Pharmorubicin RD

Pharmorubicin RD

epirubicin

Manufacturer:

Pfizer

Distributor:

Zuellig
Full Prescribing Info
Contents
Epirubicin hydrochloride.
Description
Epirubicin hydrochloride (Pharmorubicin RD) 10 mg Vial: each vial contains 10 mg of Epirubicin hydrochloride as a freeze dried powder.
Diluent for 10 mg Vial: Each ampule contains 5 mL Sterile Water for Injection.
Epirubicin hydrochloride (Pharmorubicin RD) 50 mg Vial: each vial contains 50 mg of Epirubicin hydrochloride as a freeze dried powder.
Epirubicin hydrochloride (Pharmorubicin RD) is an anthracycline antibiotic with antiblastic activity.
Action
Pharmacologic Category: Anti-neoplastic Agent.
Pharmacology: Pharmacodynamics: Epirubicin hydrochloride (Pharmorubicin RD) 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 hydrochloride (Pharmorubicin RD)'s cytotoxic and/or antiproliferative properties have not been completely elucidated.
Epirubicin hydrochloride (Pharmorubicin RD) 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 hydrochloride (Pharmorubicin RD) also inhibits DNA helicase activity, preventing the enzymatic separation of double-stranded DNA and interfering with replication and transcription. Epirubicin hydrochloride (Pharmorubicin RD) is also involved in oxidation/reduction reactions by generating cytotoxic free radicals. The antiproliferative and cytotoxic activity of Epirubicin hydrochloride (Pharmorubicin RD) is thought to result from these or other possible mechanisms.
Epirubicin hydrochloride (Pharmorubicin RD) 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.
Clinical Studies: Adjuvant Treatment of Patients with Early Breast Cancer: Two randomized, open-label, multicenter studies evaluated the use of Epirubicin hydrochloride (Pharmorubicin RD) 100 to 120 mg/m2 in combination with cyclophosphamide and fluorouracil for the adjuvant treatment of patients with axillary-node positive breast cancer and no evidence of distant metastatic disease (Stage II or III). Study MA-5 evaluated 120 mg/m2 of Epirubicin hydrochloride (Pharmorubicin RD) per course in combination with cyclophosphamide and fluorouracil (CEF-120 regimen). This study randomized premenopausal and perimenopausal women with one or more positive lymph nodes to an Epirubicin hydrochloride (Pharmorubicin RD)-containing CEF-120 regimen or to a CMF regimen. Study GFEA-05 evaluated the use of 100 mg/m2 of Epirubicin hydrochloride (Pharmorubicin RD) per course in combination with fluorouracil and cyclophosphamide (FEC-100). This study randomized pre- and postmenopausal women to the FEC-100 regimen or to a lower-dose FEC-50 regimen. In the GFEA-05 study, eligible patients were either required to have ≥4 nodes involved with tumor or, if only 1 to 3 nodes were positive, to have negative estrogen- and progesterone-receptors and a histologic tumor grade of 2 or 3. A total of 1281 women participated in these studies. Patients with T4 tumors were not eligible for either study.
Table 1 shows the treatment regimens that the patients received. The primary endpoint of the trials was relapse-free survival, i.e., time to occurrence of a local, regional, or distant recurrence, or disease-related death. Patients with contralateral breast cancer, second primary malignancy or death from causes other than breast cancer were censored at the time of the last visit prior to these events. (See Table 1.)

