Etoposide phosphate (Etopos) - Uses, Dose, Side effects, MOA, Brands

Etoposide phosphate, also known as etoposide monophosphate, is a derivative of etoposide, which is a chemotherapy medication commonly used in the treatment of various types of cancer. Etoposide itself is a topoisomerase inhibitor, which means it interferes with the action of enzymes called topoisomerases that help control the winding and unwinding of DNA strands during processes like replication and transcription.

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 special form of the cancer drug etoposide. It turns into etoposide once it's in the body. When using etoposide phosphate instead of etoposide, you should use the same amount. So, if you have a bottle with 100 mg of etoposide phosphate, it's the same as having 100 mg of etoposide.

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

Dosage:

  • Etoposide can be given via IV (intravenous) infusion.
  • The suggested dosing is:
    • 35 mg for every square meter (m^2) of body surface area, daily for 4 days OR
    • 50 mg for every square meter (m^2) of body surface area, daily for 5 days.

This treatment cycle is usually repeated every 21 to 28 days.

Combination with Other Drugs:

  • It's usually combined with cisplatin, another cancer drug.
  • The American Society of Clinical Oncology (ASCO) recommends using either cisplatin or another drug, carboplatin, combined with either etoposide or irinotecan.
  • This combined treatment should be given for 4 to 6 cycles. For patients with limited-stage disease, 4 cycles are preferred.

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

Dosage:

  • Etoposide is administered via IV (intravenous) infusion.

Dosing Options:

  • 50 to 100 mg for every square meter (m^2) of body surface area, daily from Day 1 to Day 5.
  • 100 mg for every square meter (m^2) of body surface area on Days 1, 3, and 5.

Treatment Cycle:

  • After the above doses are given, there is a break, and then the treatment is usually repeated every 21 to 28 days.

Combination Therapy:

  • It's important to note that for refractory Testicular Cancer, etoposide is used in combination with other approved chemotherapy drugs.

Indication-specific off-label dosing:

  • Refer to Etoposide monograph.

Use in Children:

Not indicated.

Etoposide phosphate Pregnancy Category: D

  • Based on animal studies and the drug's mechanism, Etoposide phosphate might harm the fetus if given during pregnancy.
  • There's a risk of restricted fetal growth and decreased blood cell counts in newborns when their mothers are treated with regimens containing Etoposide.
  • Pregnant individuals should avoid this treatment.
  • For pregnant individuals diagnosed with cancer, the European Society for Medical Oncology advises involving a specialized medical team, including obstetricians, neonatologists, and oncologists.
  • Chemotherapy is generally avoided in the first trimester of pregnancy.
  • There should be a 3-week gap between the last chemotherapy dose and the expected delivery.
  • Chemotherapy isn't usually given beyond the 33rd week of pregnancy.
  • Specific guidelines for Small Cell Lung Cancer (SCLC) treatment during pregnancy might not be available.

Reproductive Health:

  • In individuals of reproductive age, Etoposide phosphate treatment can lead to issues like amenorrhea (lack of menstrual periods), infertility, or early menopause.
  • Effective contraception should be used during treatment and for at least 6 months after the last dose.
  • In males, Etoposide phosphate might result in conditions like azoospermia (lack of sperm), oligospermia (low sperm count), or permanent infertility.
  • Sperm and testicular tissue might be damaged.
  • If male patients have female partners who could become pregnant, condoms should be used during treatment and for 4 months after the last dose.

These precautions and considerations emphasize the potential impact of Etoposide phosphate on pregnancy and reproductive health. Anyone undergoing or considering this treatment should have detailed discussions with their medical team to fully understand the risks and necessary precautions.

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:

Dosage Adjustments Based on Kidney Function (CrCl):

  • Normal to High Kidney Function (CrCl >50 mL/minute):
    • No need to change the dose; use the regular recommended dose.
  • Moderate Kidney Impairment (CrCl 15 to 50 mL/minute):
    • Decrease the dose to 75% of the usual dose.
  • Severe Kidney Impairment (CrCl <15 mL/minute):
    • Manufacturer's guidelines don't provide a specific dosage adjustment since this hasn't been studied well.
    • Consider reducing the dose even more, but specific guidance isn't provided. Consultation with a medical professional is crucial in such cases.

Additionally:

  • Etoposide phosphate quickly turns into Etoposide once in the body.
  • For additional kidney-related dosage adjustments related to Etoposide, one should refer to the detailed Etoposide guidelines (called a monograph).

Dose in Liver disease:

For Etoposide phosphate:

  • The manufacturer has not provided any specific dosage adjustments for patients with liver problems.

However, since Etoposide phosphate turns quickly into Etoposide in the body:

  • One should consult the Etoposide guidelines (often found in a detailed document called a "monograph") for any adjustments in dosage for patients with liver conditions.

