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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

Vd (mean): 18 to 29 L; poor penetration across blood-brain barrier

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, ≤8% as metabolites) within 120 hours; feces (44%) within 120 hours

Half-Life Elimination

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

Protein Binding

97% (primarily to albumin)

Special Populations: Renal Function Impairment

Total body clearance is correlated with creatinine clearance

Use: Labeled Indications

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

Testicular cancer, refractory: Treatment of refractory testicular tumors (in combination with other chemotherapy agents)

Contraindications

Hypersensitivity to etoposide products 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: 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 (cisplatin or carboplatin) 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) (Rudin 2015).

Testicular cancer, refractory (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.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

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

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

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; 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

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

Small cell lung cancer, testicular cancer (refractory): Infuse over 5 minutes to 3.5 hours. Do not administer as an IV bolus over less than 5 minutes. Etoposide phosphate may be an irritant; monitor infusion site; avoid extravasation.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). Retain in original package to protect from light. Reconstituted solution is stable for 7 days refrigerated at 2°C to 8°C (36°F to 46°F). Reconstituted solutions are stable at room temperature 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. Solutions diluted for infusion are stable for up to 24 hours 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).

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

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

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

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

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 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

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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

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

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

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

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

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. Consider therapy modification

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

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: Malaise (≤39%), chills (≤24%)

Dermatologic: Alopecia (33% to 44%)

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

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

Neuromuscular & skeletal: Weakness (≤39%)

Miscellaneous: Fever (≤24%)

1% to 10%:

Cardiovascular: Hypotension (1% to 5%), localized phlebitis (≤5%; including cellulitis at injection site, local pain, local swelling, local tissue necrosis, tissue necrosis at injection site), hypertension (3%), facial flushing (2%)

Central nervous system: Dizziness (5%)

Dermatologic: Skin rash (3%)

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

Hypersensitivity: Anaphylactoid reaction (3%; including bronchospasm, chills, diaphoresis, dyspnea, fever, pruritus, rigors, tachycardia)

Local: Extravasation (≤5%; including cellulitis at injection site, local pain, local swelling, local tissue necrosis, tissue necrosis at injection site)

<1% (Limited to important or life-threatening): Acute leukemia (with/without preleukemia phase), apnea (hypersensitivity-associated), back pain, cortical blindness (transient), cough, cyanosis, diaphoresis, dysphagia, erythema, facial swelling, febrile neutropenia, hepatotoxicity, hyperpigmentation, infection, interstitial pneumonitis, laryngospasm, maculopapular rash, optic neuritis, pruritic erythematous rash, pulmonary fibrosis, radiation recall phenomenon, seizure, Stevens-Johnson syndrome, swollen tongue, toxic epidermal necrolysis, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Etoposide phosphate is associated with hematologic toxicity, including neutropenia and thrombocytopenia. The nadir typically occurs at 10 to 14 days with recovery by day 21 (Perry 2012). Infections due to neutropenia and bleeding due to thrombocytopenia have occurred, some fatal. Monitor blood counts prior to each cycle of etoposide phosphate and more frequently if needed.

• Hypersensitivity reaction: Etoposide phosphate may cause hypersensitivity reactions, including rash, pruritus, urticaria, and anaphylaxis. Interrupt therapy immediately and begin supportive management if hypersensitivity reactions occur. Discontinue permanently in patients with severe hypersensitivity reactions. 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).

• Reproductive effects: Etoposide phosphate may result in infertility in male and female patients. Oligospermia, azoospermia, and permanent loss of fertility may occur in males; amenorrhea and premature menopause may also occur in women.

• Secondary malignancies: Secondary acute leukemias have been reported with long-term use of etoposide phosphate.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; may require dosage adjustment.

• Renal impairment: Use with caution in patients with renal impairment; may require dosage adjustment.

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.

Other warnings/precautions:

• Conversion: 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.

Monitoring Parameters

CBC with differential and platelets (prior to each cycle; more frequently if necessary), bilirubin, AST/ALT, renal function, vital signs (blood pressure)

Pregnancy Considerations

Based on animal reproduction studies and the mechanism of action, etoposide phosphate may cause fetal harm if administered during pregnancy. Women of reproductive potential should avoid pregnancy during treatment. 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 at least 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 nausea, vomiting, abdominal pain, constipation, or change in taste. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), difficulty swallowing, skin discoloration, vision changes, seizures, severe loss of strength and energy, blindness, 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 redness, burning, edema, 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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