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Etoposide Phosphate

Pronunciation

Pronunciation

(e toe POE side FOS fate)

Index Terms

  • Epipodophyllotoxin
  • ETOP

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [strength expressed as base]:

Etopophos: 100 mg (1 ea)

Brand Names: U.S.

  • Etopophos

Pharmacologic Category

  • Antineoplastic Agent, Podophyllotoxin Derivative
  • Antineoplastic Agent, Topoisomerase II Inhibitor

Pharmacology

Etoposide phosphate is converted in vivo to the active moiety, etoposide, by dephosphorylation. Etoposide inhibits mitotic activity; inhibits cells from entering prophase; inhibits DNA synthesis. Initially thought to be mitotic inhibitors similar to podophyllotoxin, but actually have no effect on microtubule assembly. However, later shown to induce DNA strand breakage and inhibition of topoisomerase II (an enzyme which breaks and repairs DNA); etoposide acts in late S or early G2 phases.

Distribution

Average Vd: 7 to 17 L/m2; poor penetration across blood-brain barrier; concentrations in CSF being <10% that of plasma

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 (Yang 2009)

Excretion

Urine (56%; 45% as etoposide) within 120 hours; feces (44%) within 120 hours

Children: Urine (~55% as etoposide) in 24 hours

Half-Life Elimination

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

Protein Binding

97%

Special Populations: Renal Function Impairment

Total body clearance is reduced, AUC is increased, and Vd is higher.

Use: Labeled Indications

Small cell lung cancer: First-line treatment of small cell lung cancer (in combination with other chemotherapy agents)

Testicular cancer, refractory: Treatment of refractory testicular tumors (in combination with other chemotherapy agents) in patients who have already received appropriate therapy with surgery, chemotherapy, and radiation

Contraindications

Hypersensitivity to etoposide, etoposide phosphate, or any component of the formulation

Dosing: Adult

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.

Small cell lung cancer (in combination with other approved chemotherapeutic drugs): IV: Etoposide 35 mg/m2/day for 4 days up to 50 mg/m2/day for 5 days. Courses are repeated at 3- to 4-week intervals after adequate recovery from toxicity.

Testicular cancer, refractory (in combination with other approved chemotherapeutic agents): IV: Etoposide 50 to 100 mg/m2/day on days 1 to 5 to 100 mg/m2/day on days 1, 3, and 5. Courses are repeated at 3- to 4-week intervals after adequate recovery from toxicity.

Indication-specific off-label dosing: Refer to Etoposide monograph.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 15 to 50 mL/minute: Administer 75% of dose.

CrCl <15 mL minute: Data are not available; 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).

Dosing: Hepatic Impairment

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

Dosing: Adjustment for Toxicity

Hematologic (ANC <500/mm3 and/or platelets <50,000/mm3): Interrupt treatment until blood counts have sufficiently recovered.

Severe adverse reactions: Reduce dose, interrupt treatment, or discontinue.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer (Note: Excludes HSCT dosing): Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Reconstitute vials with 5 mL or 10 mL SWFI, D5W, NS, bacteriostatic water for injection with benzyl alcohol, or bacteriostatic sodium chloride for injection with benzyl alcohol to a concentration of 20 mg/mL or 10 mg/mL etoposide equivalent. These solutions may be administered without further dilution or may be diluted in D5W or NS to a concentration as low as 0.1 mg/mL.

Administration

Infuse by slow IV infusion over 5 to 210 minutes; risk of hypotension may increase with rate of infusion. Do not administer as a bolus injection.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Stable in D5W, NS, SWFI.

Y-site administration: Incompatible with amphotericin B, cefepime, chlorpromazine, imipenem/cilastatin, methylprednisolone sodium succinate, mitomycin, prochlorperazine edisylate.

Storage

Store intact vials under refrigeration at 2°C to 8°C (36°F to 46°F). Protect from light. Reconstituted solution is stable refrigerated at 2°C to 8°C (36°F to 46°F) for 7 days. At room temperature of 20°C to 25°C (68°F to 77°F), reconstituted solutions are stable for 24 hours when reconstituted with SWFI, D5W, or NS, or for 48 hours when reconstituted with bacteriostatic water for injection with benzyl alcohol or bacteriostatic sodium chloride for injection with benzyl alcohol. Further diluted solutions for infusion are stable at room temperature 20°C to 25°C (68°F to 77°F) or under refrigeration 2°C to 8°C (36°F to 46°F) for up to 24 hours.

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. 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. Monitor therapy

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

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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CycloSPORINE (Systemic): May increase the serum concentration of Etoposide Phosphate. CycloSPORINE may decrease the metabolism, via CYP isoenzymes, and decrease the p-glycoprotein-mediated elimination of Etoposide Phosphate. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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

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

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. 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. Consider therapy modification

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). Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

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

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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. Consider therapy modification

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

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

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

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. Consider therapy modification

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. Avoid combination

Vitamin K Antagonists (eg, warfarin): Etoposide Phosphate may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Adverse Reactions

Note: Also see adverse reactions for etoposide; etoposide phosphate is converted to etoposide, adverse reactions experienced with etoposide would also be expected with etoposide phosphate.