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In the MA-5 trial, the median age of the study population was 45 years. Approximately 60% of patients had 1 to 3 involved nodes and approximately 40% had ≥4 nodes involved with tumor. In the GFEA-05 study, the median age was 51 years and approximately half of the patients were postmenopausal. About 17% of the study population had 1 to 3 positive nodes and 80% of patients had ≥4 involved lymph nodes. Demographic and tumor characteristics were well-balanced between treatment arms in each study.
The efficacy endpoints of relapse-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier methods in the intent-to-treat (ITT) patient populations in each study. Results for endpoints were initially analyzed after up to 5 years of follow-up and these results are presented in the text as follows and in Table 2. Results after up to 10 years of follow-up are presented in Table 2. In Study MA-5, Epirubicin hydrochloride (Pharmorubicin RD)-containing combination therapy (CEF-120) showed significantly longer RFS than CMF (5-year estimates were 62% versus 53%, stratified logrank for the overall RFS p = 0.013). The estimated reduction in the risk of relapse was 24% at 5 years. The OS was also greater for the Epirubicin hydrochloride (Pharmorubicin RD)-containing CEF-120 regimen than for the CMF regimen (5-year estimate 77% versus 70%; stratified logrank for overall survival p = 0.043; non-stratified logrank p = 0.13). The estimated reduction in the risk of death was 29% at 5 years.
In Study GFEA-05, patients treated with the higher-dose Epirubicin hydrochloride (Pharmorubicin RD) regimen (FEC-100) had a significantly longer 5-year RFS (estimated 65% versus 52%, logrank for the overall RFS p = 0.007) and OS (estimated 76% versus 65%, logrank for the overall survival p = 0.007) than patients given the lower dose regimen (FEC-50). The estimated reduction in risk of relapse was 32% at 5 years. The estimated reduction in the risk of death was 31% at 5 years.
Results of follow-up up to 10 years (median follow-up = 8.8 years and 8.3 years, respectively for Study MA-5 and Study GFEA-05) are presented in Table 2.
Although the trials were not powered for subgroup analyses, in the MA-5 study, improvements in favor of CEF-120 vs. CMF were observed, in RFS and OS both in patients with 1-3 node positive and in those with ≥4 node positive tumor involvement. In the GFEA-05 study, improvements in RFS and OS were observed in both pre- and postmenopausal women treated with FEC-100 compared to FEC-50. (See Table 2.)

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The Kaplan-Meier curves for RFS and OS from Study MA-5 are shown in Figures 1 and 2 and those for Study GFEA-05 are shown in Figures 3 and 4. (See Figures 1, 2, 3 and 4.)

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See Table 2 for statistics on 5 and 10 year analyses.
Cardiac Function: 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 (Pharmorubicin RD) (Figure 5). The estimated risk of Epirubicin hydrochloride (Pharmorubicin RD)-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. In the adjuvant treatment of breast cancer, the maximum cumulative dose used in clinical trials was 720 mg/m2. The risk of developing CHF in the absence of other cardiac risk factors increased steeply after an Epirubicin hydrochloride (Pharmorubicin RD) cumulative dose of 900 mg/m2. (See Figure 5.)

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In another retrospective survey of 469 Epirubicin hydrochloride (Pharmorubicin RD)-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.
Secondary Leukemia: An analysis of 7110 patients who received adjuvant treatment with Epirubicin hydrochloride (Pharmorubicin RD) 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 Epirubicin hydrochloride (Pharmorubicin RD) cumulative doses as shown in Figure 6. (See Figure 6.)

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AML/MDS rates increased with Epirubicin hydrochloride (Pharmorubicin RD) dose per cycle, and cumulative dose. For instance, in the MA-5 trial, in patients that received intensive doses of Epirubicin hydrochloride (Pharmorubicin RD) (120 mg/m2), the incidence of AML/MDS was 1.1% at 5 years with no additional cases observed during the second 5 years (years 6-10) of follow-up.
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 (Pharmorubicin RD) (720 mg/m2) or cyclophosphamide (6,300 mg/m2), as shown in Table 3. (See Table 3.)

