NDC 0015-3404 Etopophos

Etoposide Phosphate

NDC Product Code 0015-3404

NDC 0015-3404-20

Package Description: 1 VIAL, SINGLE-DOSE in 1 CARTON > 1 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 VIAL, SINGLE-DOSE

NDC Product Information

Etopophos with NDC 0015-3404 is a a human prescription drug product labeled by E.r. Squibb & Sons, L.l.c.. The generic name of Etopophos is etoposide phosphate. The product's dosage form is injection, powder, lyophilized, for solution and is administered via intravenous form.

Labeler Name: E.r. Squibb & Sons, L.l.c.

Dosage Form: Injection, Powder, Lyophilized, For Solution - A dosage form intended for the solution prepared by lyophilization ("freeze drying"), a process which involves the removal of water from products in the frozen state at extremely low pressures; this is intended for subsequent addition of liquid to create a solution that conforms in all respects to the requirements for Injections.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Etopophos Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • ETOPOSIDE PHOSPHATE 100 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SODIUM CITRATE (UNII: 1Q73Q2JULR)
  • DEXTRAN 40 (UNII: K3R6ZDH4DU)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Topoisomerase Inhibitor - [EPC] (Established Pharmacologic Class)
  • Topoisomerase Inhibitors - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: E.r. Squibb & Sons, L.l.c.
Labeler Code: 0015
FDA Application Number: NDA020457 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 06-01-2009 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

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Information for Patients

Etoposide Injection

Etoposide Injection is pronounced as (e toe poe' side)

Why is etoposide injection medication prescribed?
Etoposide injection is used in combination with other medications to treat cancer of the testicles that has not improved or that has worsened after treatment with other m...
[Read More]

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Etopophos Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1.1 Refractory Testicular Tumors

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

1.2 Small Cell Lung Cancer

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

2.1 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), or100 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).

2.2 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 intravenously over 5 minutes to 3.5 hours for 5 days.

2.3 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.

2.4 Preparation And Administration

PreparationReconstitute 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:Vial StrengthVolume of DiluentFinal Concentration100 mg5 mL20 mg/mL10 mL10 mg/mLFollowing reconstitution, ETOPOPHOS can be further diluted to concentrations as low as 0.1 mg/mL 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.StorageAfter 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.AdministrationDO 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.1 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.

3 Dosage Forms & Strengths

For injection: 114 mg etoposide phosphate (equivalent to 100 mg etoposide), white to off-white, lyophilized powder in single-dose vial for reconstitution [see Description (11)].

4 Contraindications

ETOPOPHOS is contraindicated in patients with a history of a severe hypersensitivity reaction to etoposide products [see Warnings and Precautions (5.3)].

5.1 Myelosuppression

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 [see Adverse Reactions (6.1)].

5.2 Secondary Leukemias

Secondary leukemias have occurred with long term use of ETOPOPHOS.

5.3 Hypersensitivity Reactions

ETOPOPHOS can cause hypersensitivity reactions, including rash, urticaria, pruritus, and anaphylaxis [see Adverse Reactions (6.1)]. If hypersensitivity reactions occur, immediately interrupt ETOPOPHOS and institute supportive management. Permanently discontinue ETOPOPHOS in patients who experience a severe hypersensitivity reaction.

5.4 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 [see Use in Specific Populations (8.1)].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 [see Use in Specific Populations (8.3)].

6 Adverse Reactions

  • The following serious adverse reactions are described elsewhere in the labeling:Myelosuppression [see Warnings and Precautions (5.1)]Secondary leukemias [see Warnings and Precautions (5.2)]Hypersensitivity reactions [see Warnings and Precautions (5.3)]

6.1 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 ReactionsGastrointestinal ToxicityNausea 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 ToxicitiesOther clinically important adverse reactions in clinical trials were:Gastrointestinal: abdominal pain, constipation, dysphagiaGeneral: feverOcular: transient cortical blindness, optic neuritisRespiratory: interstitial pneumonitis/pulmonary fibrosisSkin: pigmentation, radiation recall dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysisNeurologic: seizure, aftertasteHepatobiliary disorder: hepatotoxicity

6.2 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.ExtravasationExtravasation, 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.

