Etoposide – Uses, Dosage, Side Effects, Interaction

Etoposide Toniribate is a prodrug of etoposide, a semisynthetic derivative of podophyllotoxin extracted from the mandrake root Podophyllum peltatum, with potential antineoplastic activity. Upon intravenous administration of etoposide toniribate, etoposide is released after enzymatic cleavage of CAP7.1 by specific carboxylesterases (CE) 1 and 2, which are upregulated in certain tumor cell types. Etoposide acts primarily in the G2 and S phases of the cell cycle. This drug binds to and inhibits topoisomerase II, an enzyme elevated in tumor cells. This results in the accumulation of double-strand DNA breaks, the inhibition of DNA replication and transcription, and the induction of apoptotic cell death. The tumor-specific activation of etoposide increases its efficacy while lowering its systemic toxicity.

Etoposide Phosphate is a phosphate salt of a semisynthetic derivative of podophyllotoxin. Etoposide binds to the enzyme topoisomerase II, inducing double-strand DNA breaks, inhibiting DNA repair, and resulting in decreased DNA synthesis and tumor cell proliferation. Cells in the S and G2 phases of the cell cycle are most sensitive to this agent. (NCI04)

Etoposide has been shown to arrest metaphase in chick fibroblasts, but its principal effect in mammalian cells appears to be in the G2 phase. At etoposide concentrations of 0.3-10 ug/ml in vitro, cells are inhibited from entering prophase; at concentrations of 10 ug/ml or higher, lysis of cells entering mitosis occurs. Etoposide does not inhibit microtubule assembly. Etoposide has been shown to induce single-stranded DNA breaks in HeLa cells and in murine leukemia L1210 cells in vitro; the drug also induces double-stranded DNA breaks and DNA-protein crosslinks in L1210 cells. Etoposide-induced DNA damage appears to correlate well with the cytotoxicity of the drug. Etoposide appears to induce single-stranded DNA breaks indirectly, possibly through endonuclease activation, inhibition of intranuclear type II topoisomerase, or formation of a free-radical metabolite via an enzymatic reaction involving the hydroxyl group at the C-4′ position of the E ring. Etoposide also reversibly inhibits the facilitated diffusion of nucleosides into HeLa cells in a concentration-dependent manner in vitro.

Etoposide is an antineoplastic agent and an epipodophyllotoxin (a semisynthetic derivative of the podophyllotoxins). It inhibits DNA topoisomerase II, thereby ultimately inhibiting DNA synthesis. Etoposide is cell cycle-dependent and phase-specific, affecting mainly the S and G2 phases. Two different dose-dependent responses are seen. At high concentrations (10 µg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 µg/mL), cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of free radicals.

A prodrug of etoposide, a semisynthetic derivative of podophyllotoxin extracted from the mandrake root Podophyllum peltatum, with potential antineoplastic activity. Upon intravenous administration of etoposide toniribate, etoposide is released after enzymatic cleavage of CAP7.1 by specific carboxylesterases (CE) 1 and 2, which are upregulated in certain tumor cell types. Etoposide acts primarily in the G2 and S phases of the cell cycle. This drug binds to and inhibits topoisomerase II, an enzyme elevated in tumor cells. This results in the accumulation of double-strand DNA breaks, the inhibition of DNA replication and transcription, and the induction of apoptotic cell death. The tumor-specific activation of etoposide increases its efficacy while lowering its systemic toxicity.

Use in Cancer

Bicalutamide is approved to treat:

• Prostate cancer that has metastasized (spread to other parts of the body). It is used with a type of drug called a luteinizing hormone-releasing hormone agonist.

Bicalutamide is also being studied in the treatment of other types of cancer.

Contraindications

• a bad infection
• low amount of albumin proteins in the blood
• excess body acid
• decreased function of bone marrow
• anemia
• decreased blood platelets
• a significant decrease in certain blood clotting cells called platelets
• low levels of white blood cells
• low levels of a type of white blood cell called neutrophils
• bleeding
• a type of inflammation of the lung called interstitial pneumonitis
• a condition where there is a formation of fibrous tissue in the lung called pulmonary fibrosis
• damage to the liver and inflammation
• pregnancy
• a patient who is producing milk and breastfeeding
• moderate to severe kidney impairment
• a significant drop in a certain type of white blood cell called a neutrophil

Dosage

Strengths: 20 mg/mL; 50 mg

Testicular Cancer

In combination with other approved chemotherapeutic agents

• 50 to 100 mg/m2 IV over 30 to 60 minutes once a day on days 1 through 5 every 3 to 4 weeks to 100 mg/m2 IV over 30 to 60 minutes once a day on days 1, 3, and 5 every 3 to 4 weeks
• A longer duration of IV administration may be used if the volume of fluid to be infused is a concern.
• The dosage should be modified to consider the myelosuppressive effects of other drugs in the combination or the effects of prior x-ray therapy or chemotherapy which may have compromised bone marrow reserve.

