Etoposide 50 mg Capsule, 20-count — NDC 0378-3266-94 (Billing 00378-3266-94)

WARNINGS Patients being treated with etoposide must be frequently observed for myelosuppression both during and after therapy. Myelosuppression resulting in death has been reported. Dose-limiting bone marrow suppression is the most significant toxicity associated with etoposide therapy.

Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent cycle of etoposide: platelet count, hemoglobin, white blood cell count and differential. The occurrence of a platelet count below 50,000/mm 3 or an absolute neutrophil count below 500/mm 3 is an indication to withhold further therapy until the blood counts have sufficiently recovered. Pregnancy Etoposide can cause fetal harm when administered to a pregnant woman.

Etoposide has been shown to be teratogenic in mice and rats. In rats, an intravenous etoposide dose of 0.4 mg/kg/day (about 1/20 th of the human dose on a mg/m2 basis) during organogenesis caused maternal toxicity, embryotoxicity, and teratogenicity (skeletal abnormalities, exencephaly, encephalocele and anophthalmia); higher doses of 1.2 mg/kg/day and 3.6 mg/kg/day (about 1/7 th and 1/2 of human dose on a mg/m 2 basis) resulted in 90% and 100% embryonic resorptions. In mice, a single 1.0 mg/kg (1/16 th of human dose on a mg/m 2 basis) dose of etoposide administered intraperitoneally on days 6, 7 or 8 of gestation caused embryotoxicity, cranial abnormalities, and major skeletal malformations.

An I.P. dose of 1.5 mg/kg (about 1/10 th of human dose on a mg/m 2 basis) on day 7 of gestation caused an increase in the incidence of intrauterine death and fetal malformations and a significant decrease in the average fetal body weight. Women of childbearing potential should be advised to avoid becoming pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be warned of the potential hazard to the fetus.

Etoposide should be considered a potential carcinogen in humans. The occurrence of acute leukemia with or without a preleukemic phase has been reported in rare instances in patients treated with etoposide alone or in association with other neoplastic agents. The risk of development of a preleukemic or leukemic syndrome is unclear.

Carcinogenicity tests with etoposide have not been conducted in laboratory animals.

ADVERSE REACTIONS The following data on adverse reactions are based on both oral and intravenous administration of etoposide as a single agent, using several different dose schedules for treatment of a wide variety of malignancies. Hematologic Toxicity Myelosuppression is dose related and dose limiting, with granulocyte nadirs occurring 7 to 14 days after drug administration and platelet nadirs occurring 9 to 16 days after drug administration. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported.

Fever and infection have also been reported in patients with neutropenia. Death associated with myelosuppression has been reported. The occurrence of acute leukemia with or without a preleukemic phase has been reported rarely in patients treated with etoposide in association with other antineoplastic agents (see WARNINGS ).

Gastrointestinal Toxicity Nausea and vomiting are the major gastrointestinal toxicities. The severity of such nausea and vomiting is generally mild to moderate with treatment discontinuation required in 1% of patients. Nausea and vomiting can usually be controlled with standard antiemetic therapy.

Mild to severe mucositis/esophagitis may occur. Gastrointestinal toxicities are slightly more frequent after oral administration than after intravenous infusion. Hypotension Transient hypotension following rapid intravenous administration has been reported in 1% to 2% of patients.

It has not been associated with cardiac toxicity or electrocardiographic changes. No delayed hypotension has been noted. To prevent this rare occurrence, it is recommended that etoposide be administered by slow intravenous infusion over a 30- to 60-minute period.

If hypotension occurs, it usually responds to cessation of the infusion and administration of fluids or other supportive therapy as appropriate. When restarting the infusion, a slower administration rate should be used. Allergic Reactions Anaphylactic-like reactions characterized by chills, fever, tachycardia, bronchospasm, dyspnea and/or hypotension have been reported to occur in 0.7% to 2% of patients receiving intravenous etoposide and in less than 1% of the patients treated with the oral capsules.

These reactions have usually responded promptly to the cessation of the infusion and administration of pressor agents, corticosteroids, antihistamines or volume expanders as appropriate; however, the reactions can be fatal. Hypertension and/or flushing have also been reported. Blood pressure usually normalizes within a few hours after cessation of the infusion.

