Etopophos

Dosage Forms And Strengths

For injection: 114 mg etoposide phosphate (equivalent to 100 mg etoposide), white to off-white, lyophilized powder in single-dose vial for reconstitution.

Storage And Handling

ETOPOPHOS is supplied as a single-dose vial containing etoposide phosphate equivalent to 100 mg etoposide as a lyophilized powder for reconstitution, individually packaged in a carton:

NDC 0015-3404-20

Store unopened vials at 2° to 8°C (36°-46°F). Keep vial in outer carton to protect from light.

Handling

ETOPOPHOS is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹

REFERENCES

1. OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

Distributed by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA. Revised: March 2017.

Refractory Testicular Tumors

ETOPOPHOS is indicated, in combination with other chemotherapeutic drugs, for treatment of patients with refractory testicular tumors.

Small Cell Lung Cancer

ETOPOPHOS is indicated, in combination with cisplatin, for first-line treatment of patients with small cell lung cancer.

Refractory Testicular Tumors

The recommended dose of ETOPOPHOS is:

• 50 to 100 mg/m² per day administered intravenously over 5 minutes to 3.5 hours on days 1 through 5 of each 21-day (or 28-day cycle), or
• 100 mg/m² administered intravenously over 5 minutes to 3.5 hours on days 1, 3, and 5 of each 21-day (or 28-day cycle).

Small Cell Lung Cancer

The recommended dose of ETOPOPHOS is 35 mg/m² per day administered intravenously over 5 minutes to 3.5 hours for 4 days or 50 mg/m² per day administered for 5 days.

Dosage Modification

In patients with a creatinine clearance (CLcr) 15-50 mL/min, administer 75% of the recommended dose. Data are not available in patients with CLcr less than 15 mL/min. Consider further dose reduction in these patients.

Preparation And Administration

Preparation

Reconstitute with Sterile Water for Injection, USP; 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; Bacteriostatic Water for Injection with Benzyl Alcohol; or Bacteriostatic Sodium Chloride for Injection with Benzyl Alcohol, using the quantity of diluent shown below:

Following reconstitution, ETOPOPHOS can be further diluted to concentrations as low as 0.1 mg/m²L with either 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Storage

After reconstitution, store under the following conditions:

Refrigerated 2° to 8°C (36° to 46°F) for 7 days;

Room temperature at 20° to 25°C (68° to 77°F) for 24 hours following reconstitution with Sterile Water for Injection, USP, 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP;

Room temperature 20° to 25°C (68° to 77°F) for 48 hours following reconstitution with Bacteriostatic Water for Injection with benzyl alcohol or Bacteriostatic Sodium Chloride for Injection with benzyl alcohol.

Reconstituted ETOPOPHOS solutions further diluted as directed can be stored under refrigeration 2° to 8°C (36° to 46°F) or at room temperature 20° to 25°C (68° to 77°F) for 24 hours.

Administration

DO NOT GIVE ETOPOPHOS BY BOLUS INTRAVENOUS INJECTION. ETOPOPHOS solutions may be administered at infusion rates up to 3.5 hours. Extravasation of ETOPOPHOS may result in swelling, pain, cellulitis, and necrosis including skin necrosis.

ETOPOPHOS is a cytotoxic drug. Follow applicable special handling and disposal procedures. To minimize the risk of dermal exposure, use of gloves is recommended. If dermal contact occurs, immediately and thoroughly wash areas of skin contact with soap and water and flush mucosa with water.

ETOPOPHOS is contraindicated in patients with a history of a severe hypersensitivity reaction to etoposide products.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Myelos uppression

ETOPOPHOS causes myelosuppression that results in thrombocytopenia and neutropenia. Fatal infections and bleeding have occurred. Obtain complete blood counts prior to each cycle of ETOPOPHOS and more frequently as clinically indicated.

Secondary Leukemias

Secondary leukemias have occurred with long term use of ETOPOPHOS.

Hypersensitivity Reactions

ETOPOPHOS can cause hypersensitivity reactions, including rash, urticaria, pruritus, and anaphylaxis . If hypersensitivity reactions occur, immediately interrupt ETOPOPHOS and institute supportive management. Permanently discontinue ETOPOPHOS in patients who experience a severe hypersensitivity reaction.

Embryo-Fetal Toxicity

Based on animal studies and its mechanism of action, ETOPOPHOS can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential hazard to the fetus.