>10%:

Central nervous system: Chills/fever (24%)

Dermatologic: Alopecia (33% to 44%)

Gastrointestinal: Nausea/vomiting (37%), anorexia (16%), mucositis (11%)

Hematologic: Leukopenia (91%; grade 4: 17%; nadir: day 15-22; recovery: usually by day 21), neutropenia (88%; grade 4: 37%; nadir: day 12-19; recovery: usually by day 21), anemia (72%; grades 3/4: 19%), thrombocytopenia (23%; grade 4: 9%; nadir: day 10-15; recovery: usually by day 21)

Neuromuscular & skeletal: Weakness/malaise (39%)

1% to 10%:

Cardiovascular: Hypotension (1% to 5%), hypertension (3%), facial flushing (2%)

Central nervous system: Dizziness (5%)

Dermatologic: Skin rash (3%)

Gastrointestinal: Constipation (8%), abdominal pain (7%), diarrhea (6%), taste perversion (6%)

Local: Extravasation/phlebitis (5%; including swelling, pain, cellulitis, necrosis, and/or skin necrosis at site of infiltration)

Miscellaneous: Anaphylactic-type reactions (3%; including chills, diaphoresis, fever, rigor, tachycardia, bronchospasm, dyspnea, pruritus)

<1% (Limited to important or life-threatening): Acute leukemia (with/without preleukemia phase), anaphylactic-like reactions, blindness (transient, cortical), cyanosis, dysphagia, erythema, facial swelling, hepatic toxicity, hyperpigmentation, hypersensitivity-associated apnea, infection, interstitial pneumonitis, laryngospasm, maculopapular rash, neutropenic fever, optic neuritis, perivasculitis, pruritus, pulmonary fibrosis, radiation recall dermatitis, seizure, Stevens-Johnson syndrome, tongue swelling, toxic epidermal necrolysis, urticaria

ALERT: U.S. Boxed Warning

Experienced physician:

Etoposide should be administered under the supervision of a qualified health care provider experienced in the use of cancer chemotherapeutic agents.

Bone marrow suppression:

Severe myelosuppression with resulting infection or bleeding may occur.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Severe myelosuppression with resulting infection or bleeding may occur. Myelosuppression is dose-limiting; fatalities due to myelosuppression have been reported following etoposide administration. Hematologic toxicity may occur both during or after therapy; the leukocyte nadir occurs at days 15 to 22; ANC nadir occurs at days 12 to 19, and the platelet nadir occurs at days 10 to 15. Marrow recovery usually occurs by day 21, although may be delayed. Treatment should be withheld for platelets <50,000/mm3 or absolute neutrophil count (ANC) <500/mm3. Monitor blood counts prior to therapy initiation and before each cycle of etoposide phosphate.

• Hypersensitivity reaction: May cause anaphylactic-like reactions manifested by chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension. In addition, facial/tongue swelling, coughing, throat tightness, cyanosis, laryngospasm, diaphoresis, back pain, hypertension, flushing, apnea and loss of consciousness have also been reported less commonly. Anaphylactic-type reactions have occurred with the first infusion. Infusion should be interrupted and medications for the treatment of anaphylaxis should be available for immediate use. Underlying mechanisms behind the development of hypersensitivity reactions is unknown, but have been attributed to high drug concentration and rate of infusion. Another possible mechanism may be due to the differences between available etoposide intravenous formulations. Etoposide intravenous formulation contains polysorbate 80 and benzyl alcohol, while etoposide phosphate (the water soluble prodrug of etoposide) intravenous formulation does not contain either vehicle. Case reports have suggested that etoposide phosphate has been used successfully in patients with previous hypersensitivity reactions to etoposide (Collier 2008; Siderov 2002).

• Fertility: Etoposide phosphate may result in infertility in male and female patients. In addition, spermatozoa and testicular tissue damage may occur in males; amenorrhea and premature menopause may also occur in women. Males with female partners of childbearing potential should use condoms during therapy and for at least 4 months after the last dose; females of childbearing potential should use effective contraception during therapy and for 6 months after the last dose.

• Secondary malignancies: Secondary acute leukemias have been reported with etoposide, either as monotherapy or in combination with other chemotherapy agents.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage should be adjusted.

• Hypoalbuminemia: Use with caution in patients with low serum albumin; may increase risk for toxicities.

• Renal impairment: Use with caution in patients with renal impairment; dosage should be adjusted.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution in elderly patients; may be more likely to develop severe myelosuppression and/or GI effects.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Administration: Administer by slow IV infusion; hypotension has been reported with etoposide phosphate administration, generally associated with rapid IV infusion. Injection site reactions may occur; monitor infusion site closely.

• Dosage: Doses of etoposide phosphate >175 mg/m2 have not been evaluated. Each 100 mg vial of etoposide phosphate is equivalent to 100 mg of etoposide. Equivalent doses should be used when converting from etoposide to etoposide phosphate.

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

Monitoring Parameters

CBC with differential and platelets (prior to initial treatment and each cycle), bilirubin, AST/ALT, renal function, vital signs (blood pressure)

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Fetal growth restriction and newborn myelosuppression have been observed following maternal use of regimens containing etoposide during pregnancy (NTP 2013; Peccatori 2013). The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). In general, if chemotherapy is indicated, it should be avoided during in the first trimester, there should be a 3-week time period between the last chemotherapy dose and anticipated delivery, and chemotherapy should not be administered beyond week 33 of gestation. Guidelines for the treatment of SCLC are not provided (Peccatori 2013).

In women of reproductive potential, etoposide phosphate may cause amenorrhea, infertility, or premature menopause; effective contraception should be used during therapy and for ≥6 months after the last dose. In males, azoospermia, oligospermia, or permanent loss of fertility may occur. In addition, spermatozoa and testicular tissue may be damaged. Males with female partners of reproductive potential should use condoms during therapy and for ≥4 months after the last dose.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite, constipation, alopecia, or mouth sores. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), burning or numbness feeling, severe abdominal pain, angina, tachycardia, shortness of breath, severe dizziness, passing out, severe headache, sweating a lot, flushing, skin discoloration, back pain, severe diarrhea, severe nausea, vomiting, vision changes, seizures, loss of strength and energy, signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), or severe injection site pain or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating, and advising patients.

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