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Pharmacokinetics: Epirubicin hydrochloride (Pharmorubicin RD) 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.
Distribution: Following intravenous administration, Epirubicin hydrochloride (Pharmorubicin RD) is rapidly and widely distributed into the tissues. Binding of Epirubicin hydrochloride (Pharmorubicin RD) to plasma proteins, predominantly albumin, is about 77% and is not affected by drug concentration. Epirubicin hydrochloride (Pharmorubicin RD) also appears to concentrate in red blood cells; whole blood concentrations are approximately twice those of plasma.
Metabolism: Epirubicin hydrochloride (Pharmorubicin RD) 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 hydrochloride (Pharmorubicin RD). 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 hydrochloride (Pharmorubicin RD) 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 hydrochloride (Pharmorubicin RD) or its major metabolites in bile and urine, respectively, in the 4 days after treatment.
Pharmacokinetics in Special Populations: Hepatic Impairment: Epirubicin hydrochloride (Pharmorubicin RD) 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 (Pharmorubicin RD) 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 (Pharmorubicin RD) 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 (Pharmorubicin RD) doses of 12.5 to 120 mg/m2. The median plasma clearance of Epirubicin hydrochloride (Pharmorubicin RD) 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 & Administration and Precautions).
Renal Impairment: No significant alterations in the pharmacokinetics of Epirubicin hydrochloride (Pharmorubicin RD) 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 Dosage & Administration and Precautions). Patients on dialysis have not been studied.
Toxicology: Preclinical Safety Data: Epirubicin hydrochloride (Pharmorubicin RD) is mutagenic, clastogenic, and carcinogenic in animals.
Indications/Uses
Epirubicin hydrochloride (Pharmorubicin RD) is indicated for the treatment of the following: Transitional cell bladder cancer; Early breast cancer; Metastatic/advanced breast cancer; Gastro-esophageal cancer; Head and neck cancer; Primary hepatocellular cancer; Acute leukemia; Non-small-cell lung cancer; Small-cell lung cancer; Non-Hodgkin's lymphoma; Hodgkin's lymphoma; Multiple myeloma; Ovarian cancer; Pancreatic cancer; Hormone-refractory prostatic cancer; Rectal cancer; Soft-tissue and bone sarcomas.
Dosage/Direction for Use
Epirubicin hydrochloride (Pharmorubicin RD) is usually administered by intravenous injection. Intravesical administration has been found beneficial in the treatment of superficial bladder cancer as well as in the prophylaxis of tumor recurrence after transurethral resection. The intra-arterial route of administration has also been used to produce intense local activity with reduced general toxicity (see Additional Warnings and Precautions for Other Routes of Administration under Precautions).
Intravenous (IV) Administration: The total Epirubicin hydrochloride (Pharmorubicin RD) dose per cycle may differ according to its use within a specific treatment regimen (e.g., given as a single agent or in combination with other cytotoxic drugs) and according to the indication.
Epirubicin hydrochloride (Pharmorubicin RD) should be administered into the tubing of a freely flowing intravenous infusion (0.9% sodium chloride or 5% glucose solution). To minimize the risk of thrombosis or perivenous extravasation, the usual infusion times range between 3 and 20 minutes depending upon dosage and volume of the infusion solution. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration (see Precautions).
Standard starting dose regimens: As a single agent, the recommended standard starting dose of Epirubicin hydrochloride (Pharmorubicin RD) per cycle in adults is 60-120 mg/m2 of body surface area. The recommended starting dose of Epirubicin hydrochloride (Pharmorubicin RD) when used as a component of adjuvant therapy in patients with axillary-node positive breast cancer is 100 to 120 mg/m2. The total starting dose per cycle may be given as a single dose or divided over 2-3 successive days. Under conditions of normal recovery from drug-induced toxicity (particularly bone marrow depression and stomatitis), each treatment cycle could be repeated every 3 to 4 weeks. If Epirubicin hydrochloride (Pharmorubicin RD) is used in combination with other cytotoxic drugs with potentially overlapping toxicities, the recommended dose per cycle should be reduced accordingly.
High starting dose regimens: High starting doses of Epirubicin hydrochloride (Pharmorubicin RD) may be used in the treatment of breast and lung cancer. As a single agent, the recommended high starting dose of Epirubicin hydrochloride (Pharmorubicin RD) per cycle in adults (up to 135 mg/m2) should be administered on day 1 or in divided doses on days 1, 2, 3, every 3 to 4 weeks. In combination therapy, the recommended high starting dose (up to 120 mg/m2) should be administered on day 1, every 3 to 4 weeks.
Dose Modifications: Renal Dysfunction: While no specific dose recommendation can be made based on the limited available data in patients with renal impairment, lower starting doses should be considered in patients with severe renal impairment (serum creatinine >5 mg/dL).
Hepatic Dysfunction: Dose reductions are recommended in patients with the following serum chemistry values: Bilirubin 1.2 to 3 mg/dL or AST 2 to 4 times upper limit of normal: ½ of recommended starting dose.
Bilirubin >3 mg/dL or AST >4 times upper limit of normal: ¼ of recommended starting dose.
Other Special Populations: Lower starting doses or longer intervals between cycles may need to be considered for heavily pre-treated patients or patients with neoplastic bone marrow infiltration (see Precautions). Standard starting doses and regimens have been used in the elderly.
