Ellence

Unless your doctor tells you otherwise, continue your normal diet.

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include the following:

• sores in the mouth and throat
• fever, sore throat, chills, or other signs of infection
• unusual bleeding or bruising
• black and tarry stools
• red blood in stools
• bloody vomit
• vomited material that looks like coffee grounds

This medicine can pass into body fluids (urine, feces, vomit). For at least 48 hours after you receive a dose, avoid allowing your body fluids to come into contact with your hands or other surfaces. Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Do not receive a "live" vaccine while using epirubicin, or you could develop a serious infection. Live vaccines include measles, mumps, rubella (MMR), rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

Many drugs can interact with epirubicin. Not all possible interactions are listed here. Tell your doctor about all your medications and any you start or stop using during treatment with epirubicin, especially:

• acetaminophen (Tylenol);
• auranofin or gold injections to treat arthritis;
• cimetidine;
• rosiglitazone;
• an antibiotic or antifungal medication;
• an antidepressant--amitriptyline, doxepin, clomipramine, desipramine, imipramine, nortriptyline;
• birth control pills or hormone replacement therapy;
• cholesterol medications--atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin;
• heart or blood pressure medicine--amlodipine, atenolol, carvedilol, digoxin, diltiazem, enalapril, labetalol, lisinopril, methyldopa, nifedipine, verapamil, and others;
• HIV/AIDS medications;
• NSAIDs (non-steroidal anti-inflammatory drugs) such as ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others;
• other cancer medications, especially docetaxel or paclitaxel; or
• seizure medications--carbamazepine, divalproex, phenobarbital, phenytoin, valproic acid, and others.

This list is not complete and many other drugs can interact with epirubicin. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Ellence falls into category D. Women who are pregnant should not receive Ellence therapy. While there are no studies of Ellence in pregnant women, it causes fetal harm in animals. Tell your doctor if you are pregnant or plan to become pregnant, or if you become pregnant while receiving Ellence.

Ellence can interfere with the normal menstrual cycle (period) in women, and may stop sperm production, or cause DNA damage to sperm in men. Men and women receiving Ellence should use effective birth control methods to avoid pregnancy.

Ellence is usually administered by a healthcare provider in a medical setting making it unlikely for an overdose to occur. However, if overdose is suspected, seek emergency medical attention.
 

Keep all laboratory and doctor's appointments.

WARNING: RISK OF TISSUE NECROSIS, CARDIAC TOXICITY, SECONDARY ACUTE MYELOGENOUS LEUKEMIA, AND MYELOSUPPRESSION

1. Severe local tissue necrosis will occur if there is extravasation during administration. Ellence must not be given by the intramuscular or subcutaneous route.
2. Cardiac toxicity, including fatal congestive heart failure (CHF), may occur either during therapy with Ellence or months to years after termination of therapy. The probability of developing clinically evident CHF is estimated as approximately 0.9% at a cumulative dose of 550 mg/m2, 1.6% at 700 mg/m2, and 3.3% at 900 mg/m2. In the adjuvant treatment of breast cancer, the maximum cumulative dose used in clinical trials was 720 mg/m2. The risk of developing CHF increases rapidly with increasing total cumulative doses of Ellence in excess of 900 mg/m2; this cumulative dose should only be exceeded with extreme caution. Active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with Ellence may occur at lower cumulative doses whether or not cardiac risk factors are present.
3. Secondary acute myelogenous leukemia (AML) has been reported in patients with breast cancer treated with anthracyclines, including Ellence. The occurrence of refractory secondary leukemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. The cumulative risk of developing treatment-related AML or myelodysplastic syndrome (MDS), in 7110 patients with breast cancer who received adjuvant treatment with Ellence-containing regimens, was estimated as 0.27% at 3 years, 0.46% at 5 years, and 0.55% at 8 years.
4. Severe myelosuppression may occur.

Before you are treated with epirubicin, tell your doctor about all other cancer medications and treatments you have received, including radiation.