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:

  • If someone has a severe hypersensitivity (allergic reaction) to etoposide products or any component found in its formulation, they should NOT receive etoposide or etoposide phosphate.
  • Hypersensitivity reactions can be life-threatening. Symptoms may include hives, difficulty breathing, swelling of the face/lips/tongue/throat, rapid heartbeat, and even shock. If any of these symptoms are observed after receiving the drug, immediate medical attention is necessary.
  • Before starting treatment, patients should always inform their healthcare provider about any known allergies or adverse reactions they've had to medications in the past. This will help avoid potential serious reactions and determine the best treatment plan.

Warnings and precautions

Suppression of bone marrow

  • Etoposide phosphate can lead to problems with the bone marrow, which is responsible for producing blood cells.
  • Hematologic toxicity includes issues like neutropenia (low levels of neutrophils, a type of white blood cell that fights infection) and thrombocytopenia (low platelet count, affecting blood clotting).
  • The lowest point (nadir) of blood cell counts typically happens around 10 to 14 days after taking Etoposide phosphate.
  • Recovery of blood cell counts generally occurs by around day 21.
  • Neutropenia can increase the risk of infections, and thrombocytopenia can cause bleeding issues. In some cases, these complications have been fatal.
  • Monitoring and Management:
    • Regular monitoring of blood counts is crucial before each cycle of Etoposide phosphate treatment.
    • If necessary, blood counts might need to be monitored more frequently.
    • This helps healthcare providers catch any significant drops in blood cell counts early and manage potential complications.

Hypersensitivity

  • Etoposide phosphate has the potential to trigger hypersensitivity reactions in some individuals.
  • These reactions might manifest as symptoms such as rash, itching (pruritus), hives (urticaria), or even severe allergic reactions like anaphylaxis.
  • If hypersensitivity reactions occur, treatment with Etoposide phosphate should be stopped right away.
  • Supportive care and management should be initiated to address the symptoms.
  • Severe Hypersensitivity:
    • If severe hypersensitivity reactions happen, Etoposide phosphate should be discontinued permanently.
    • The underlying reasons for these hypersensitivity reactions are not fully understood.
    • Factors like the drug's concentration and the rate of infusion might contribute.
    • Differences between the available intravenous formulations of Etoposide (containing additives like polysorbate 80 and benzyl alcohol) could also be involved.
    • In some cases, patients who had experienced hypersensitivity reactions to regular Etoposide have been successfully treated with Etoposide phosphate.

Failure of the renal system:

  • Acute renal failure, which is a sudden decline in kidney function, can happen when high doses of Etoposide phosphate (specifically 2,220 mg/m^2) are given.
  • This risk is especially observed when Etoposide phosphate is used together with total body irradiation in the context of hematopoietic stem cell transplant.
  • It's worth noting that this adverse effect has been predominantly seen in children.
  • Monitoring and Management:
    • Given this potential risk, it's essential to monitor the kidney function of patients both before starting Etoposide phosphate therapy and after completing it.
    • Monitoring should continue until there's full recovery of the kidney function to ensure patient safety.

Reproductive effects

  • Etoposide phosphate treatment can have significant impacts on the reproductive abilities of both males and females.
  • In Males:
    • Conditions like oligospermia (low sperm count), azoospermia (absence of sperm), and permanent loss of fertility might occur due to Etoposide phosphate treatment.
  • In Females:
    • Women might experience amenorrhea (absence of menstrual periods) and premature menopause as a result of Etoposide phosphate treatment.

Secondary malignancies

  • There have been cases where secondary leukemias (new leukemia that wasn't present before) developed in patients who have been on Etoposide phosphate for an extended period.

Hepatic impairment

  • Etoposide phosphate should be used carefully in patients with liver issues.
  • These patients might need adjustments to the usual dose of Etoposide phosphate.

Renal impairment

  • Etoposide phosphate should be administered cautiously to patients with kidney issues.
  • Dosage adjustments might be needed for these patients based on the degree of their kidney function impairment.

Etoposide phosphate: Drug Interaction

Risk Factor C (Monitor therapy)

Atovaquone

May increase the serum concentration of Etoposide Phosphate. Management: Consider separating the administration of atovaquone and etoposide by at least 1 to 2 days.

Bosentan

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Chloramphenicol (Ophthalmic)

May enhance the adverse/toxic effect of Myelosuppressive Agents.

CloZAPine

Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased.

Coccidioides immitis Skin Test

Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test.

CYP3A4 Inducers (Moderate)

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Deferasirox

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Denosumab

May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.

Erdafitinib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Erdafitinib

May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.

Ivosidenib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Ocrelizumab

May enhance the immunosuppressive effect of Immunosuppressants.

P-glycoprotein/ABCB1 Inhibitors

May increase the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of pglycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).

Pidotimod

Immunosuppressants may diminish the therapeutic effect of Pidotimod.

Promazine

May enhance the myelosuppressive effect of Myelosuppressive Agents.

Ranolazine

May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.

Sarilumab

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Siltuximab

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Siponimod

Immunosuppressants may enhance the immunosuppressive effect of Siponimod.

Tertomotide

Immunosuppressants may diminish the therapeutic effect of Tertomotide.

Tocilizumab

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Trastuzumab

May enhance the neutropenic effect of Immunosuppressants.