Intravesical Administration: Epirubicin hydrochloride (Pharmorubicin RD) should be instilled using a catheter and retained intravesically for 1 hour. During instillation, the patient should be rotated to ensure that the vesical mucosa of the pelvis receives the most extensive contact with the solution. To avoid undue dilution with urine, the patient should be instructed not to drink any fluid in the 12 hours prior to instillation. The patient should be instructed to void at the end of the instillation. Intravesical administration is not suitable for the treatment of invasive tumors which have penetrated the muscular layer of the bladder wall.
Superficial bladder tumors: Single instillation: A single instillation of 80-100 mg immediately following transurethral resection (TUR) is recommended.
4-8 week course followed by monthly instillation: Eight weekly instillations of 50 mg (in 25-50 mL of saline solution) starting 2 to 7 days following TUR are recommended. In the case of local toxicity (chemical cystitis), the dose should be reduced to 30 mg. Patients may receive 4 weekly administrations of 50 mg followed by 11 monthly instillations at the same dosage.
Intra-arterial Administration: Patients with hepatocellular carcinoma may receive a bolus infusion into the main hepatic artery in doses of 60 to 90 mg/m2 at intervals of 3 weeks to 3 months or in doses of 40 to 60 mg/m2 in 4-week cycles.
Overdosage
Acute overdosage with Epirubicin hydrochloride (Pharmorubicin RD) will result in severe myelosuppression (mainly leukopenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucositis) and acute cardiac complications.
Contraindications
Hypersensitivity to Epirubicin hydrochloride (Pharmorubicin RD) or any other component of the product, other anthracyclines or anthracenediones.
Intravenous use: Persistent myelosuppression; Severe hepatic impairment; Myocardiopathy; Recent myocardial infarction; Severe arrhythmias; Previous treatments with maximum cumulative doses of Epirubicin hydrochloride (Pharmorubicin RD) and/or other anthracyclines and anthracenediones (see Precautions).
Intravesical use: Urinary tract infections; Inflammation of the bladder; Hematuria.
Special Precautions
General: Epirubicin hydrochloride (Pharmorubicin RD) should be administered only under the supervision of qualified physicians experienced in the use of cytotoxic therapy.
Patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) of prior cytotoxic treatment before beginning treatment with Epirubicin hydrochloride (Pharmorubicin RD).
While treatment with high doses of Epirubicin hydrochloride (Pharmorubicin RD) (e.g., ≥90 mg/m2 every 3 to 4 weeks) causes adverse events generally similar to those seen at standard doses (<90 mg/m2 every 3 to 4 weeks), the severity of the neutropenia and stomatitis/mucositis may be increased. Treatment with high doses of Epirubicin hydrochloride (Pharmorubicin RD) does require special attention for possible clinical complications due to profound myelosuppression.
Cardiac Function: Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e., acute) or late (i.e., delayed) events.
Early (i.e., Acute) Events: Early cardiotoxicity of Epirubicin hydrochloride (Pharmorubicin RD) consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes. Tachyarrhythmias, including premature ventricular contractions, ventricular tachycardia, and bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not a consideration for the discontinuation of Epirubicin hydrochloride (Pharmorubicin RD) treatment.
Late (i.e., Delayed) Events: Delayed cardiotoxicity usually develops late in the course of therapy with Epirubicin hydrochloride (Pharmorubicin RD) or within 2 to 3 months after treatment termination, but later events (several months to years after completion of treatment) have also been reported. Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF) such as dyspnea, pulmonary edema, dependent edema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.
The risk of developing CHF increases rapidly with increasing total cumulative doses of Epirubicin hydrochloride (Pharmorubicin RD) in excess of 900 mg/m2; this cumulative dose should only be exceeded with extreme caution (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Cardiac function should be assessed before patients undergo treatment with Epirubicin hydrochloride (Pharmorubicin RD) and must be monitored throughout therapy to minimize the risk of incurring severe cardiac impairment. The risk may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of Epirubicin hydrochloride (Pharmorubicin RD) at the first sign of impaired function. The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up.
Given the risk of cardiomyopathy, a cumulative dose of 900 mg/m2 Epirubicin hydrochloride (Pharmorubicin RD) should be exceeded only with extreme caution.
Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, and concomitant use of other drugs with the ability to suppress cardiac contractility or cardiotoxic drugs (e.g., trastuzumab). Anthracyclines including Epirubicin hydrochloride (Pharmorubicin RD) should not be administered in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored (see Interactions). Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity. The reported half-life of trastuzumab is variable. Trastuzumab may persist in the circulation for up to 7 months. Therefore, physicians should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible. If anthracyclines are used before this time, careful monitoring of cardiac function is recommended.
Cardiac function monitoring must be particularly strict in patients receiving high cumulative doses and in those with risk factors. However, cardiotoxicity with Epirubicin hydrochloride (Pharmorubicin RD) may occur at lower cumulative doses whether or not cardiac risk factors are present.
It is probable that the toxicity of Epirubicin hydrochloride (Pharmorubicin RD) and other anthracyclines or anthracenediones is additive.
