Epirubicin

Epirubicin may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• nausea
• vomiting
• sores in the mouth and throat
• stomach pain
• diarrhea
• loss of appetite or weight
• unusual tiredness or weakness
• hair loss
• hot flashes
• red discoloration of urine (for 1 to 2 days after dose)
• sore or red eyes
• eye pain
• darkening of the skin or nails

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical treatment:

• pale skin
• fainting
• dizziness
• rash
• hives
• itching
• difficulty breathing or swallowing

Epirubicin may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Epirubicin may be found in some form under the following brand names:

• Ellence

Epirubicin is part of the drug class:

• Anthracyclines and related substances

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. epirubicin 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 epirubicin 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 epirubicin 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 epirubicin 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 epirubicin. 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 epirubicin-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.

Usual Adult Dose for Breast Cancer -- Adjuvant:

For use as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer:

Starting Dose: 100 to 120 mg/m2 by intravenous infusion every 3 to 4 weeks. The total dose may either be given on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle.

Use epirubicin 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.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about epirubicin, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about epirubicin. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using epirubicin.

Review Date: October 4, 2017

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) [seeClinical Studies (14.1 )] evaluating Epirubicin hydrochloride-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 regimen (FEC-100/CEF-120), 280 patients received the lower-dose Epirubicin hydrochloride 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

FEC & CEF = cyclophosphamide + Epirubicin hydrochloride + 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

*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. However, an association between anthracyclines such as Epirubicin hydrochloride 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 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 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 [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. 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 (5.9) ].

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; 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 (Figure 1). The estimated risk of Epirubicin hydrochloride-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 cumulative dose of 900 mg/m2[see Warnings and Precautions (5.3)]. 

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

In another retrospective survey of 469 Epirubicin hydrochloride-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, 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 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 0.4) 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 cumulative doses as shown in Figure 2.

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

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 HCl (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 and Cyclophosphamide

Injection-Site Reactions [see Warnings and Precautions (5.1)]. 

Post-Marketing Experience

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

Mechanism of Action

Epirubicin is an anthracycline cytotoxic agent. Although it is known that anthracyclines can interfere with a number of biochemical and biological functions within eukaryotic cells, the precise mechanisms of Epirubicin’s cytotoxic and/or antiproliferative properties have not been completely elucidated.

Epirubicin forms a complex with DNA by intercalation of its planar rings between nucleotide base pairs, with consequent inhibition of nucleic acid (DNA and RNA) and protein synthesis.

Such intercalation triggers DNA cleavage by topoisomerase II, resulting in cytocidal activity. Epirubicin also inhibits DNA helicase activity, preventing the enzymatic separation of double-stranded DNA and interfering with replication and transcription. Epirubicin is also involved in oxidation/reduction reactions by generating cytotoxic free radicals. The antiproliferative and cytotoxic activity of Epirubicin is thought to result from these or other possible mechanisms.

Epirubicin is cytotoxic in vitro to a variety of established murine and human cell lines and primary cultures of human tumors. It is also active in vivo against a variety of murine tumors and human xenografts in athymic mice, including breast tumors.

Pharmacokinetics

Epirubicin pharmacokinetics are linear over the dose range of 60 to 150 mg/m2 and plasma clearance is not affected by the duration of infusion or administration schedule. Pharmacokinetic parameters for Epirubicin following 6 to 10 minute, single-dose intravenous infusions of Epirubicin hydrochloride at doses of 60 to 150 mg/m2 in patients with solid tumors are shown in Table 4. The plasma concentration declined in a triphasic manner with mean half-lives for the alpha, beta, and gamma phases of about 3 minutes, 2.5 hours, and 33 hours, respectively.

Table 4. Summary of Mean (±SD) Pharmacokinetic Parameters in Patientsa with Solid Tumors Receiving Intravenous Epirubicin Hydrochloride 60 to 150 mg/m2

a Advanced solid tumor cancers, primarily of the lung

b N=6 patients per dose level

c Plasma concentration at the end of 6 to 10 minute infusion

d Area under the plasma concentration curve

e Half-life of terminal phase

f Plasma clearance

g Steady state volume of distribution

Distribution

Following intravenous administration, Epirubicin is rapidly and widely distributed into the tissues. Binding of Epirubicin to plasma proteins, predominantly albumin, is about 77% and is not affected by drug concentration. Epirubicin also appears to concentrate in red blood cells; whole blood concentrations are approximately twice those of plasma.