Vitamin K Antagonists (eg, warfarin)

Etoposide Phosphate may enhance the anticoagulant effect of Vitamin K Antagonists.

Risk Factor D (Consider therapy modification)

Baricitinib

Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted.

CycloSPORINE (Systemic)

May increase the serum concentration of Etoposide Phosphate. CycloSPORINE may decrease the metabolism, via CYP isoenzymes, and decrease the pglycoprotein-mediated elimination of Etoposide Phosphate.

CYP3A4 Inducers (Strong)

May decrease the serum concentration of Etoposide Phosphate. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide phosphate. If these combinations cannot be avoided, monitor patients closely for diminished etoposide phosphate response.

Dabrafenib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).

Enzalutamide

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring.

Fingolimod

Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections).

Leflunomide

Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly.

Lenograstim

Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy.

Lipegfilgrastim

Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy.

Lorlatinib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.

Mitotane

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane.

Nivolumab

Immunosuppressants may diminish the therapeutic effect of Nivolumab.

Palifermin

May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy.

Pitolisant

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant.

Roflumilast

May enhance the immunosuppressive effect of Immunosuppressants.

Sipuleucel-T

Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy.

St John's Wort

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling.

Tofacitinib

Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants.

Vaccines (Inactivated)

Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.

Risk Factor X (Avoid combination)

BCG (Intravesical)

Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical).

BCG (Intravesical)

Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).

Cladribine

May enhance the immunosuppressive effect of Immunosuppressants.

Cladribine

May enhance the myelosuppressive effect of Myelosuppressive Agents.

Deferiprone

Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone.

Dipyrone

May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased

Natalizumab

Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.

Pimecrolimus

May enhance the adverse/toxic effect of Immunosuppressants.

Tacrolimus (Topical)

May enhance the adverse/toxic effect of Immunosuppressants.

Vaccines (Live)

Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants.

Monitoring parameters:

Blood Tests:

  • Complete Blood Count (CBC):
    • Check before every treatment cycle.
    • Do it more often if needed.
  • Liver Tests:
    • Bilirubin: Checks liver health.
    • AST/ALT: Tests for liver damage or inflammation.

Kidney Test:

  • Renal Function:
    • Check before and after taking the medicine.
    • Continue checking until kidneys are fully back to normal.

Vital Signs:

  • Blood Pressure:
    • Regularly monitor to ensure it's at a safe level.

How to administer Etoposide phosphate?

Conditions:

  • Small cell lung cancer
  • Refractory testicular cancer

How to Administer:

  • Infuse into the bloodstream over a period ranging from 5 minutes to 3.5 hours.
  • Important: Do not give it all at once (bolus) in less than 5 minutes.

Cautions:

  • Etoposide phosphate can be irritating.
  • Keep an eye on the site where the medicine is being infused.
  • Make sure the medicine doesn't leak out of the vein (extravasation), as this can cause harm.

Mechanism of action of Etoposide phosphate:

Conversion and Activation:

  • Etoposide phosphate transforms inside the body to become etoposide, which is the active part of the drug.
  • This change happens through a process called dephosphorylation.

Effects on Cell Activity:

  • Etoposide, the active part, affects how cells behave during division.
  • It stops cells from entering a specific phase called prophase.
  • It also puts a halt on DNA synthesis, the process of making new DNA.

Not About Microtubules:

  • Even though it was first thought to work like other drugs that affect microtubules, it's not the case for etoposide.

DNA and Topoisomerase II:

  • Etoposide works differently by causing breaks in DNA strands.
  • It also blocks an enzyme called topoisomerase II, which usually helps DNA break and then repair itself.
  • Etoposide mostly acts when cells are in the late S phase or early G2 phase of their life cycle.

Distribution:

  • Volume of Distribution (V): 18 to 29 L.
  • Brain Penetration: Etoposide doesn't cross the blood-brain barrier well, so it doesn't reach the brain in significant amounts.

Protein Binding:

  • Etoposide binds to proteins in the blood at a rate of 97%, mainly attaching to albumin.

Metabolism:

  • Etoposide Phosphate: It quickly and fully turns into etoposide once it's in the bloodstream.
  • Etoposide: The liver processes etoposide. It does this mainly with the help of enzymes called CYP3A4 and 3A5. These enzymes change etoposide into different substances. Other processes, involving prostaglandin synthases, myeloperoxidase, GSTT1/GSTP1, and UGT1A1, further modify etoposide in the body.

Half-life Elimination:

  • Terminal Half-life: The time it takes for half of the drug to leave the body ranges from 4 to 11 hours.
  • In Children: If they have normal liver and kidney function, it's about 6 to 8 hours.

Excretion:

  • How the body gets rid of etoposide:
    • Urine: About 56% of the drug leaves the body in the urine within 120 hours. From this, 45% is still in the form of etoposide, and up to 8% is in the form of changed etoposide (metabolites).
    • Feces: About 44% is removed through feces within 120 hours.

International Brand Names of Etoposide phosphate:

  • Etopos
  • Fytosid
  • Posyd
  • Etopophos
  • Etopofos

Etoposide phosphate Brand Names in Pakistan:

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