Hematologic Toxicity: As with other cytotoxic agents, Epirubicin hydrochloride (Pharmorubicin RD) may produce myelosuppression. Hematologic profiles should be assessed before and during each cycle of therapy with Epirubicin hydrochloride (Pharmorubicin RD), including differential white blood cell (WBC) counts. A dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of Epirubicin hydrochloride (Pharmorubicin RD) hematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leukopenia and neutropenia are generally more severe with high-dose schedules, reaching the nadir in most cases between days 10 and 14 after drug administration; this is usually transient with the WBC/neutrophil counts returning to normal values in most cases by day 21. Thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death.
Secondary Leukemia: Secondary leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines, including Epirubicin hydrochloride (Pharmorubicin RD). Secondary leukemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pre-treated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukemias can have a 1- to 3-year latency period (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Gastrointestinal: Epirubicin hydrochloride (Pharmorubicin RD) is emetigenic.
Mucositis/stomatitis 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.
Liver Function: The major route of elimination of Epirubicin hydrochloride (Pharmorubicin RD) is the hepatobiliary system. Serum total bilirubin and AST levels should be evaluated before and during treatment with Epirubicin hydrochloride (Pharmorubicin RD). Patients with elevated bilirubin or AST may experience slower clearance of drug with an increase in overall toxicity. Lower doses are recommended in these patients (see Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions). Patients with severe hepatic impairment should not receive Epirubicin hydrochloride (Pharmorubicin RD) (see Contraindications).
Renal Function: Serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary in patients with serum creatinine >5 mg/dL (see Dosage & Administration).
Effects at Site of Injection: Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimize the risk of phlebitis/thrombophlebitis at the injection site (see Dosage & Administration).
Extravasation: Extravasation of Epirubicin hydrochloride (Pharmorubicin RD) during intravenous injection may produce local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. Should signs or symptoms of extravasation occur during intravenous administration of Epirubicin hydrochloride (Pharmorubicin RD), the drug infusion should be immediately stopped.
Other: As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal), have been coincidentally reported with the use of Epirubicin hydrochloride (Pharmorubicin RD).
Tumor-Lysis Syndrome: Epirubicin hydrochloride (Pharmorubicin RD) may induce hyperuricemia because of the extensive purine catabolism that accompanies rapid drug-induced lysis of neoplastic cells (tumor-lysis syndrome). Blood uric acid levels, potassium, calcium phosphate, and creatinine should be evaluated after initial treatment. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor-lysis syndrome.
Immunosuppressant Effects/Increased Susceptibility to Infections: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including Epirubicin hydrochloride (Pharmorubicin RD), may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving Epirubicin hydrochloride (Pharmorubicin RD). Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Additional Warnings and Precautions for Other Routes of Administration: Intravesical route: Administration of Epirubicin hydrochloride (Pharmorubicin RD) may produce symptoms of chemical cystitis (such as dysuria, polyuria, nocturia, stranguria, hematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction. Special attention is required for catheterization problems (e.g., urethral obstruction due to massive intravesical tumors).
Intra-arterial route: Intra-arterial administration of Epirubicin hydrochloride (Pharmorubicin RD) (transcatheter arterial embolization for the localized or regional therapies of primary hepatocellular carcinoma or liver metastases) may produce (in addition to systemic toxicity qualitatively similar to that observed following intravenous administration of Epirubicin hydrochloride (Pharmorubicin RD)) localized or regional events which include gastro-duodenal ulcers (probably due to reflux of the drugs into the gastric artery) and narrowing of bile ducts due to drug-induced sclerosing cholangitis. This route of administration can lead to widespread necrosis of the perfused tissue.
Effects on Ability to Drive and Use Machines: The effect of Epirubicin hydrochloride (Pharmorubicin RD) on the ability to drive or use machinery has not been systematically evaluated.
Use In Pregnancy & Lactation
(See Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Impairment of Fertility: Epirubicin hydrochloride (Pharmorubicin RD) could induce chromosomal damage in human spermatozoa. Men undergoing treatment with Epirubicin hydrochloride (Pharmorubicin RD) should use effective contraceptive methods.
Epirubicin hydrochloride (Pharmorubicin RD) may cause amenorrhea or premature menopause in premenopausal women.
Pregnancy: Women of child-bearing potential should be advised to avoid becoming pregnant during treatment and should use effective contraceptive methods.
Experimental data in animals suggest that Epirubicin hydrochloride (Pharmorubicin RD) may cause fetal harm when administered to a pregnant woman. If Epirubicin hydrochloride (Pharmorubicin RD) is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
There are no studies in pregnant women. Epirubicin hydrochloride (Pharmorubicin RD) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: It is not known whether Epirubicin hydrochloride (Pharmorubicin RD) is excreted in human milk. Because many drugs, including other anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Epirubicin hydrochloride (Pharmorubicin RD), mothers should discontinue nursing prior to taking this drug.
Adverse Reactions
A large number of clinical trials with Epirubicin hydrochloride (Pharmorubicin RD), administered at both conventional and high doses in different indications, have been conducted. Serious drug-related adverse events that occurred during clinical trials are listed as follows. Data from post-marketing surveillance are also included. (See Table 4.)