You should not use this medication if you are allergic to epirubicin or similar medications (Cerubidine, Adriamycin, Idamycin, Novantrone), or if you have:

• an untreated or uncontrolled infection (including mouth sores);

• severe liver disease;

• severe heart problems; or

• if you have recently had a heart attack.

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

• liver or kidney disease;

• bone marrow suppression;

• heart disease; or

• if you have been treated before with doxorubicin, daunorubicin, epirubicin, idarubicin, or mitoxantrone.

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

Do not use epirubicin if you are pregnant. It could harm the unborn baby. Tell your doctor if you become pregnant during treatment.

Use birth control to prevent pregnancy while you are receiving epirubicin, whether you are a man or a woman. Epirubicin use by either parent may cause birth defects.

It is not known whether epirubicin passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using epirubicin.

Call your doctor for instructions if you miss an appointment for your epirubicin injection.

This medicine can pass into body fluids (urine, feces, vomit). For at least 48 hours after you receive a dose, avoid allowing your body fluids to come into contact with your hands or other surfaces. Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Do not receive a "live" vaccine while using epirubicin, or you could develop a serious infection. Live vaccines include measles, mumps, rubella (MMR), rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

General

• Optimize results and minimize adverse effects by basing dose on clinical, cardiac, hepatic, renal, and hematologic response; patient tolerance; and other chemotherapy or irradiation being used.1

• Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.

Administration

Extremely irritating to tissues.1 Administer IV only; do not administer IM or sub-Q.1

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer slowly into tubing of a freely running IV infusion of 0.9% sodium chloride or 5% dextrose injection.1 Do not use veins over joints or in extremities with compromised venous or lymphatic drainage.1

Avoid extravasation.1 If signs or symptoms of extravasation occur, immediately stop the injection or infusion and restart at another site.1

Handle cautiously (by trained nonpregnant personnel); use protective equipment (e.g., latex gloves) and wash hands after removal of the latex gloves.1

Immediately treat accidental contact with the skin, mucous membranes, or eyes by copious lavage with water, soap and water, or sodium bicarbonate solution, but avoid abrasion of skin by use of a scrub brush; seek prompt medical attention.1

Usually administered over 3–20 minutes, depending on the volume of the infusion solution and the dosage.1

Rapid administration may cause local erythematous streaking along the vein and/or facial flushing;1 local phlebitis or thrombophlebitis may follow.1

Dosage

Available as epirubicin hydrochloride; dosage expressed in terms of the salt.1

Adults

100–120 mg/m2 in repeated 3- to 4-week cycles; give total dose for each cycle as a single dose on day 1 or as 2 equally divided doses on days 1 and 8.1 4

In clinical trials, the 100-mg/m2 epirubicin hydrochloride regimen included fluorouracil 500 mg/m2 and cyclophosphamide 500 mg/m2, with all drugs administered IV on day 1 of a 21-day cycle and repeated for 6 cycles.1 4

In clinical trials, the 120-mg/m2 epirubicin hydrochloride regimen was given IV as 60 mg/m2 of the anthracycline and fluorouracil 500 mg/m2 on days 1 and 8 of each cycle combined with oral cyclophosphamide 75 mg/m2 on days 1–14 of each cycle, with the cycles being repeated at 28-day intervals, for 6 cycles.1

Adjust dosage after first treatment cycle based on hematologic and nonhematologic toxicities.1

In patients with nadir platelet counts <50,000/mm3, absolute neutrophil counts (ANCs) <250/mm3, neutropenic fevers, or grade 3 or 4 nonhematologic toxicity, reduce day-1 dose of each antineoplastic agent in subsequent cycles to 75% of the day-1 dose given in current cycle.1

Delay day-1 chemotherapy in subsequent cycles until platelet counts are ≥100,000/mm3, ANCs are ≥1500/mm3, and nonhematologic toxicities have recovered to grade 1 or better.1

If epirubicin hydrochloride dose is divided between days 1 and 8, reduce the day-8 dose of each drug to 75% of the day-1 dose if platelet counts and ANCs are 75,000–100,000 and 1000–1499/mm3, respectively.1