Advise females of reproductive potential to use effective contraception during treatment with ETOPOPHOS and for at least 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

ETOPOPHOS was non-mutagenic in an in vitro Ames microbial mutagenicity assay; however, ETOPOPHOS is rapidly and completely converted to etoposide in vivo. Therefore, as etoposide is mutagenic in the Ames assay, ETOPOPHOS is considered mutagenic in vivo.

In rats, oral dosing of ETOPOPHOS for 5 consecutive days at doses greater than or equal to 86 mg/kg/day (about 10 times the 50 mg/m² human dose based on BSA) resulted in irreversible testicular atrophy. Irreversible testicular atrophy was also present in rats treated with ETOPOPHOS intravenously for 30 days at 5.11 mg/kg/day (about 0.5 times the 50 mg/m² human dose based on BSA).

Use In Specific Populations

Pregnancy

Risk Summary

Based on animal data and its mechanism of action, ETOPOPHOS can cause fetal harm when administered to a pregnant woman. Etoposide, the active moiety of etoposide phosphate is teratogenic in mice and rats. Advise pregnant women of the potential hazard to a fetus.

Advise women of childbearing potential to avoid becoming pregnant.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In rats, an intravenous etoposide dose of 0.4 mg/kg/day (about 0.05 times of the 50 mg/m² human dose based on body surface area [BSA]) during organogenesis caused maternal toxicity, embryotoxicity, and teratogenicity (skeletal abnormalities, exencephaly, encephalocele, and anophthalmia); higher doses of 1.2 and 3.6 mg/kg/day (about 0.14 and 0.5 times the 50 mg/m² human dose based on BSA) resulted in 90% and 100% embryonic resorptions. In mice, a single etoposide dose of 1.0 mg/kg (approximately 0.06 times the 50 mg/m² human dose based on BSA) administered intraperitoneally on days 6, 7, or 8 of gestation caused embryotoxicity, cranial abnormalities, and major skeletal malformations. An intraperitoneal dose of 1.5 mg/kg (about 0.1 times the 50 mg/m² human based on BSA) 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.

Lactation

There is no information regarding the presence of etoposide in human milk or its effects on breastfed infant milk production. Because of the potential for serious adverse reactions in nursing infants from ETOPOPHOS, advise women not to breastfeed during treatment with ETOPOPHOS.

Females And Males Of Reproductive Potential

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with ETOPOPHOS and for 6 months after the final dose.

Males

ETOPOPHOS may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during treatment with ETOPOPHOS and for 4 months after the final dose.

Infertility

Females

In females of reproductive potential, ETOPOPHOS may cause infertility and result in amenorrhea. Premature menopause can occur with ETOPOPHOS. Recovery of menses and ovulation is related to age at treatment.

Males

In male patients, ETOPOPHOS may result in oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men, and in some cases, have occurred several years after the end of therapy.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of etoposide did not include sufficient numbers (n=71) of patients aged 65 years and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients.

SIDE EFFECTS

The following serious adverse reactions are described elsewhere in the labeling:

• Myelosuppression
• Secondary leukemias
• Hypersensitivity reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates, observed in the clinical trials of a drug, cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

ETOPOPHOS has been used as a single agent in clinical studies involving 206 patients with a variety of malignancies (including one non-Hodgkin’s lymphoma) and in combination with cisplatin in 60 patients with small cell lung cancer. The most common adverse reaction was neutropenia.

Other Important Adverse Reactions

Gastrointestinal Toxicity

Nausea and vomiting are the major gastrointestinal toxicities. The severity of nausea and vomiting is generally mild to moderate, with treatment discontinuation required in 1% of patients. Nausea and vomiting are managed with standard antiemetic therapy.

Other Toxicities

Other clinically important adverse reactions in clinical trials were:

Gastrointestinal: abdominal pain, constipation, dysphagia

General: fever

Ocular: transient cortical blindness, optic neuritis

Respiratory: interstitial pneumonitis/pulmonary fibrosis

Skin: pigmentation, radiation recall dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis

Neurologic: seizure, aftertaste

Hepatobiliary disorder: hepatotoxicity

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of ETOPOPHOS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Extravasation

Extravasation, resulting in local soft tissue toxicity, was identified in postmarketing reports. Extravasation of ETOPOPHOS may result in swelling, pain, cellulitis, and necrosis including skin necrosis.