Metabolism

Epirubicin is extensively and rapidly metabolized by the liver and is also metabolized by other organs and cells, including red blood cells. Four main metabolic routes have been identified:

(1) reduction of the C-13 keto-group with the formation of the 13(S)-dihydro derivative, Epirubicinol; (2) conjugation of both the unchanged drug and Epirubicinol with glucuronic acid; (3) loss of the amino sugar moiety through a hydrolytic process with the formation of the doxorubicin and doxorubicinol aglycones; and (4) loss of the amino sugar moiety through a redox process with the formation of the 7-deoxy-doxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. Epirubicinol has in vitro cytotoxic activity one-tenth that of Epirubicin. As plasma levels of Epirubicinol are lower than those of the unchanged drug, they are unlikely to reach in vivo concentrations sufficient for cytotoxicity. No significant activity or toxicity has been reported for the other metabolites.

Excretion

Epirubicin and its major metabolites are eliminated through biliary excretion and, to a lesser extent, by urinary excretion. Mass-balance data from 1 patient found about 60% of the total radioactive dose in feces (34%) and urine (27%). These data are consistent with those from 3 patients with extrahepatic obstruction and percutaneous drainage, in whom approximately 35% and 20% of the administered dose were recovered as Epirubicin or its major metabolites in bile and urine, respectively, in the 4 days after treatment.

Effect of Age

A population analysis of plasma data from 36 cancer patients (13 males and 23 females, 20 to 73 years) showed that age affects plasma clearance of Epirubicin in female patients. The predicted plasma clearance for a female patient of 70 years of age was about 35% lower than that for a female patient of 25 years of age. An insufficient number of males > 50 years of age were included in the study to draw conclusions about age-related alterations in clearance in males. Although a lower Epirubicin hydrochloride starting dose does not appear necessary in elderly female patients, and was not used in clinical trials, particular care should be taken in monitoring toxicity when Epirubicin hydrochloride is administered to female patients > 70 years of age [see Patient Counseling Information (17)]. 

Effect of Gender

In patients ≤ 50 years of age, mean clearance values in adult male and female patients were similar. The clearance of Epirubicin is decreased in elderly women.

Effect of Race

The influence of race on the pharmacokinetics of Epirubicin has not been evaluated.

Effect of Hepatic Impairment

Epirubicin is eliminated by both hepatic metabolism and biliary excretion and clearance is reduced in patients with hepatic dysfunction. In a study of the effect of hepatic dysfunction, patients with solid tumors were classified into 3 groups. Patients in Group 1 (n=22) had serum AST (SGOT) levels above the upper limit of normal (median: 93 IU/L) and normal serum bilirubin levels (median: 0.5 mg/dL) and were given Epirubicin hydrochloride doses of 12.5 to 90 mg/m2. Patients in Group 2 had alterations in both serum AST (median: 175 IU/L) and bilirubin levels (median: 2.7 mg/dL) and were treated with an Epirubicin hydrochloride dose of 25 mg/m2 (n=8). Their pharmacokinetics were compared to those of patients with normal serum AST and bilirubin values, who received Epirubicin hydrochloride doses of 12.5 to 120 mg/m2. The median plasma clearance of Epirubicin was decreased compared to patients with normal hepatic function by about 30% in patients in Group 1 and by 50% in patients in Group 2. Patients with more severe hepatic impairment have not been evaluated [see Dosage and Administration (2.2) , and Warnings and Precautions (5.5)]. 

Effect of Renal Impairment

No significant alterations in the pharmacokinetics of Epirubicin or its major metabolite, Epirubicinol, have been observed in patients with serum creatinine < 5 mg/dL. A 50% reduction in plasma clearance was reported in four patients with serum creatinine ≥ 5 mg/dL [see Warnings and Precautions (5.6) and Dosing and Administration(2.2)]. Patients on dialysis have not been studied.