7 Drug Interactions

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

8.1 Pregnancy

Risk SummaryBased 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 [see Data]. 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.DataAnimal DataIn 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 [see Nonclinical Toxicology (13.1)].

8.2 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.

8.3 Females And Males Of Reproductive Potential

ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with ETOPOPHOS and for 6 months after the final dose.MalesETOPOPHOS 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.InfertilityFemalesIn 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.MalesIn 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 [See Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 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.

10 Overdosage

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

11 Description

ETOPOPHOS (etoposide phosphate) is a topoisomerase inhibitor. The chemical name for etoposide phosphate is: 4'-Demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-β-D-glucopyranoside], 4' (dihydrogen phosphate).Etoposide phosphate has the following structure:Etoposide phosphate is a phosphate ester of etoposide, a semi-synthetic derivative of podophyllotoxin. ETOPOPHOS is available for intravenous infusion as a sterile lyophilized powder in single-dose vials for reconstitution containing 114 mg etoposide phosphate, equivalent to 100 mg etoposide, 32.7 mg sodium citrate USP, and 300 mg dextran 40.

12.1 Mechanism Of Action

Etoposide phosphate is a prodrug that is converted to its active moiety, etoposide, by dephosphorylation. Etoposide causes the induction of DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of free radicals, leading to cell cycle arrest, primarily at the G2 stage of the cell cycle, and cell death.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

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.DistributionFollowing 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.EliminationThe terminal elimination half-life of etoposide ranges from 4 to 11 hours. Total body clearance values range from 33 to 48 mL/min.MetabolismFollowing 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.ExcretionAt 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.Specific PopulationsFollowing intravenous administration of etoposide in adults, the total body clearance of etoposide was correlated with creatinine clearance, serum albumin concentration, and non-renal clearance. No clinically significant differences in the pharmacokinetics of etoposide were observed based on age and sex.Drug Interaction StudiesCisplatin: Co-administration of cisplatin may increase exposure to etoposide.Highly protein-bound drugs: Phenylbutazone, sodium salicylate, and aspirin displaced protein-bound etoposide in vitro.Select antiepileptic medications: Co-administration with antiepileptic medications including phenytoin, phenobarbital, carbamazepine, and valproic acid may increase etoposide clearance.Etoposide may be a substrate of the P-glycoprotein (P-gp) transporter system based upon in vitro studies.

13.1 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).

14 Clinical Studies

Study 1 was a multicenter trial in patients, with previously untreated, small cell lung cancer, randomized (1:1) to receive either etoposide phosphate (80 mg/m2/day) plus cisplatin (20 mg/m2/day) for 5 days, or etoposide (80 mg/m2/day) plus cisplatin (20 mg/m2/day). The major efficacy outcome measure was objective response rate (ORR).Among the 121 patients enrolled, the median age was 64 years, 65% of patients were male, 89% were White, and ECOG performance score was 0 to 2.Study 1 demonstrated an overall response rate of 61% (95% confidence interval [CI] 47, 73) for patients treated with etoposide phosphate plus cisplatin, and 58% (95% CI: 45, 71) for those receiving etoposide plus cisplatin.

15 References

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

16 How Supplied/Storage And Handling

How Supplied/StorageETOPOPHOS 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 0015-3404-20Store unopened vials at 2° to 8°C (36°-46°F). Keep vial in outer carton to protect from light.HandlingETOPOPHOS is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

17 Patient Counseling Information

  • MyelosuppressionAdvise patients that periodic monitoring of their blood counts is required. Advise patients to contact their healthcare provider for new onset of bleeding, fever, or symptoms of infection [see Warnings and Precautions (5.1)].Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1, 8.3)].Advise females of reproductive potential to use effective contraception during and 6 months after treatment with ETOPOPHOS [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1, 8.3)].Advise males with female sexual partners of reproductive potential to use condoms during treatment with ETOPOPHOS and for at least 4 months after the final dose [see Warnings and Precautions (5.4) and Use in Specific Populations (8.3)].Manufactured for:Baxter Healthcare CorporationDeerfield, IL 60015 USAProduct of GermanyDistributed by:Bristol-Myers Squibb CompanyPrinceton, NJ 08543 USA[Print code]

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