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Epirubicin (Epirubicin Hydrochloride) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

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 epirubicin hydrochloride injection-containing combination regimens in patients with early breast cancer. Of the 1260 patients treated in these studies, 620 patients received the higher-dose epirubicin hydrochloride injection regimen (FEC-100/CEF-120), 280 patients received the lower-dose epirubicin hydrochloride injection 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.

Table 1. Clinically Relevant Acute Adverse Events in Patients With Early Breast Cancer
Event % of Patients

FEC-100/CEF-120

(N = 620)

FEC-50

(N = 280)

CMF

(N = 360)

Grades 1 to 4 Grades 3/4 Grades 1 to 4 Grades 3/4 Grades 1 to 4 Grades 3/4
Hematologic
   Leukopenia 80.3 58.6 49.6 1.5 98.1 60.3
   Neutropenia 80.3 67.2 53.9 10.5 95.8 78.1
   Anemia 72.2 5.8 12.9 0 70.9 0.9
   Thrombocytopenia 48.8 5.4 4.6 0 51.4 3.6
Endocrine
   Amenorrhea 71.8 0 69.3 0 67.7 0
   Hot flashes 38.9 4 5.4 0 69.1 6.4
Body as a Whole
   Lethargy 45.8 1.9 1.1 0 72.7 0.3
   Fever 5.2 0 1.4 0 4.5 0
Gastrointestinal
   Nausea/vomiting 92.4 25 83.2 22.1 85 6.4
   Mucositis 58.5 8.9 9.3 0 52.9 1.9
   Diarrhea 24.8 0.8 7.1 0 50.7 2.8
   Anorexia 2.9 0 1.8 0 5.8 0.3
Infection
   Infection 21.5 1.6 15 0 25.9 0.6
   Febrile neutropenia NA 6.1 0 0 NA 1.1
Ocular
   Conjunctivitis/keratitis 14.8 0 1.1 0 38.4 0
Skin
   Alopecia 95.5 56.6 69.6 19.3 84.4 6.7
   Local toxicity 19.5 0.3 2.5 0.4 8.1 0
   Rash/itch 8.9 0.3 1.4 0 14.2 0
   Skin changes 4.7 0 0.7 0 7.2 0

FEC & CEF = cyclophosphamide + epirubicin hydrochloride injection + 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.

Delayed Events

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

Table 2. 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)

Cardiac events
Asymptomatic drops in LVEF 2.1 1 1.4 0.8
CHF 1.5 0.4 0.3
Leukemia
AML 0.8 0 0.3

1 In study MA-5, cardiac function was not monitored after 5 years.

Two cases of acute lymphoid leukemia (ALL) were also observed in patients receiving epirubicin hydrochloride injection. However, an association between anthracyclines such as epirubicin hydrochloride injection 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 epirubicin hydrochloride injection 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, epirubicin hydrochloride injection 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 epirubicin hydrochloride injection [see Warnings and Precautions (5.2)].

Gastrointestinal

A dose-dependent mucositis (mainly oral stomatitis, less often esophagitis) may occur in patients treated with epirubicin hydrochloride injection. 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 epirubicin hydrochloride injection; 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 epirubicin hydrochloride injection (Figure 1). The estimated risk of epirubicin hydrochloride injection-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 epirubicin hydrochloride injection cumulative dose of 900 mg/m2 [see Warnings and Precautions (5.4)].

Figure 1. Risk of CHF in 9144 Patients Treated With Epirubicin Hydrochloride Injection

Figure 1. Risk of CHF in 9144 Patients Treated With Epirubicin Hydrochloride Injection

In another retrospective survey of 469 epirubicin hydrochloride injection-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 epirubicin hydrochloride injection, 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 epirubicin hydrochloride injection 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 to 0.40) at 3 years, 0.46% (approximate 95% CI, 0.28 to 0.65) at 5 years, and 0.55% (approximate 95% CI, 0.33 to 0.78) at 8 years. The risk of developing AML/MDS increased with increasing epirubicin hydrochloride injection cumulative doses as shown in Figure 2.

Figure 2. Risk of AML/MDS in 7110 Patients Treated With Epirubicin Hydrochloride Injection

Figure 2. Risk of AML/MDS in 7110 Patients Treated With Epirubicin Hydrochloride Injection

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 epirubicin hydrochloride injection (720 mg/m2) or cyclophosphamide (6,300 mg/m2), as shown in Table 3.