If day-8 platelet counts or ANCs are <75,000 or 1000/mm3, respectively, or grade 3 or 4 nonhematologic toxicity has occurred, omit day-8 dose of each drug.1

Special Populations

Hepatic Impairment

In clinical studies, patients with serum bilirubin concentration of 1.2–3 mg/dL or AST concentration 2–4 times the upper limit of normal (ULN) received 50% of recommended initial dosage of epirubicin hydrochloride.1

In clinical studies, patients with serum bilirubin concentration of >3 mg/dL or AST >4 times the ULN received 25% of initial recommended dosage of epirubicin hydrochloride.1

Epirubicin is not recommended in patients with severe hepatic impairment.1

Renal Impairment

Consider dosage reduction if Scr is >5 mg/dL; not studied in those undergoing dialysis.1

Bone Marrow Impairment

Consider decreasing dosage for the initial cycle to 75–90 mg/m2 in patients with bone marrow impairment (e.g., extensive pretreatment, preexisting myelosuppression, neoplastic bone marrow infiltration).1

Storage

Parenteral

2–8° C.1 Do not freeze; protect from light.1 Discard unused solution within 24 hours after initial entry into vial.1 HID

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Incompatible with any alkaline pH solution (hydrolysis of drug).1

Manufacturer states that epirubicin hydrochloride should not be mixed with other drugs in the same syringe.1

• Pharmacologic actions similar to those of daunorubicin and doxorubicin.1 2 3 4

• Intercalates between base pairs causing template disordering and steric obstruction; thereby inhibits DNA synthesis, DNA-dependent RNA synthesis, and protein synthesis 1 2 4 and triggers DNA cleavage by topoisomerase II.1 2 3 4 Also inhibits DNA helicase and generates cytotoxic free radicals.1 2 3 4

• Compared with doxorubicin, is more lipophilic, may have improved therapeutic index, 3 4 and is less toxic;2 3 similar spectrum of activity against a wide variety of solid tumors and hematologic malignancies, and complete cross-resistance.2 3 4

Use Ellence as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions 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.

Integrated safety data are available from two studies (Studies MA-5 and GFEA-05) [see Clinical Studies (14.1)] evaluating Ellence-containing combination regimens in patients with early breast cancer. Of the 1260 patients treated in these studies, 620 patients received the higher-dose Ellence regimen (FEC-100/CEF-120), 280 patients received the lower-dose Ellence regimen (FEC-50), and 360 patients received CMF. Serotonin-specific antiemetic therapy and colony-stimulating factors were not used in these trials. Clinically relevant acute adverse events are summarized in Table 1.

Delayed Events

Table 2 describes the incidence of delayed adverse events in patients participating in the MA-5 and GFEA-05 trials.

Two cases of acute lymphoid leukemia (ALL) were also observed in patients receiving Ellence. However, an association between anthracyclines such as Ellence and ALL has not been clearly established.

Overview of Acute and Delayed Toxicities

Hematologic

Dose-dependent, reversible leukopenia and/or neutropenia is the predominant manifestation of hematologic toxicity associated with Ellence and represents the most common acute dose-limiting toxicity of this drug. In most cases, the white blood cell (WBC) nadir is reached 10 to 14 days from drug administration. Leukopenia/neutropenia is usually transient, with WBC and neutrophil counts generally returning to normal values by Day 21 after drug administration. As with other cytotoxic agents, Ellence at the recommended dose in combination with cyclophosphamide and fluorouracil can produce severe leukopenia and neutropenia. Severe thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, septicemia, septic shock, hemorrhage, tissue hypoxia, symptomatic anemia, or death. If myelosuppressive complications occur, use appropriate supportive measures (e.g., intravenous antibiotics, colony-stimulating factors, transfusions). Myelosuppression requires careful monitoring. Assess total and differential WBC, red blood cell (RBC), and platelet counts before and during each cycle of therapy with Ellence [see Warnings and Precautions (5.2)].

