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

• FDA Approval: Yes (first approval date: November 10, 1983)
• Trade Names: VePesid (United States), Lastet (Türkiye)
• Active Ingredient: Etoposide
• Administration: Oral tablet (by mouth)
• Class: Topoisomerase II inhibitor
• Category: Antineoplastic
• Manufacturer: Bristol-Myers Squibb (VePesid); Onko-Koçsel İlaç in Türkiye
• Distribution in Türkiye: Licensed and sold under the name “Lastet” by Onko-Koçsel İlaç.
• Cancers for Which It Is Approved: Small cell lung cancer (combined with cisplatin) and refractory testicular tumors (in combination treatment)

What Is Lastet and How Does It Work?

Lastet contains etoposide, an antineoplastic chemotherapy agent. It is used particularly for certain solid tumors, including small cell lung cancer and testicular tumors.

How Does It Work?

• Lastet works by stopping cancer cell proliferation.
• Cells copy their DNA when they divide. This process requires an enzyme called topoisomerase II.
• Lastet blocks this enzyme, preventing DNA strands from properly opening and closing.
• As a result, DNA structure is disrupted and the cell is forced to destroy itself through apoptosis (programmed cell death).
• This mechanism is particularly effective in rapidly dividing cancer cells.

FDA (United States Food and Drug Administration) Approval History

Etoposide, sold in Türkiye under the Lastet brand, was first approved by the Food and Drug Administration (FDA) on November 10, 1983. This approval particularly covers treatment of refractory testicular tumors and small cell lung cancer.

Licensing in Türkiye

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

Therapeutic Indications

• Small cell lung cancer
• Non-small cell lung cancer
• Germ cell tumors (such as testicular cancer)
• Ovarian cancer
• Breast cancer
• Hodgkin lymphoma
• Non-Hodgkin lymphoma

Is Lastet 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: Lastet 50 mg, 20 capsules: 3.064. 66 TL.

Mechanisms of Resistance

• Overexpression of transmembrane transport proteins such as P-glycoprotein causes etoposide to be expelled from cells. This prevents adequate intracellular concentrations and leads to treatment nonresponse.
• Reduced or mutated topoisomerase II: Cellular levels of topoisomerase II, etoposide's primary target, may decrease. Structural changes (mutations) in the enzyme may prevent etoposide binding, making DNA break formation more difficult.
• Increased DNA damage repair: Cells may repair etoposide-induced double-strand DNA breaks more effectively. Increased repair prevents apoptosis (programmed cell death), producing treatment resistance.
• Etoposide is particularly active during the S and G2 phases. Cells that escape or slow these phases become less sensitive to it.
• Disrupted apoptosis pathways: Some tumor cells fail to respond to apoptosis signals despite DNA damage. In particular, p53 mutations or imbalances in Bcl-2 family proteins may protect cells from death.
• Cells with high glutathione (GSH) levels may neutralize drug-induced free radicals and reactive oxygen species, reducing cytotoxicity.

Absorption

• After oral administration, Lastet capsules are absorbed through the digestive tract into the bloodstream.
• Absorption varies between individuals, but bioavailability is generally 25% - 75%.
• Food does not substantially change absorption.
• Peak drug concentrations are usually reached within 1-2 hours.

Distribution

• Circulating etoposide distributes into many body tissues.
• However, entry into the brain and central nervous system is limited because it crosses the blood–brain barrier poorly.
• Up to 90% is transported bound to plasma proteins.
• It may concentrate particularly in the liver and kidneys.

Metabolism

• Etoposide is mainly metabolized in the liver.
• It is broken down by a liver enzyme called CYP3A4.
• Both active and inactive metabolites are formed.
• However, a substantial proportion of etoposide is eliminated unchanged, without being metabolized.
• Careful dose adjustment is therefore required in patients with impaired liver function.

Elimination

• Much of etoposide is eliminated in urine through the kidneys, with 40–60% excreted unchanged.
• A small proportion is eliminated through bile into feces.
• Its half-life, the time taken for its concentration to fall by half, averages 4 to 11 hours.
• Elimination slows in kidney impairment, so dose reduction may be needed.

Dose Range

• Small Cell Lung Cancer: Oral dose: 50–100 mg/m²/day, usually for 5 days. Cycles may be repeated every 21–28 days, combined with cisplatin or carboplatin.
• Testicular Cancer (Refractory Germ Cell Tumors): Oral or IV dose: 50–100 mg/m²/day for 5 days. Combined with other medicines, for example in the BEP protocol: bleomycin, etoposide, and cisplatin.
• Ovarian Cancer: Oral dose: 50–100 mg/m²/day for 5 days, generally combined with platinum-based medicines.
• Hodgkin and Non-Hodgkin Lymphomas: Used in combination regimens such as BEACOPP or ESHAP. Doses are generally 100 mg/m²/day for 2–5 days.
• Acute Leukemias (AML, ALL): 100 mg/m²/day may be given for 5 days, generally in combination with medicines such as idarubicin and arabinoside.
• Because oral bioavailability varies, the oral dose is usually approximately 2 times the IV dose (for example, 100 mg/m² orally ≈ 50 mg/m² IV).
• Tablets should generally be taken after meals.

Drug Interactions

• Etoposide is metabolized in the liver by CYP3A4. Medicines affecting this enzyme alter etoposide blood levels. CYP3A4 inhibitors increase levels and toxicity risk: ketoconazole and itraconazole (antifungals), erythromycin and clarithromycin (antibiotics), verapamil and diltiazem (cardiac medicines), and grapefruit juice.
• CYP3A4 inducers reduce blood levels and effectiveness: rifampicin (a tuberculosis medicine), phenytoin and carbamazepine (antiepileptics), and St. John's wort (an herbal product).
• P-gp inhibitors such as verapamil and cyclosporin may increase etoposide levels. P-gp inducers may reduce them.
• Cisplatin is frequently combined with etoposide. However, its effects on the kidneys may slow etoposide elimination. Combining etoposide with medicines such as bleomycin and ifosfamide may increase toxicity, particularly pulmonary and bone marrow toxicity.
• Combining etoposide with anticoagulants, particularly warfarin, may increase bleeding risk. INR (a measure of blood clotting time) should be monitored closely.
• It must not be combined with live vaccines. Because etoposide suppresses immunity, live vaccines may create a serious infection risk. Vaccination should be scheduled before treatment where possible.
• Combining it with cyclosporine may reduce hepatic clearance of etoposide, raising drug levels and toxicity risk.

Precautions

• Take tablets at the dose and for the duration recommended by the physician. Taking them after meals is generally recommended to protect the stomach. Capsules must be swallowed whole without chewing.
• Complete blood counts (CBC) should be monitored regularly during treatment, particularly white blood cells, platelets, and hemoglobin. Liver and kidney function should also be checked periodically.
• Lastet may suppress immunity and increase infection risk. Report fever, sore throat, chills, or cough to the physician immediately. Avoid crowds and people who are ill whenever possible.
• Low platelet counts may cause easy bruising, nosebleeds, or bleeding gums. Use a soft toothbrush and take care when shaving.
• It must not be used during pregnancy because it may harm the unborn baby. Effective contraception must be used during treatment. It must also not be used while breastfeeding.
• Live vaccines, such as measles, mumps, or chickenpox vaccines, must not be given during treatment. Immune suppression may create a serious infection risk.
• Temporary hair loss, nausea, loss of appetite, and mouth sores may occur.

Adverse Reactions

• 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%