Etoposide phosphate is a prodrug of etoposide that inhibits the cellular proliferation of tumor cells by inhibiting DNA repair and inducing breaks in the double-stranded DNA.

Etoposide phosphate Uses:

• Small cell lung cancer:

  • It is used for the first-line treatment of small cell lung cancer (in combination with cisplatin).

• Refractory Testicular cancer:

  • It is used for the treatment of refractory testicular tumors (in combination with other chemotherapy agents)

Etoposide phosphate Dose in Adults

Note: Etoposide phosphate is a prodrug of etoposide; equivalent doses should be used when converting from etoposide to etoposide phosphate. Each 100 mg vial of etoposide phosphate is equivalent to 100 mg of etoposide.

Etoposide phosphate Dose in the treatment of Small cell lung cancer:

• IV: Etoposide 35 mg/m²/day for 4 days OR
• 50 mg/m²/day for 5 days every 21 to 28 days (in combination with cisplatin).
• According to American Society of Clinical Oncology (ASCO) guidelines, platinum-based therapy ( carboplatin or cisplatin ) in combination with either etoposide or irinotecan for 4 to 6 cycles is recommended over other regimens for limited-stage or extensive-stage disease (4 cycles preferred for limited-stage).

Etoposide phosphate Dose in the treatment of refractory testicular cancer, (in combination with other approved chemotherapeutic agents):

• IV: Etoposide 50 to 100 mg/m²/day on days 1 to 5 every 21 to 28 days OR
• 100 mg/m²/day on days 1, 3, and 5 every 21 to 28 days.

Indication-specific off-label dosing:

• Refer to Etoposide monograph.

Use in Children:

Not indicated.

Etoposide phosphate Pregnancy Category: D

• Based on animal reproduction studies, and the mechanism of action, it is possible that etoposidephosphate can cause harm to fetal health if given during pregnancy.
• Following maternal use of etoposide-containing regimens during pregnancy, fetal growth restrictions and myelosuppression were observed in newborns.
• Treatment should be avoided for females with reproductive potential.
• These guidelines recommend that you refer to a cancer center during pregnancy.
• They also encourage the use of a multidisciplinary team (obstetrician/neonatalian, oncology team).
• Guidelines for treatment and follow-up for cancer in pregnancy have been published by the European Society for Medical Oncology.
• If chemotherapy is indicated, it should not be given during the first trimester.
• There should be a three-week period between the last dose of chemotherapy and the delivery date. Additionally, chemotherapy should not exceed week 33 of gestation.
• Etoposide phosphate can cause premature menopause in females with reproductive potential.
• Effective contraception should also be used during therapy as well as for at least six months after the last dose.
• There are no guidelines for treating SCLC.
• For males, there may be azoospermia or oligospermia.
• Additionally, testicular and spermatozoa tissue can be affected.
• Condoms should be used by males who have female partners with reproductive potential during therapy, and for at least 4 months following the last dose.

Use of etoposide-phosphate during breastfeeding

• Breastmilk contains etoposide. The manufacturer recommends against breastfeeding while on therapy due to the risk of serious adverse reactions in breastfed infants.

Dose in Kidney Disease:

• CrCl >50 mL/minute:

  • No dosage adjustment required.

• CrCl 15 to 50 mL/minute:

  • Reduce dose to 75 percent of the recommended dose.

• CrCl <15 mL minute:

  • There is no dosage adjustment provided in the manufacturer’s labeling (has not been studied); consider further dose reductions.
  • Etoposide phosphate is rapidly and completely converted to etoposide in plasma, please refer to Etoposide monograph for additional renal dosing adjustments (for etoposide).

Dose in Liver disease:

• There are no dosage adjustments provided in the manufacturer’s labeling.
• Etoposide phosphate is rapidly and completely converted to etoposide in plasma; refer to Etoposide monograph for etoposide hepatic dosing adjustments.

Common Side Effects of Etoposide phosphate:

• Central Nervous System:

  • Malaise
  • Chills

• Dermatologic:

  • Alopecia

• Gastrointestinal:

  • Nausea And Vomiting
  • Anorexia
  • Mucositis

• Hematologic & Oncologic:

  • Leukopenia
  • Neutropenia
  • Anemia
  • Thrombocytopenia

• Neuromuscular & Skeletal:

  • Weakness

• Miscellaneous:

  • Fever

Less Common Side Effects Of Etoposide Phosphate:

• Cardiovascular:

  • Hypotension
  • Localized Phlebitis
  • Hypertension
  • Facial Flushing

• Central Nervous System:

  • Dizziness

• Dermatologic:

