Etopophos

Etoposide phosphate is a cancer medicine that interferes with the growth of cancer cells and slows their growth and spread in the body.

Etoposide phosphate is used to treat cancer of the lung or testicles.

Etoposide phosphate may also be used for purposes not listed in this medication guide.

Etoposide phosphate is a cancer medication.

Etoposide phosphate can lower blood cells that help your body fight infections and help your blood to clot. You may get an infection or bleed more easily. Call your doctor if you have unusual bruising or bleeding, or signs of infection (fever, chills, body aches).

Etoposide phosphate can cause a severe allergic reaction. Tell your caregiver right away if you feel light-headed or have a fast heart rate, trouble breathing, or swelling in your face.

You should not use this medication if you are allergic to etoposide.

To make sure etoposide phosphate is safe for you, tell your doctor if you have:

• kidney disease; or
• a weak immune system (from disease or from taking certain medicines).

Using etoposide phosphate during pregnancy could harm the unborn baby. Use birth control to prevent pregnancy, whether you are a man or a woman. Etoposide phosphate use by either parent may cause birth defects.

For women: Use effective birth control while you are using etoposide phosphate and for at least 6 months after your treatment ends.

For men: Use a condom to prevent pregnancy during your treatment. Continue using condoms for at least 4 months after you stop using etoposide phosphate.

Tell your doctor right away if a pregnancy occurs while either parent is using etoposide phosphate.

It is not known whether etoposide phosphate passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are being treated with etoposide phosphate.

Using etoposide phosphate may increase your risk of developing other types of cancer, such as leukemia. Talk with your doctor about your specific risk.

Your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests.

While being treated with etoposide phosphate, use birth control to prevent pregnancy, whether you are a man or a woman. Tell your doctor right away if a pregnancy occurs while either parent is using etoposide phosphate.

Etoposide phosphate is injected into a vein through an IV. A healthcare provider will give you this injection.

Etoposide phosphate is usually given for 4 or 5 days in a row every 3 to 4 weeks. Follow your doctor's instructions.

Tell your caregivers if you feel any burning, pain, or swelling around the IV needle when etoposide phosphate is injected.

Etoposide phosphate can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests.

Get emergency medical help if you have signs of an allergic reaction: fever, chills, sweating, fast heartbeats, fainting; hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• pain, burning, irritation, or skin changes where the injection was given;

• severe nausea and vomiting;

• low blood cell counts--fever, chills, flu-like symptoms, swollen gums, mouth sores, skin sores, easy bruising, unusual bleeding, feeling light-headed; or

• severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• nausea, vomiting;

• constipation;

• fever;

• trouble swallowing; or

• unusual or unpleasant taste in the mouth.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Etoposide injection (also known as VP-16) is used in combination with other cancer medicines to treat cancer of the testicles and small cell lung cancer. It is also sometimes used to treat some other kinds of cancer in both males and females.

Etoposide belongs to the group of medicines known as antineoplastic agents. The exact way that etoposide acts against cancer is not known. However, it seems to interfere with the growth of the cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by etoposide, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, like hair loss, may not be serious but may cause concern. Some effects may not occur until months or years after the medicine is used.

Before you begin treatment with etoposide, you and your doctor should talk about the benefits of this medicine as well as the risks of using it.

This medicine is to be given only by or under the supervision of your doctor.

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)].

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 [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.

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)].

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 [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.

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 [see Nonclinical Toxicology (13.1)].

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 [See Nonclinical Toxicology (13.1)].

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.

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.

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.

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.

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.

Specific Populations
Following 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 Studies
Cisplatin: 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.

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).

How Supplied/Storage
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

Applies to etoposide: oral capsule, oral capsule liquid filled

Other dosage forms:

• intravenous powder for solution, intravenous solution

Along with its needed effects, etoposide (the active ingredient contained in Etopophos) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking etoposide:

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• chest pain
• chills
• cough
• fever
• painful or difficult urination
• pale skin
• pinpoint red spots on the skin
• shortness of breath
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• swollen glands
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness

• Blurred vision
• confusion
• cough
• difficulty with swallowing
• dizziness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fast heartbeat
• feeling of warmth
• headache
• hives
• itching
• nervousness
• numbness or tingling in the fingers or toes
• pounding in the ears
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• redness of the face, neck, arms, and occasionally, upper chest
• skin rash
• slow or fast heartbeat
• sweating
• tightness in the chest
• wheezing

• Bone pain

• Abdominal or stomach pain, severe
• blistering, peeling, or loosening of the skin
• cough or hoarseness
• dark urine
• diarrhea
• difficult breathing
• drowsiness
• joint or muscle pain
• loss of appetite
• lower back or side pain
• muscle tremors
• nausea or vomiting
• rapid, deep breathing
• red, irritated eyes
• red skin lesions, often with a purple center
• restlessness
• seizures
• stomach cramps
• yellow eyes or skin

Some side effects of etoposide may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Hair loss or thinning of the hair
• swelling or inflammation of the mouth
• weight loss

• Bad, unusual, or unpleasant (after) taste
• change in taste
• constipation
• cracked lips
• general feeling of discomfort or illness
• heartburn
• lack or loss of strength
• pain or burning in the throat
• sleepiness or unusual drowsiness