Anaphylactic-like reactions have occurred during the initial infusion of etoposide. Facial/tongue swelling, coughing, diaphoresis, cyanosis, tightness in throat, laryngospasm, back pain and/or loss of consciousness have sometimes occurred in association with the above reactions. In addition, an apparent hypersensitivity-associated apnea has been reported rarely.

Rash, urticaria, and/or pruritus have infrequently been reported at recommended doses. At investigational doses, a generalized pruritic erythematous maculopapular rash, consistent with perivasculitis, has been reported. Alopecia Reversible alopecia, sometimes progressing to total baldness, was observed in up to 66% of patients.

Other Toxicities The following adverse reactions have been infrequently reported: abdominal pain, aftertaste, constipation, dysphagia, asthenia, fatigue, malaise, somnolence, transient cortical blindness, optic neuritis, interstitial pneumonitis/pulmonary fibrosis, fever, seizure (occasionally associated with allergic reactions), Stevens-Johnson Syndrome, and toxic epidermal necrolysis, pigmentation, and a single report of radiation recall dermatitis. Hepatic toxicity, generally in patients receiving higher doses of the drug than those recommended, has been reported with etoposide.

Metabolic acidosis has also been reported in patients receiving higher doses. The incidences of adverse reactions in the table t… [Excerpted — this section continues on DailyMed.]

Drug Interactions High-dose cyclosporin A resulting in concentrations above 2000 ng/mL administered with oral etoposide has led to an 80% increase in etoposide exposure with a 38% decrease in total body clearance of etoposide compared to etoposide alone.

PRECAUTIONS General In all instances where the use of etoposide is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician.

Reinstitution of etoposide therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity. Patients with low serum albumin may be at an increased risk for etoposide associated toxicities. Drug Interactions High-dose cyclosporin A resulting in concentrations above 2000 ng/mL administered with oral etoposide has led to an 80% increase in etoposide exposure with a 38% decrease in total body clearance of etoposide compared to etoposide alone.

Laboratory Tests Periodic complete blood counts should be done during the course of etoposide treatment. They should be performed prior to each cycle of therapy and at appropriate intervals during and after therapy. At least one determination should be done prior to each dose of etoposide.

Renal Impairment In patients with impaired renal function, the following initial dose modification should be considered based on measured creatinine clearance: Measured Creatinine Clearance > 50 mL/min 15 to 50 mL/min etoposide 100% of dose 75% of dose Subsequent etoposide dosing should be based on patient tolerance and clinical effect. Data are not available in patients with creatinine clearances < 15 mL/min and further dose reduction should be considered in these patients. Carcinogenesis (see WARNINGS), Mutagenesis, Impairment of Fertility Etoposide has been shown to be mutagenic in Ames assay.

Treatment of Swiss-Albino mice with 1.5 mg/kg I.P. of etoposide on day 7 of gestation increased the incidence of intrauterine death and fetal malformations as well as significantly decreased the average fetal body weight. Maternal weight gain was not affected. Irreversible testicular atrophy was present in rats treated with etoposide intravenously for 30 days at 0.5 mg/kg/day (about 1/16 th of the human dose on a mg/m 2 basis).

Pregnancy Teratogenic Effects Pregnancy Category D (see WARNINGS ). Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from etoposide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of more than 600 patients in four clinical studies in the NDA databases who received etoposide or etoposide phosphate in combination with other chemotherapeutic agents for the treatment of small cell lung cancer (SCLC), about one-third were older than 65 years. When advanced age was determined to be a prognostic factor for response or survival in these studies, comparisons between treatment groups were performed for the elderly subset.

In the one study (etoposide in combination with cyclophosphamide and vincristine compared with cyclophosphamide and vincristine or cyclophosphamide, vincristine and doxorubicin) where age was a significant prognostic factor for survival, a survival benefit for elderly patients was observed for the etoposide regimen compared with the control regimens. No differences in myelosuppression were seen between elderly and younger patients in these studies except for an increased frequency of WHO Grade III or IV leukopenia among elderly patients in a study of etoposide phosphate or etoposide in combination with cisplatin.

Elderly patients in this study also had more anorexia, mucositis, dehydration, somnolence a… [Excerpted — this section continues on DailyMed.]