Effect of Paclitaxel

The administration of paclitaxel (175 to 225 mg/m2 as a 3 hour infusion) immediately before or after Epirubicin (90 mg/m2 as bolus) caused variable increases in the systemic exposure (mean AUC) of Epirubicin ranging from 5% to 109%. At same doses of Epirubicin and paclitaxel, the mean AUC of the inactive metabolites of Epirubicin (Epirubicinol and 7-deoxy-aglycone) increased by 120% and 70%, respectively, when paclitaxel was immediately administered after Epirubicin. Epirubicin had no effect on the exposure of paclitaxel whether it was administered before or after paclitaxel.

Effect of Docetaxel

The administration of docetaxel (70 mg/m2 as 1 hour infusion) immediately before or after Epirubicin (90 mg/m2 as bolus) had no effect on the systemic exposure (mean AUC) of Epirubicin. However, the mean AUC of Epirubicinol and 7-deoxy-aglycone increased by 22.5% and 95%, respectively, when docetaxel was immediately administered after Epirubicin compared to Epirubicin alone. Epirubicin had no effect on the exposure of docetaxel whether it was administered before or after docetaxel.

Effect of Cimetidine

Coadministration of cimetidine (400 mg twice daily for 7 days starting 5 days before chemotherapy) increased the mean AUC of Epirubicin (100 mg/m2) by 50% and decreased its plasma clearance by 30%.

Drugs Metabolized by Cytochrome P-450 Enzymes.

No systematic in vitro or in vivo evaluation has been performed to examine the potential for inhibition or induction by Epirubicin of oxidative cytochrome P-450 isoenzymes.

Epirubicin Hydrochloride Injection, USP is available in glass single-use vials containing 2 mg Epirubicin hydrochloride per mL as a sterile, preservative-free, ready-to-use solution in the following strengths:

NDC 0143-9202-01; 50 mg/25 mL single use vial; individually boxed.

NDC 0143-9203-01; 200 mg/100 mL single use vial; individually boxed.

Store refrigerated between 2ºC and 8ºC (36ºF and 46ºF). Do not freeze. Protect from light.

Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15 to 25ºC). Solution for injection should be used within 24 hours after removal from refrigeration.

Manufactured by:

THYMOORGAN PHARMAZIE GmbH,

Schiffgraben 23, 38690 Goslar, Germany

Distributed by:

West-Ward Pharmaceuticals

Eatontown, NJ 07724 USA

Revised January 2016

127.207.013/00

Note: Patients receiving 120 mg/m2/cycle as part of combination therapy (CEF-120 regimen) should also receive prophylactic antibiotic therapy with sulfamethoxazole/trimethoprim or a fluoroquinolone. Lower starting doses may be necessary for heavily pretreated patients, patients with preexisting myelosuppression, or with bone marrow involvement. If clinically reasonable, delay epirubicin therapy until other cardiotoxic agents with long half-lives (eg, trastuzumab) have been cleared. The recommended lifetime maximum dose is 900 mg/m2. Epirubicin is associated with a moderate to high emetic potential (depending on dose or regimen); antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2011; Roila 2016).

Breast cancer, adjuvant treatment: IV: Usual dose: 100 to 120 mg/m2 per 3- or 4-week treatment cycle as follows:

60 mg/m2 on days 1 and 8 every 28 days for 6 cycles in combination with cyclophosphamide and fluorouracil (CEF-120 regimen; Levine 2005) or

100 mg/m2 on day 1 every 21 days for 6 cycles in combination with cyclophosphamide and fluorouracil (FEC-100 regimen; Bonneterre 2005) or

Breast cancer (off-label regimens): IV:

EC regimen: 100 mg/m2 on day 1 every 21 days for 8 cycles in combination with cyclophosphamide (Piccart 2001) or

EP or EC regimen: 75 mg/m2 on day 1 every 21 days for up to 6 cycles in combination with either paclitaxel or cyclophosphamide (Langley 2005) or

FEC regimen ± paclitaxel: 90 mg/m2 on day 1 every 21 days for 6 cycles in combination with fluorouracil and cyclophosphamide or for 4 cycles in combination with fluorouracil and cyclophosphamide followed by paclitaxel (Martin 2008) or

FEC regimen followed by pertuzumab + trastuzumab + docetaxel: 100 mg/m2 on day 1 every 21 days for 3 cycles in combination with fluorouracil and cyclophosphamide, followed by 3 cycles of pertuzumab, trastuzumab, and docetaxel (Schneeweiss 2013) or

