
• Availability in Türkiye: Available for prescription use in hospitals and oncology centers
• Cancers for Which It Is Approved:Small cell lung cancer, testicular cancer, non-Hodgkin lymphoma (in some protocols), acute myeloid leukemia (in combination treatment), and ovarian cancer (in some circumstances)

What Is Etoposide and How Does It Work?

Etoposide is a chemotherapy medicine used to treat several cancers. It was developed from a derivative of podophyllotoxin, a plant-derived compound. It is generally used for rapidly proliferating tumors such as small cell lung cancer and testicular cancer. Both oral and intravenous formulations are available.

How Does It Work?

• Topoisomerase II, an enzyme that repairs cellular DNA and enables proliferation, is etoposide's main target.
• Topoisomerase II inhibition: Etoposide interferes with topoisomerase II's temporary cutting of the DNA double helix. These breaks occur during DNA replication and are normally repaired again by the enzyme.
• DNA breaks and cell death: Etoposide prevents repair of these temporary breaks, creating permanent double-strand DNA breaks. As damage accumulates, the cell cycle stops and apoptosis (programmed cell death) is triggered.
• Cell cycle effects: It is particularly active in the S (DNA synthesis) and G2 phases, making etoposide effective against rapidly dividing cells.

FDA (United States Food and Drug Administration) Approval History

• November 10, 1983: The FDA first approved it for refractory testicular tumors.
• Date uncertain: Approved as first-line treatment for small cell lung cancer in combination with cisplatin. (The study by Hainsworth et al., 1995, is cited as the basis for this approval.)
• February 22, 2012: A new indication and dosage were approved for ovarian cancer progressing after chemotherapy.
• March 26, 2019: A new indication was approved for use before tumor-specific T-cell infusion therapy.

Licensing in Türkiye

The conditions/therapeutic indications for which etoposide is licensed in Türkiye are listed as follows:

Therapeutic Indications

• Etoposide is an intravenously administered antineoplastic agent. It may be used alone or with other antineoplastic agents.
• Etoposide may be used for small cell lung cancer in combination with other chemotherapy agents of proven efficacy. For nonseminomatous testicular carcinoma, it may be combined with other chemotherapy agents of proven efficacy in patients who have received appropriate surgery, chemotherapy, or radiotherapy.
• Objective responses have also been demonstrated in palliative treatment of non-small cell lung cancer, reinduction treatment of Hodgkin disease, induction treatment of non-Hodgkin lymphoma and acute myelocytic leukemia, and induction and reinduction treatment of choriocarcinoma.

Is Etoposide Reimbursed?

It is on the list of medicines for which an indication requirement is not applied to a cancer diagnosis. SGK reimburses it for all cancer diagnoses.

Price: Etopsid 100 mg vial: 369.42 TL; Etoposid 50 mg vial: 305.14 TL

Mechanisms of Resistance

• Decreased or increased drug uptake: P-glycoprotein (P-gp/MDR1), a cell membrane transporter, expels medicines such as etoposide, reducing their effects. Multidrug resistance-associated proteins (MRPs) also expel etoposide and lower intracellular concentrations. This mechanism is known as multidrug resistance (MDR).
• Changes in topoisomerase II levels or function: Reduced topoisomerase II expression lowers levels of etoposide's target enzyme, making the drug ineffective.
• Topoisomerase II gene mutations: Structural changes in the enzyme make etoposide binding difficult, causing loss of drug activity.
• Increased DNA damage repair: If cells repair etoposide-induced DNA breaks, apoptosis is not triggered.
• Repair pathways such as non-homologous end joining (NHEJ) and homologous recombination (HR) may activate.
• Glutathione and detoxification systems: Enzymes such as glutathione S-transferase (GST) may detoxify and inactivate etoposide. Levels of these enzymes are particularly high in chemotherapy-resistant cells.
• Disrupted apoptosis pathways: Changes such as P53 mutations or Bcl-2 overexpression prevent cell death despite DNA damage, making cells resistant to chemotherapy.

Absorption

Oral etoposide is absorbed through the gastrointestinal tract, but absorption is limited and varies between individuals. Oral bioavailability is approximately 25–75%. Food has little effect, but absorption may become saturated at high doses rather than increasing proportionally with dose.

Distribution

Etoposide is widely distributed throughout the body. Plasma protein binding is very high (93–98%), mainly to serum albumin. It crosses the blood–brain barrier only to a limited extent, making it less effective in central nervous system tumors. Volume of distribution (Vd) may be affected by age, albumin levels, and other factors.

Metabolism

• Etoposide undergoes phase II metabolism in the liver.
• Glucuronidation and sulfation convert it into more water-soluble compounds.
• The UGT (UDP-glucuronosyltransferase) family plays the main enzymatic role.
• Some etoposide may also be metabolized by cytochrome P450, particularly CYP3A4.

Elimination

• Etoposide is eliminated through both the kidneys (urine) and bile (feces).
• Approximately 40-60% of the dose is excreted unchanged in urine.
• The remainder is eliminated as metabolites through urine or bile.
• The half-life generally ranges from 4–11 hours but may be prolonged in liver or kidney dysfunction.