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Drug Interactions
Epirubicin hydrochloride (Pharmorubicin RD) is mainly used in combination with other cytotoxic drugs. Additive toxicity may occur especially with regard to bone marrow/hematologic and gastro-intestinal effects (see Precautions). The use of Epirubicin hydrochloride (Pharmorubicin RD) in combination chemotherapy with other potentially cardiotoxic drugs, as well as the concomitant use of other cardioactive compounds (e.g., calcium channel blockers), requires monitoring of cardiac function throughout treatment.
Epirubicin hydrochloride (Pharmorubicin RD) is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect Epirubicin hydrochloride (Pharmorubicin RD) metabolism, pharmacokinetics, therapeutic efficacy and/or toxicity (see Precautions).
Cimetidine increased the AUC of Epirubicin hydrochloride (Pharmorubicin RD) by 50% and should be stopped during treatment with Epirubicin hydrochloride (Pharmorubicin RD).
When given prior to Epirubicin hydrochloride (Pharmorubicin RD), paclitaxel can cause increased plasma concentrations of unchanged Epirubicin hydrochloride (Pharmorubicin RD) and its metabolites, the latter being, however, neither toxic nor active. Coadministration of paclitaxel or docetaxel did not affect the pharmacokinetics of Epirubicin hydrochloride (Pharmorubicin RD) when Epirubicin hydrochloride (Pharmorubicin RD) was administered prior to the taxane.
Caution For Usage
Special Precautions for Disposal and Other Handling: Preparation of the freeze-dried powder for intravenous administration: Dissolve in sodium chloride/water for injection.
The vial contents will be under a negative pressure. To minimize aerosol formation during reconstitution, particular care should be taken when the needle is inserted. Inhalation of any aerosol produced during reconstitution must be avoided.
Epirubicin hydrochloride (Pharmorubicin RD) should be used within 24 hours of first penetration of the rubber stopper. Discard any unused solution.
Protective measures: The following protective recommendations are given due to the toxic nature of this substance: Personnel should be trained in good technique for reconstitution and handling; Pregnant staff should be excluded from working with this drug; Personnel handling Epirubicin hydrochloride (Pharmorubicin RD) should wear protective clothing: goggles, gowns, disposable gloves and masks; A designated area should be defined for reconstitution (preferably under a laminar flow system); the work surface should be protected by disposable, plastic-backed, absorbent paper; All items used for reconstitution, administration or cleaning, including gloves, should be placed in high-risk, waste-disposal bags for high temperature incineration; Spillage or leakage should be treated with dilute sodium hypochloride (1% available chlorine) solution, preferably by soaking, and then water; All cleaning materials should be disposed of as indicated previously; In case of skin contact thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush; In case of contact with the eye(s), hold back the eyelid of the affected eye(s) and flush with copious amounts of water for at least 15 minutes. Then seek medical evaluation by a physician; Always wash hands after removing gloves.
Incompatibilities:
Epirubicin hydrochloride (Pharmorubicin RD) should not be mixed with other drugs. Contact with any solution of an alkaline pH should be avoided, as it will result in hydrolysis of Epirubicin hydrochloride (Pharmorubicin RD). Epirubicin hydrochloride (Pharmorubicin RD) should not be mixed with heparin due to chemical incompatibility that may lead to precipitation.
Storage
Store at temperatures not exceeding 25°C.
ATC Classification
L01DB03 - epirubicin ; Belongs to the class of cytotoxic antibiotics, anthracyclines and related substances. Used in the treatment of cancer.
Presentation/Packing
Powd for inj (vial + 5-mL sterile water for inj) 10 mg x 1's. 50 mg x 1's.
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