DRUG INTERACTIONS

Warfarin: Co-administration of ETOPOPHOS with warfarin may result in elevated international normalized ratio (INR). Measure INR frequently.

Risk Summary

Based on animal data and its mechanism of action, ETOPOPHOS can cause fetal harm when administered to a pregnant woman. Etoposide, the active moiety of etoposide phosphate is teratogenic in mice and rats. Advise pregnant women of the potential hazard to a fetus.

Advise women of childbearing potential to avoid becoming pregnant.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In rats, an intravenous etoposide dose of 0.4 mg/kg/day (about 0.05 times of the 50 mg/m² human dose based on body surface area [BSA]) during organogenesis caused maternal toxicity, embryotoxicity, and teratogenicity (skeletal abnormalities, exencephaly, encephalocele, and anophthalmia); higher doses of 1.2 and 3.6 mg/kg/day (about 0.14 and 0.5 times the 50 mg/m² human dose based on BSA) resulted in 90% and 100% embryonic resorptions. In mice, a single etoposide dose of 1.0 mg/kg (approximately 0.06 times the 50 mg/m² human dose based on BSA) administered intraperitoneally on days 6, 7, or 8 of gestation caused embryotoxicity, cranial abnormalities, and major skeletal malformations. An intraperitoneal dose of 1.5 mg/kg (about 0.1 times the 50 mg/m² human based on BSA) 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.

The following serious adverse reactions are described elsewhere in the labeling:

• Myelosuppression
• Secondary leukemias
• Hypersensitivity reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates, observed in the clinical trials of a drug, cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

ETOPOPHOS has been used as a single agent in clinical studies involving 206 patients with a variety of malignancies (including one non-Hodgkin’s lymphoma) and in combination with cisplatin in 60 patients with small cell lung cancer. The most common adverse reaction was neutropenia.

Other Important Adverse Reactions

Gastrointestinal Toxicity

Nausea and vomiting are the major gastrointestinal toxicities. The severity of nausea and vomiting is generally mild to moderate, with treatment discontinuation required in 1% of patients. Nausea and vomiting are managed with standard antiemetic therapy.

Other Toxicities

Other clinically important adverse reactions in clinical trials were:

Gastrointestinal: abdominal pain, constipation, dysphagia

General: fever

Ocular: transient cortical blindness, optic neuritis

Respiratory: interstitial pneumonitis/pulmonary fibrosis

Skin: pigmentation, radiation recall dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis

Neurologic: seizure, aftertaste

Hepatobiliary disorder: hepatotoxicity

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of ETOPOPHOS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Extravasation

Extravasation, resulting in local soft tissue toxicity, was identified in postmarketing reports. Extravasation of ETOPOPHOS may result in swelling, pain, cellulitis, and necrosis including skin necrosis.

No antidote has been established for ETOPOPHOS overdosage in humans. Based on animal studies, overdosage may result in neurotoxicity.

Following intravenous administration of 90, 100, and 110 mg/m² dose of ETOPOPHOS over 60 minutes, mean nadir values (expressed as percent decrease from baseline) for granulocytes, hemoglobin, and thrombocytes were 81.0 ± 16.5%, 21.4 ± 9.9%, and 44.1 ± 20.7%, respectively.

Following intravenous administration of an etoposide formulation, the area under the concentration time curve (AUC) and maximum plasma concentration (Cmax) values increased linearly and etoposide did not accumulate in the plasma following daily administration for 4 to 5 days.

Distribution

Following administration of an injectable etoposide formulation, the mean volume of distribution of etoposide at steady state was 18 to 29 liters.

Etoposide enters the CSF poorly.

In vitro, etoposide is 97% bound to human plasma proteins, primarily albumin.

Elimination

The terminal elimination half-life of etoposide ranges from 4 to 11 hours. Total body clearance values range from 33 to 48 mL/min.

Metabolism

Following intravenous administration of ETOPOPHOS, etoposide phosphate is completely converted to etoposide in plasma. Etoposide is metabolized by opening of the lactone ring, O-demethylation, and conjugation (i.e., glucuronidation and sulfation). O-demethylation occurs through the CYP450 3A4 isoenzyme pathway to produce the active catechol metabolite.

Excretion

At 120 hours after intravenous administration of radiolabeled etoposide formulation, the mean recovery of radioactivity in the urine was 56% of the dose, 45% of which was excreted as etoposide and 8% or less as metabolites. Fecal recovery of radioactivity was 44% of the dose.