Dose Range

• Small cell lung cancer: Combination treatment, for example with cisplatin. IV dose: 100–120 mg/m²/day for 3 consecutive days, generally in 21-day cycles. Oral dose: 100–200 mg/m²/day for 5 days, in 21–28-day cycles.
• Germ cell tumors (including testicular cancer): Combination treatment, such as BEP (bleomycin, etoposide, cisplatin). IV dose: 100 mg/m²/day on days 1–5 of a 21-day cycle, generally for 3–4 cycles.
• Non-Hodgkin/Hodgkin lymphoma: Combination regimens such as ESHAP or BEACOPP. IV dose: 60–100 mg/m²/day, generally for 2–5 days, depending on the treatment schedule and combination partners.
• Ovarian cancer (advanced or recurrent): IV/oral dose: 50–100 mg/m²/day for 5 days, generally at 21-day intervals, as monotherapy or combination treatment.
• Acute myeloid leukemia (AML), salvage treatment: IV dose: 100 mg/m²/day for 3–5 days, for example in the ICE protocol (idarubicin, etoposide, cytarabine).
• Pediatric use, particularly brain tumors and neuroblastoma: Dose: 50–100 mg/m²/day for 3–5 days. Children's doses are generally individualized according to age and body surface area.

Drug Interactions

• Medicines affecting cytochrome P450 enzymes: Etoposide is partly metabolized in the liver by CYP3A4. Medicines affecting this enzyme may therefore alter etoposide levels. CYP3A4 inhibitors, such as ketoconazole, erythromycin, or verapamil, may increase levels and toxicity risk. CYP3A4 inducers, such as rifampicin, phenytoin, or carbamazepine, may reduce effectiveness by accelerating metabolism.
• P-glycoprotein substrates or inhibitors: P-glycoprotein in the cell membrane may expel etoposide. Inhibitors such as verapamil or cyclosporine may increase intracellular etoposide, strengthening both its effects and adverse reactions. Combination with other chemotherapy medicines:
• Cisplatin increases etoposide's effectiveness, but the combination has a higher risk of myelosuppression. Combination with bleomycin and other antineoplastics may produce synergistic effects while increasing adverse reactions, particularly bone marrow suppression.
• Anticoagulants (blood thinners): Combining it with medicines such as warfarin may increase bleeding risk. Etoposide may alter anticoagulant metabolism through effects on liver enzymes.
• Vaccines: Combining it with live vaccines, such as measles or chickenpox vaccines, may increase vaccine-related infection risk because of immune suppression. Live vaccines are generally not recommended in patients receiving etoposide.
• Diuretics and aminoglycosides: Combined use may further impair kidney function, slowing etoposide elimination and increasing toxicity risk.

Precautions

• Myelosuppression: Etoposide suppresses bone marrow and may cause leukopenia (low white blood cells), thrombocytopenia (low platelets), and anemia. Complete blood counts should be monitored before and regularly throughout treatment.
• Kidney and liver function: Etoposide is eliminated through both organs. Dose adjustment may be necessary in kidney impairment. Liver dysfunction may slow metabolism and increase toxicity.
• Infection risk: Immune suppression increases susceptibility to infection. Monitor closely for fever, sore throat, and other infection symptoms, and start antibiotics when necessary.
• Drug interactions: Use caution with medicines that may interact through CYP3A4 or P-glycoprotein, such as phenytoin, verapamil, or warfarin. These may increase or decrease etoposide levels.
• Nausea and vomiting: It has moderate emetogenic potential. Antiemetic support should be provided before treatment.
• Secondary cancer risk: Prolonged use may rarely cause second primary cancers such as treatment-related leukemia. This risk particularly increases when combined with other alkylating agents.
• Pregnancy and breastfeeding: Pregnancy category D (harmful fetal effects have been demonstrated in humans). It must not be used in pregnant or breastfeeding patients.
• Older and frail patients: More careful dose adjustment is needed in older patients because organ function may be reduced. Toxicity risk is greater in patients with poor nutritional or general status.
• Allergic reactions: Rare hypersensitivity reactions may occur, including rash, breathing difficulties, or hypotension. Observe the patient closely during the first dose.

Adverse Reactions

Rates may vary with the patient population, oral/IV dosage regimen, combination treatments, and individual differences.

• Leukopenia (low white blood cell count): 60% – 91%
• Thrombocytopenia (low platelet count): 22% – 41%
• Anemia: 18% – 72%
• Nausea/vomiting: 30% – 40%
• Mouth sores (mucositis): 6% – 17%
• Allergic reactions (rash, redness): 2% – 4%
• Alopecia (hair loss): 8% – 66%
• Hypotension (low blood pressure): 1% – 2% (after IV injection)
• Hyperbilirubinemia (hepatic effect): 2% – 7%
• Infection risk: 12% – 30%
• Febrile neutropenia (fever + neutropenia): 5% – 9%
• Fatigue and weakness: 10% – 30%
• Constipation: 10% – 20%
• Diarrhea: 5% – 10%