Ellence Side Effects

Generic Name: epirubicin

Please note - some side effects for Ellence may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Ellence - for the Consumer

Ellence

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Ellence:

Changes in menstrual periods; diarrhea; hair loss; hot flashes; nausea; skin changes; tiredness.

Seek medical attention right away if any of these SEVERE side effects occur when using Ellence:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); absence of menstrual cycle; black, tarry stools; blood in the urine or stools; burning, stinging, or pain during or after the injection of Ellence; chest pain; coughing up blood; facial flushing; fast, slow, or irregular heartbeat; fever, chills, or persistent cough or sore throat; itching, pain, redness, or swelling at the injection site; redness or discharge of the eyes; shortness of breath; stomach pain or tenderness; sudden, unexplained weight gain; swelling of the hands, ankles, or feet; swelling or soreness of the mouth or tongue; symptoms of dehydration (eg, dry mouth or eyes, decreased urination, fast heartbeat, sluggishness, unusual thirst); tenderness, pain, redness, or swelling of an arm or leg; unusual bruising or bleeding; unusual tiredness or weakness; vomiting.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Ellence Side Effects - for the Professional

Ellence

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 2.

Table 2. Clinically Relevant Acute Adverse Events in Patients with Early Breast Cancer

Event	% of Patients
	FEC-100/CEF-120		FEC-50		CMF
	(N=620)		(N=280)		(N=360)
	Grades 1–4	Grades 3/4	Grades 1–4	Grades 3/4	Grades 1–4	Grades 3/4
FEC & CEF = cyclophosphamide + Ellence + fluorouracil; CMF = cyclophosphamide + methotrexate + fluorouracil; NA = not available
Grade 1 or 2 changes in transaminase levels were observed but were more frequently seen with CMF than with CEF.
Hematologic   Leukopenia   Neutropenia   Anemia   Thrombocytopenia	80.3 80.3 72.2 48.8	58.6 67.2 5.8 5.4	49.6 53.9 12.9 4.6	1.5 10.5 0 0	98.1 95.8 70.9 51.4	60.3 78.1 0.9 3.6
Endocrine   Amenorrhea   Hot flashes	71.8 38.9	0 4.0	69.3 5.4	0 0	67.7 69.1	0 6.4
Body as a Whole   Lethargy   Fever	45.8 5.2	1.9 0	1.1 1.4	0 0	72.7 4.5	0.3 0
Gastrointestinal   Nausea/vomiting   Mucositis   Diarrhea   Anorexia	92.4 58.5 24.8 2.9	25.0 8.9 0.8 0	83.2 9.3 7.1 1.8	22.1 0 0 0	85.0 52.9 50.7 5.8	6.4 1.9 2.8 0.3
Infection   Infection   Febrile neutropenia	21.5 NA	1.6 6.1	15.0 0	0 0	25.9 NA	0.6 1.1
Ocular   Conjunctivitis/keratitis	14.8	0	1.1	0	38.4	0
Skin   Alopecia   Local toxicity   Rash/itch   Skin changes	95.5 19.5 8.9 4.7	56.6 0.3 0.3 0	69.6 2.5 1.4 0.7	19.3 0.4 0 0	84.4 8.1 14.2 7.2	6.7 0 0 0

Delayed Events

Table 3 describes the incidence of delayed adverse events in patients participating in the MA-5 and GFEA-05 trials.

Table 3. Long-Term Adverse Events in Patients with Early Breast Cancer

Event	% of Patients
	FEC-100/CEF-120 (N=620)	FEC-50 (N=280)	CMF (N=360)
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.
* In study MA-5, cardiac function was not monitored after 5 years.
Cardiac events Asymptomatic drops in LVEF CHF	2.1* 1.5	1.4 0.4	0.8* 0.3
Leukemia AML	0.8	0	0.3

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)].

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 1.

Table 1. Cumulative Probability of AML/MDS in Relation to Cumulative Doses of Ellence and Cyclophosphamide

Years from Treatment Start	Cumulative Probability of Developing AML/MDS % (95% CI)
	Cyclophosphamide Cumulative Dose ≤6,300 mg/m2		Cyclophosphamide Cumulative Dose >6,300 mg/m2
	Ellence Cumulative Dose ≤720 mg/m2 N=4760	Ellence Cumulative Dose >720 mg/m2 N=111	Ellence Cumulative Dose ≤720 mg/m2 N=890	Ellence Cumulative Dose >720 mg/m2 N=261
3	0.12 (0.01–0.22)	0.00 (0.00–0.00)	0.12 (0.00–0.37)	4.37 (1.69–7.05)
5	0.25 (0.08–0.42)	2.38 (0.00–6.99)	0.31 (0.00–0.75)	4.97 (2.06–7.87)
8	0.37 (0.13–0.61)	2.38 (0.00–6.99)	0.31 (0.00–0.75)	4.97 (2.06–7.87)

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

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Side Effects by Body System - for Healthcare Professionals

Hematologic

Hematologic effects of epirubicin when used in combination chemotherapy with cyclophosphamide and fluorouracil have been reported to include leukopenia (up to 80.3%), neutropenia (up to 80.3%), anemia (up to 72.2%), and thrombocytopenia (up to 48.4%). Long-term hematologic effects of epirubicin when used in combination chemotherapy with cyclophosphamide and fluorouracil have been reported to include acute myelogenous leukemia (up to 0.8%).

Endocrine

Endocrine effects of epirubicin when used in combination chemotherapy with cyclophosphamide and fluorouracil have been reported to include amenorrhea (up to 71.8%) and hot flashes (up to 38.9%).

General

General effects of epirubicin when used in combination chemotherapy with cyclophosphamide and fluorouracil have been reported to include lethargy (up to 45.8%) and fever (up to 5.2%).

Gastrointestinal

Gastrointestinal effects of epirubicin when used in combination chemotherapy with cyclophosphamide and fluorouracil have been reported to include nausea/vomiting (up to 92.4%), mucositis (up to 58.5%), diarrhea (up to 24.8%), and anorexia (up to 2.9%). Abdominal pain and hyperpigmentation of the oral mucosa has also been reported.

The mucositis is dose-dependent. Clinical manifestations of mucositis may include a painful or burning sensation, erythema, erosions, ulcerations, bleeding, or infections.

Immunologic

Immunologic effects of epirubicin when used in combination chemotherapy with cyclophosphamide and fluorouracil have been reported to include infection (up to 21.5%) and febrile neutropenia (up to 6.1%).

Ocular

Ocular effects of epirubicin when used in combination chemotherapy with cyclophosphamide and fluorouracil have been reported to include conjunctivitis/keratitis (up to 14.8%).

Dermatologic

Dermatologic effects of epirubicin when used in combination chemotherapy with cyclophosphamide and fluorouracil have been reported to include alopecia (up to 95.5%), rash/itch (up to 8.9%) and skin changes (up to 4.7%).

Alopecia has been reported to usually be reversible. Hair growth may occur within two to three months after therapy is discontinued.

Cardiovascular

Long-term cardiovascular effects of epirubicin when used in combination chemotherapy with cyclophosphamide and fluorouracil have included asymptomatic drops in LVEF (up to 1.8%) and CHF (up to 1.5%). One large retrospective study reported a significantly increased risk of CHF in patients who received cumulative doses greater than 950 mg/m2. The study also found that previous irradiation against the heart leads to an increased risk of developing CHF with an accelerated course to death. This indicates an additive cardiotoxic effect with the use of irradiation and epirubicin.

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