CEF regimen: 50 mg/m2 on days 1 and 8 every 21 or 28 days for 6 to 9 cycles in combination with cyclophosphamide and fluorouracil (Ackland 2001)

Esophageal cancer (off-label use): IV:

ECF, ECX, EOF, and EOX regimens: 50 mg/m2 on day 1 every 21 days for up to 8 cycles in combination with cisplatin (C), oxaliplatin (O), fluorouracil (F), and/or capecitabine (X) (Cunningham 2008) or

ECF regimen: 50 mg/m2 on day 1 every 21 days for 3 preoperative and 3 postoperative cycles in combination with cisplatin and fluorouracil (Cunningham 2006)

Gastric cancer (off-label use): IV:

ECF, ECX, EOF, and EOX regimens: 50 mg/m2 on day 1 every 21 days for up to 8 cycles in combination with cisplatin (C), oxaliplatin (O), fluorouracil (F), and/or capecitabine (X) (Cunningham 2008; Waters 1999) or

ECF regimen: 50 mg/m2 on day 1 every 21 days for 3 preoperative and 3 postoperative cycles in combination with cisplatin and fluorouracil (Cunningham 2006)

Osteosarcoma (off-label use): IV: 90 mg/m2 on day 1 every 21 days for 3 cycles before surgery and 90 mg/m2 on day 1 every 28 days for 3 cycles after surgery (in combination with cisplatin, ifosfamide and mesna) (Basaran 2007)

Soft tissue sarcoma (off-label use): IV: 25 mg/m2 on days 1, 2, and 3 every 28 days for 4 cycles (in combination with ifosfamide and mesna) (Petrioli 2002) or 60 mg/m2 on days 1 and 2 every 21 days for 5 cycles (in combination with ifosfamide, mesna, and filgrastim) (Frustaci 2001)

Dosage adjustment for toxicity (breast cancer; labeled dosing):

Note: Heavily-treated patients, patients with preexisting bone marrow depression or neoplastic bone marrow infiltration: Lower starting doses (75 to 90 mg/m2) should be considered.

Delay day 1 dose of subsequent cycles until platelets are ≥100,000/mm3, ANC ≥1500/mm3, and nonhematologic toxicities have recovered to ≤grade 1

Reduce day 1 dose in subsequent cycles to 75% of previous day 1 dose if patient experiences nadir platelet counts <50,000/mm3, ANC <250/mm3, neutropenic fever, or grade 3/4 nonhematologic toxicity during the previous cycle

For CEF-120 regimen, reduce day 8 dose to 75% of day 1 dose if platelet counts are 75,000 to 100,000/mm3 and ANC is 1000 to 1499/mm3; omit day 8 dose if platelets are <75,000/mm3, ANC <1000/mm3, or grade 3/4 nonhematologic toxicity

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: May cause severe myelosuppression, including leukopenia, thrombocytopenia, and anemia. Myelosuppression is the dose-limiting toxicity. Obtain baseline and periodic blood counts. Patients should recover from myelosuppression due to prior chemotherapy treatment before beginning treatments. Severe neutropenia and severe infections may require supportive care.

• Extravasation: [US Boxed Warning]: For IV administration only. Vesicant; if extravasation occurs, severe local tissue damage and necrosis may occur. Not for IM or SubQ use. Injection into a small vein or repeated administration in the same vein may result in venous sclerosis. Ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation. If perivenous infiltration occurs, immediately discontinue infusion and restart in another vein.

• Gastrointestinal toxicity: Epirubicin is associated with a moderate to high emetic potential (depending on dose or regimen); antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2011; Roila 2016).