Gastrointestinal

A dose-dependent mucositis (mainly oral stomatitis, less often esophagitis) may occur in patients treated with Ellence. Clinical manifestations of mucositis may include a pain or burning sensation, erythema, erosions, ulcerations, bleeding, or infections. Mucositis generally appears early after drug administration and, if severe, may progress over a few days to mucosal ulcerations; most patients recover from this adverse event by the third week of therapy. Hyperpigmentation of the oral mucosa may also occur. Nausea, vomiting, and occasionally diarrhea and abdominal pain can also occur. Severe vomiting and diarrhea may produce dehydration. Antiemetics may reduce nausea and vomiting; consider prophylactic use of antiemetics before therapy [see Warnings and Precautions (5.10)].

Cutaneous and Hypersensitivity Reactions

Alopecia occurs frequently, but is usually reversible, with hair regrowth occurring within 2 to 3 months from the termination of therapy. Flushes, skin and nail hyperpigmentation, photosensitivity, and hypersensitivity to irradiated skin (radiation-recall reaction) have been observed. Urticaria and anaphylaxis have been reported in patients treated with Ellence; signs and symptoms of these reactions may vary from skin rash and pruritus to fever, chills, and shock.

Cardiovascular

In a retrospective survey, including 9144 patients, mostly with solid tumors in advanced stages, the probability of developing CHF increased with increasing cumulative doses of Ellence (Figure 1). The estimated risk of Ellence-treated patients developing clinically evident CHF was 0.9% at a cumulative dose of 550 mg/m2, 1.6% at 700 mg/m2, and 3.3% at 900 mg/m2. The risk of developing CHF in the absence of other cardiac risk factors increased steeply after an Ellence cumulative dose of 900 mg/m2 [see Warnings and Precautions (5.4)].

Figure 1. Risk of CHF in 9144 Patients Treated with Ellence

In another retrospective survey of 469 Ellence-treated patients with metastatic or early breast cancer, the reported risk of CHF was comparable to that observed in the larger study of over 9000 patients [see Warnings and Precautions (5.3)].

Other serious drug-related cardiovascular adverse events that occurred during clinical trials with Ellence, administered in different indications, include ventricular tachycardia, AV block, bundle branch block, bradycardia and thromboembolism.

Secondary Leukemia

An analysis of 7110 patients who received adjuvant treatment with Ellence in controlled clinical trials as a component of poly-chemotherapy regimens for early breast cancer, showed a cumulative risk of secondary acute myelogenous leukemia or myelodysplastic syndrome (AML/MDS) of about 0.27% (approximate 95% CI, 0.14–0.40) at 3 years, 0.46% (approximate 95% CI, 0.28–0.65) at 5 years, and 0.55% (approximate 95% CI, 0.33–0.78) at 8 years. The risk of developing AML/MDS increased with increasing Ellence cumulative doses as shown in Figure 2.

Figure 2. Risk of AML/MDS in 7110 Patients Treated with Ellence

The cumulative probability of developing AML/MDS was found to be particularly increased in patients who received more than the maximum recommended cumulative dose of Ellence (720 mg/m2) or cyclophosphamide (6,300 mg/m2), as shown in Table 3.

Injection-Site Reactions [see Warnings and Precautions (5.9)].

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Ellence. 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.

Infections and infestations: sepsis, pneumonia

Immune system disorders: anaphylaxis

Metabolism and nutrition disorders: dehydration, hyperuricemia

Vascular disorders: shock, haemorrhage, embolism arterial, thrombophlebitis, phlebitis

Respiratory, thoracic and mediastinal disorders: pulmonary embolism

Gastrointestinal disorders: erosions, ulcerations, pain or burning sensation, bleeding, hyperpigmentation of the oral mucosa

Skin and subcutaneous tissue disorders: erythema, flushes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity to irradiated skin (radiation-recall reaction), urticaria

Renal and urinary disorders: red coloration of urine for 1 to 2 days after administration

General disorders and administration site conditions: fever, chills

Injury, poisoning and procedural complications: chemical cystitis (following intravesical administration)