  • Skin Rash

• Gastrointestinal:

  • Constipation
  • Abdominal Pain
  • Diarrhea
  • Dysgeusia

• Hypersensitivity:

  • Anaphylactoid Reaction

• Local:

  • Extravasation

Contraindications to Etoposide phosphate:

• Hypersensitivity severe to etoposide products and any component of the formulation

Warnings and precautions

• Suppression of bone marrow

  • The nadir usually occurs between 10 and 14 days, with recovery occurring by day 21 (Perry 2012).
  • Etoposidephosphate can cause hematologic toxicities, such as neutropenia or thrombocytopenia.
  • Some infections due to neutropenia or bleeding due to thrombocytopenia can be fatal. 
  • Monitoring blood counts before each cycle of etoposidephosphate is recommended. If necessary, you should monitor them more often.

• Hypersensitivity

  • Patients with severe hypersensitivity reactions should be discontinued permanently 
  • Although the exact mechanisms that cause hypersensitivity reactions are not known, they have been linked to high drug levels and fast infusion rates.
  • Hypersensitivity reactions may occur with Etoposide Phosphate, such as rash, urticaria and pruritus.
  • If hypersensitivity reactions develop, interrupt therapy immediately and start supportive management.
  • Etoposide intravenous formula contains polysorbate 80, benzyl alcohol, and etoposide prodrug of Eposide (the water-soluble prodrug) intravenous formula does not contain either.
  • One possible reason could be the difference in intravenous etoposide formulations.
  • There have been cases that show that etoposidephosphate was used in patients who had previously experienced hypersensitivity reactions to the drug.

• Failure of the renal system:

  • High doses (2,220 mg/m2) or total body radiation may cause renal failure. This is most commonly seen in children.
  • Before starting treatment, monitor the kidney function and continue monitoring it until the condition is resolved.

• Reproductive effects

  • It can cause infertility in both male and female patients.
  • Permanent loss of fertility, zoospermia and Oligospermia may be experienced in males. Premature and amenorrhea may also occur in females.

• Secondary malignancies

  • Long-term drug use has been linked to secondary malignancies. 
  • Patients should be closely monitored and asked to report any changes in their clinical status during long-term therapy.

• Hepatic impairment

  • Patients with hepatic impairment should be cautious. Dosage adjustment may be necessary.

• Renal impairment

  • Patients with impaired renal function should be cautious. Dosage adjustment may be necessary.

Etoposide phosphate: Drug Interaction

Monitoring parameters:

• CBC with differential and platelets (prior to each cycle; more frequently if required),
• bilirubin, AST, and ALT,
• renal function (before and after administration until complete renal function recovery),
• Vital signs (blood pressure)

How to administer Etoposide phosphate?

IV: Small cell lung cancer and refractory testicular cancer:

• Infuse over 5 minutes to 3.5 hours.
• Do not administer as an IV bolus over less than 5 minutes.
• The drug may be an irritant; monitor the infusion site for vesication. Avoid extravasation.

Mechanism of action of Etoposide phosphate:

• It is converted by dephosphorylation in vivo into the active moiety, known as etoposide.
• Etoposide inhibits mitotic activities; cells are prevented from entering prophase; it inhibits DNA synthesis.
• They were initially thought to be mitotic inhibitors similar to podophyllotoxin but have no effect upon microtubule assembly.
• Later, however, it was shown that etoposide can induce DNA strand breaking and inhibit topoisomerase II (an enzyme that breaks and repairs DNA); etoposide is active in the late S and early G2 phases.

Distribution:

• Poor penetration across the blood-brain barrier

Protein binding:

• 97% (primarily to albumin)

Metabolism:

• Etoposide phosphate:
  •  Rapidly and completely converted to etoposide in plasma
• Etoposide:
  • Hepatic, via CYP3A4 and 3A5 to various metabolites; in addition, conversion of etoposide to the O-demethylated metabolites (catechol and quinine) via prostaglandin synthases or myeloperoxidase occurs, as well as glutathione and glucuronide conjugation via GSTT1/GSTP1 and UGT1A1.

Half-life elimination:

• Terminal: 4 to 11 hours;
• Children: Normal renal/hepatic function: 6 to 8 hours

Excretion:

• Urine (56%; 45% as etoposide, ≤8% as metabolites) within 120 hours;
• feces (44%) within 120 hours

International Brand Names of Etoposide phosphate:

• Etopos
• Fytosid
• Posyd
• Etopophos
• Etopofos

Etoposide phosphate Brand Names in Pakistan:

No Brands Available in Pakistan.