ETOPOPHOS PRESERVATIVE FREE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ETOPOPHOS PRESERVATIVE FREE (ETOPOPHOS PRESERVATIVE FREE).
Etopophos is a prodrug of etoposide, a topoisomerase II inhibitor. It forms a ternary complex with topoisomerase II and DNA, preventing religation of DNA breaks, leading to DNA damage and apoptosis.
| Metabolism | Etopophos is rapidly converted to etoposide by dephosphorylation. Etoposide is metabolized primarily by O-demethylation via CYP3A4 and CYP2E1, and also undergoes glucuronidation and sulfation. |
| Excretion | Renal excretion accounts for approximately 30-50% of the dose as unchanged drug. Fecal elimination is minimal (<10%). The remainder is hepatically metabolized. |
| Half-life | Terminal elimination half-life is approximately 4-8 hours in adults with normal renal function. May be prolonged in renal impairment (up to 20 hours in severe dysfunction). |
| Protein binding | Approximately 90% bound to serum proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution at steady state is 0.15-0.35 L/kg, suggestive of limited extravascular distribution. |
| Bioavailability | Oral bioavailability is approximately 50% (range 25-75%). Intravenous is 100%. |
| Onset of Action | Intravenous: rapid, within 1 hour. Oral: 2-4 hours. |
| Duration of Action | Duration of myelosuppression is typically 5-10 days, with nadir at day 7-14. Clinical effect persists through multiple treatment cycles. |
50-100 mg/m2 intravenously over 30-60 minutes once daily for 5 days, repeated every 3-4 weeks.
| Dosage form | INJECTABLE |
| Renal impairment | CrCl >50 mL/min: no adjustment; CrCl 10-50 mL/min: reduce dose to 75% of normal; CrCl <10 mL/min: data insufficient, consider dose reduction to 50%. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose to 50%; Child-Pugh C: not recommended. |
| Pediatric use | 100-150 mg/m2 intravenously over 30-60 minutes once daily for 3-5 days, repeated every 3-4 weeks. |
| Geriatric use | No specific dose adjustment, but consider increased susceptibility to myelosuppression; monitor renal function and reduce dose if CrCl <50 mL/min. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ETOPOPHOS PRESERVATIVE FREE (ETOPOPHOS PRESERVATIVE FREE).
| Breastfeeding | Contraindicated during breastfeeding due to potential for severe adverse effects in the infant (e.g., myelosuppression, carcinogenesis). M/P ratio: unknown; excreted in human milk in low concentrations. |
| Teratogenic Risk | Category D. First trimester: High risk of major malformations (neural tube defects, skeletal abnormalities), intrauterine growth restriction, and fetal death. Second and third trimesters: Risk of myelosuppression, pancytopenia, and low birth weight; potential for fetal hemorrhage. |
■ FDA Black Box Warning
Etopophos can cause severe myelosuppression resulting in infection or bleeding. Should be administered under the supervision of a qualified physician experienced in cancer chemotherapy.
| Serious Effects |
Severe hypersensitivity to etoposide or any component of the formulation, severe bone marrow suppression, and concurrent use with yellow fever vaccine.
| Precautions | Myelosuppression, secondary acute myeloid leukemia, hypersensitivity reactions, hypotension, renal toxicity, hepatotoxicity, extravasation necrosis, and infertility. |
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| Fetal Monitoring |
| Complete blood count (CBC) with differential weekly; liver and renal function tests periodically; fetal ultrasound for growth and anomalies; non-stress test or biophysical profile in third trimester. |
| Fertility Effects | Etoposide may cause gonadal suppression, amenorrhea in females, and azoospermia in males; potential for permanent infertility, especially with high cumulative doses. |