Small Cell Lung Cancer

IV:
In combination with other approved chemotherapeutic agents:

• 35 mg/m2 IV over 30 to 60 minutes once a day for 4 days to 50 mg/m2 IV over 30 to 60 minutes once a day for 5 days every 3 to 4 weeks

Oral:
In combination with other approved chemotherapeutic agents:

• The recommended dose is 2 times the IV dose rounded to the nearest 50 mg (i.e., 2 times 35 mg/m2 IV once a day for 4 days to 50 mg/m2 IV once a day for 5 days equaling 70 mg/m2 orally once a day for 4 days to 100 mg/m2 orally once a day for 5 days)
• A longer duration of IV administration may be used if the volume of fluid to be infused is a concern.
• The dosage should be modified to consider the myelosuppressive effects of other drugs in the combination or the effects of prior x-ray therapy or chemotherapy which may have compromised bone marrow reserve.

Renal Dose Adjustments

• CrCl greater than 50 mL/min: Administer 100% of the normal dose
• CrCl 15 to 50 mL/min: Administer 75% of the normal dose
• CrCl less than 15 mL/min: Data not available

Side Effects

The Most Common

• nausea
• vomiting
• sores in the mouth and throat
• stomach pain
• diarrhea
• constipation
• loss of appetite or weight
• unusual tiredness or weakness
• pale skin
• fainting
• dizziness
• hair loss
• pain, burning, or tingling in the hands or feet
• eye pain
• vision problems
• rash
• hives
• itching
• difficulty breathing or swallowing
• fast, irregular, or pounding heartbeat
• seizures
• yellowing of the skin or eyes

More Common

• sudden chest pain or discomfort, wheezing, dry cough or hack;
• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;
• vision problems;
• seizure (convulsions);
• liver problems–loss of appetite, stomach pain (upper right side), tiredness, itching, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
• low red blood cells (anemia)–pale skin, unusual tiredness, feeling light-headed or short of breath, cold hands and feet; or
• low white blood cell counts–fever, mouth sores, skin sores, sore throat, cough, trouble breathing.
• sores or white patches in or around your mouth, trouble swallowing or talking, dry mouth, bad breath, altered sense of taste;
• nausea, vomiting; or
• temporary hair loss.

Rare

• appetite loss
• diarrhea
• nausea and vomiting
• temporary loss of hair
• dizziness or lightheadedness
• low blood pressure
• numbness or tingling in fingers and toes
• pain at the site of injection
• painful swallowing
• seizures
• signs of bleeding (e.g., bloody nose, blood in urine, coughing blood, cuts that don’t stop bleeding, unusual bleeding or bruising black or tarry stools, or blood in urine)
• signs of liver problems (e.g., nausea, vomiting, diarrhea, loss of appetite, weight loss, yellowing of the skin or whites of the eyes, dark urine, pale stools)
• skin rash or itching
• signs of infection (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
• sores in the mouth or on the lips
• unusual tiredness or weakness
• signs of a serious allergic reaction (i.e., abdominal cramps, difficulty breathing, nausea and vomiting, sweating, fast heartbeat, or swelling of the face and throat)

Drug Interaction

Pregnancy and Lactation

AU TGA pregnancy category D

US FDA pregnancy category D

Pregnancy

Etoposide can cause harm to the unborn baby when it is taken by pregnant women. It should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately. Etoposide can cause changes to sperm in men, decreasing fertility. Women and men receiving etoposide should use effective contraceptive methods.

Lactation

Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. It might be possible to breastfeed safely during intermittent therapy with etoposide after an appropriate period of breastfeeding abstinence. A period of at least 24 hours is required after a dose of 80 mg/sq. m. or less. Others have suggested an abstinence period of 72 hours after etoposide use.[1] Chemotherapy may adversely affect the normal microbiome and chemical makeup of breast milk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.

References