• Myocardial toxicity: Myocardial toxicity, including fatal heart failure (HF) may occur, particularly in patients who have received prior anthracyclines (or anthracenediones), prior or concomitant radiotherapy to the mediastinal/pericardial area, who have preexisting cardiac disease (active or dormant), or with concomitant cardiotoxic medications. Cardiotoxicity may be concurrent or delayed (months to years after treatment). The risk of HF is ~0.9% at a cumulative dose of 550 mg/m2, ~1.6% at a cumulative dose of 700 mg/m2, and ~3.3% at a cumulative dose of 900 mg/m2. Cardiotoxicity may also occur at lower cumulative doses or without risk factors. The risk of delayed cardiotoxicity increases more steeply with cumulative doses >900 mg/m2, and this dose should be exceeded only with extreme caution. The maximum cumulative dose used in adjuvant studies was 720 mg/m2. Cardiotoxicity is dose-limiting. Early toxicity may consist of tachyarrhythmias, including sinus tachycardia, premature ventricular contractions, and ventricular tachycardia, as well as bradycardia. Electrocardiographic changes including ST-T wave changes, atrioventricular and bundle-branch block have also been reported. These effects are not necessarily predictive of subsequent delayed cardiotoxicity. Delayed toxicity is typically caused by cardiomyopathy which presents as decreased left ventricular ejection fraction (LVEF) and/or signs/symptoms of HF (eg, tachycardia, dyspnea, pulmonary edema, edema, hepatomegaly, ascites, pleural effusion, gallop rhythm). Total cumulative dose should take into account prior treatment with other anthracyclines or anthracenediones, previous or concomitant treatment with other cardiotoxic agents or irradiation of chest. Although the risk increases with cumulative dose, irreversible cardiotoxicity may occur at any dose level. Patients with active or dormant cardiovascular disease, concurrent administration of cardiotoxic drugs, prior therapy with other anthracyclines or anthracenediones, prior or concurrent chest irradiation, advanced age, and infants and children are at increased risk. Children are at increased risk for developing delayed cardiotoxicity. Regular monitoring of LVEF and discontinuation at the first sign of impairment is recommended especially in patients with cardiac risk factors or impaired cardiac function. Discontinue treatment with signs of decreased LVEF. The half-life of other cardiotoxic agents (eg, trastuzumab) must be considered in sequential therapy.

• Secondary malignancy: [US Boxed Warning]: Treatment with anthracyclines (including epirubicin) may increase the risk of secondary acute myeloid leukemia (AML). AML is more common when given in combination with other antineoplastic agents, in patients who have received multiple courses of previous chemotherapy, or with escalated anthracycline doses. In breast cancer patients, the risk for treatment-related AML or myelodysplastic syndrome (MDS) was estimated at 0.27% at 3 years, 0.46% at 5 years, and 0.55% at 8 years after treatment. The latency period for secondary leukemias may be short (1 to 3 years).

• Thromboembolic events: Thrombophlebitis and thromboembolic phenomena (including pulmonary embolism) have occurred.

• Tumor lysis syndrome: May cause tumor lysis syndrome (TLS). Although TLS does not generally occur in patients with breast cancer, if TLS risk is suspected, consider monitoring serum uric acid, potassium, calcium, phosphate and serum creatinine after initial administration; hydration and antihyperuricemic prophylaxis may minimize potential TLS complications.

Disease-related concerns:

• Hepatic impairment: [US Boxed Warning]: Dosage reduction is recommended in patients with mild-to-moderate hepatic impairment; use is not recommended in severe hepatic impairment. Evaluate hepatic function at baseline and during treatment. Epirubicin is predominantly hepatically eliminated; impaired hepatic function may lead to increased exposure and toxicity.

• Renal impairment: Dosage reduction is recommended in patients with serum creatinine >5 mg/dL. Evaluate renal function at baseline and during treatment. Has not been studied in patients on dialysis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Women ≥70 years of age should be closely monitored for toxicity.

• Pediatric: Children may be at increased risk for developing acute and delayed cardiotoxicity; long-term periodic cardiac function monitoring is recommended.

• Radiation recipients: Epirubicin may have radiosensitizing activity; radiation recall (inflammatory) has also been reported.

Other warnings/precautions:

• Appropriate use: Patients should recover from acute toxicities (stomatitis, myelosuppression, infections) prior to initiating treatment. Assess baseline labs (blood counts, bilirubin, ALT, AST, serum creatinine) and cardiac function (with LVEF). Prophylactic antibiotics should be administered with the CDF-120 regimen.

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

• Immunizations: Patients should not be immunized with live viral vaccines during or shortly after treatment. Inactivated vaccines may be administered (response may be diminished).

If a patient has a bilirubin of 1.2 to 3 mg/dL or AST 2 to 4 times the upper limit of normal, then they should receive 1/2 of the normally recommended starting dose.

If a patient has a bilirubin >3 mg/dL or AST >4 times the upper limit of normal, then they should receive 1/4 of the normally recommended starting dose