Table 3. Cumulative Probability of AML/MDS in Relation to Cumulative Doses of Epirubicin Hydrochloride Injection 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

Epirubicin Hydrochloride Injection Cumulative Dose

≤ 720 mg/m2

N = 4760

Epirubicin Hydrochloride Injection Cumulative Dose

> 720 mg/m2

N = 111

Epirubicin Hydrochloride Injection Cumulative Dose

≤ 720 mg/m2

N = 890

Epirubicin Hydrochloride Injection Cumulative Dose

> 720 mg/m2

N = 261

3 0.12 (0.01 to 0.22) 0 (0 to 0) 0.12 (0 to 0.37) 4.37 (1.69 to 7.05)
5 0.25 (0.08 to 0.42) 2.38 (0 to 6.99) 0.31 (0 to 0.75) 4.97 (2.06 to 7.87)
8 0.37 (0.13 to 0.61) 2.38 (0 to 6.99) 0.31 (0 to 0.75) 4.97 (2.06 to 7.87)

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

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of epirubicin hydrochloride injection. 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)



REPORTS OF SUSPECTED EPIRUBICIN SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Epirubicin. The information is not vetted and should not be considered as verified clinical evidence.

Possible Epirubicin side effects / adverse reactions in 18 year old female

Reported by a health professional (non-physician/pharmacist) from India on 2011-10-04

Patient: 18 year old female

Reactions: Jaundice, Enterococcal Infection, Encephalopathy, Ascites, Weight Increased, Hepatomegaly, Venoocclusive Liver Disease, Oedema Peripheral, Acute Hepatic Failure, Pleural Effusion, Gallbladder Disorder

Suspect drug(s):
Epirubicin
    Indication: Acute Lymphocytic Leukaemia

Dexamethasone
    Indication: Acute Lymphocytic Leukaemia

Vincristine
    Indication: Acute Lymphocytic Leukaemia

Asparaginase
    Indication: Acute Lymphocytic Leukaemia



Possible Epirubicin side effects / adverse reactions in 42 year old female

Reported by a health professional (non-physician/pharmacist) from Germany on 2011-10-06

Patient: 42 year old female weighing 86.0 kg (189.2 pounds)

Reactions: Intracranial Venous Sinus Thrombosis

Adverse event resulted in: life threatening event, hospitalization

Suspect drug(s):
Aranesp
    Indication: Breast Cancer
    Start date: 2007-06-14
    End date: 2007-08-24

Granisetron
    Dosage: on day 0 to 3
    Administration route: Oral
    Indication: Prophylaxis
    Start date: 2007-06-13
    End date: 2007-09-30

Taxol
    Dosage: 40 mg/m2 (09-aug-2007 to 27-sep-2007), weekly.
    Indication: Breast Cancer
    Start date: 2007-08-09
    End date: 2007-10-10

Cyclophosphamide
    Indication: Breast Cancer
    Start date: 2007-06-14
    End date: 2007-07-26

Dexamethasone
    Dosage: daily on day 1 to 4, 4mg (13-jun-2007 to 30-sep-2007).
    Indication: Prophylaxis

Ranitidine
    Dosage: 1 df= 50 units nos, once a day on day 1
    Indication: Antiallergic Therapy

Epirubicin
    Indication: Breast Cancer
    Start date: 2007-06-14
    End date: 2007-07-26

Capecitabine
    Dosage: 500 mg/m2 (09-aug-2007 to 27-sep-2007), twice daily.
    Administration route: Oral
    Indication: Breast Cancer
    Start date: 2007-08-09
    End date: 2007-10-10

Other drugs received by patient: Ibuprofen



Possible Epirubicin side effects / adverse reactions in 18 year old female

Reported by a individual with unspecified qualification from India on 2011-10-12

Patient: 18 year old female

Reactions: General Physical Health Deterioration, Encephalopathy, Ascites, Weight Increased, Hepatomegaly, Oedema Peripheral, Venoocclusive Liver Disease, Pleural Effusion, Enterococcus Test Positive, Acute Hepatic Failure, Gallbladder Disorder

Suspect drug(s):
Asparaginase (Asparaginase) (Asparaginase)
    Indication: Acute Lymphocytic Leukaemia

Dexamethasone
    Indication: Acute Lymphocytic Leukaemia

Epirubicin
    Indication: Acute Lymphocytic Leukaemia

Vincristine
    Indication: Acute Lymphocytic Leukaemia



See index of all Epirubicin side effect reports >>

Drug label data at the top of this Page last updated: 2013-04-11

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