epirubicin hydrochloride

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Overview

What is epirubicin hydrochloride?

Epirubicin is an anthracycline cytotoxic agent, intended for intravenous administration. Epirubicin is supplied as a sterile, clear, red solution and is available in polypropylene vials containing 50 and 200 mg of epirubicin hydrochloride as a preservative-free, ready-to-use solution. Each milliliter of solution contains 2 mg of epirubicin hydrochloride. Inactive ingredients include sodium chloride, USP, and water for injection, USP. The pH of the solution has been adjusted to 3.0 with hydrochloric acid, NF.

Epirubicin hydrochloride is the 4-epimer of doxorubicin and is a semi-synthetic derivative of daunorubicin. The chemical name is (8S- )-10-[(3-amino-2,3,6-trideoxy-α-L- -hexopyranosyl)oxy]-7,8,9,10- tetrahydro6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione hydrochloride. The active ingredient is a red-orange hygroscopic powder, with the empirical formula CHNO HCl and a molecular weight of 579.95. The structural formula is as follows:

What does epirubicin hydrochloride look like?

What are the available doses of epirubicin hydrochloride?

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What should I talk to my health care provider before I take epirubicin hydrochloride?

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How should I use epirubicin hydrochloride?

Epirubicin Injection is indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer.

Epirubicin Injection is administered to patients by intravenous infusion. Epirubicin is given in repeated 3- to 4-week cycles. The total dose of Epirubicin Hydrochloride Injection may be given on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle. The recommended dosages of epirubicin are as follows:

What interacts with epirubicin hydrochloride?

Patients should not be treated with epirubicin Injection if they have any of the following conditions: baseline neutrophil count < 1500 cells/mm; severe myocardial insufficiency, recent myocardial infarction, severe arrhythmias; previous treatment with anthracyclines up to the maximum cumulative dose; hypersensitivity to epirubicin, other anthracyclines, or anthracenediones; or severe hepatic dysfunction (see and ).

What are the warnings of epirubicin hydrochloride?

When ganglion blockers or other potent antihypertensive drugs are discontinued suddenly, hypertensive levels return. In patients with malignant hypertension and others, this may occur abruptly and may cause fatal cerebral vascular accidents or acute congestive heart failure. When INVERSINE is withdrawn, this should be done gradually and other antihypertensive therapy usually must be substituted. On the other hand, the effects of INVERSINE sometimes may last from hours to days after therapy is discontinued.

Hematologic Toxicity

A dose-dependent, reversible leukopenia and/or neutropenia is the predominant manifestation of hematologic toxicity associated with epirubicin 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 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, appropriate supportive measures (e.g., intravenous antibiotics, colony-stimulating factors, transfusions) may be required. Myelosuppression requires careful monitoring. Total and differential WBC, red blood cell (RBC), and platelet counts should be assessed before and during each cycle of therapy with epirubicin..

Cardiac Function

Cardiotoxicity is a known risk of anthracycline treatment. Anthracycline-induced cardiac toxicity may be manifested by early (or acute) or late (delayed) events. Early cardiac toxicity of epirubicin consists mainly of sinus tachycardia and/or ECG abnormalities such as non-specific ST-T wave changes, but tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, 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 considered an indication for the suspension of epirubicin treatment. Delayed cardiac toxicity results from a characteristic cardiomyopathy that is manifested by reduced LVEF and/or signs and symptoms of congestive heart failure (CHF) such as tachycardia, dyspnea, pulmonary edema, dependent edema, hepatomegaly, ascites, pleural effusion, gallop rhythm. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy. This toxicity appears to be dependent on the cumulative dose of epirubicin and represents the cumulative dose-limiting toxicity of the drug. If it occurs, delayed cardiotoxicity usually develops late in the course of therapy with epirubicin or within 2 to 3 months after completion of treatment, but later events (several months to years after treatment termination) have been reported.

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 (Figure 5). The estimated risk of epirubicin-treated patients developing clinically evident CHF was 0.9% at a cumulative dose of 550 mg/m, 1.6% at 700 mg/m, and 3.3% at 900 mg/m. The risk of developing CHF in the absence of other cardiac risk factors increased steeply after an epirubicin cumulative dose of 900 mg/m.

In another retrospective survey of 469 epirubicin-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.

Given the risk of cardiomyopathy, a cumulative dose of 900 mg/m epirubicin should be exceeded only with extreme caution. Risk factors (active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other drugs with the ability to suppress cardiac contractility) may increase the risk of cardiac toxicity. Although not formally tested, it is probable that the toxicity of epirubicin and other anthracyclines or anthracenediones is additive. Cardiac toxicity with epirubicin may occur at lower cumulative doses whether or not cardiac risk factors are present.

Although endomyocardial biopsy is recognized as the most sensitive diagnostic tool to detect anthracycline-induced cardiomyopathy, this invasive examination is not practically performed on a routine basis. Electrocardiogram (ECG) changes such as dysrhythmias, a reduction of the QRS voltage, or a prolongation beyond normal limits of the systolic time interval may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity. The risk of serious cardiac impairment may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of epirubicin at the first sign of impaired function. The preferred method for repeated assessment of cardiac function is evaluation of LVEF measured by multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiac toxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent through follow-up. In patients with risk factors, particularly prior anthracycline or anthracenedione use, the monitoring of cardiac function must be particularly strict and the risk-benefit of continuing treatment with epirubicin in patients with impaired cardiac function must be carefully evaluated.

Secondary Leukemia

The occurrence of secondary acute myelogenous leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines. 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 the anthracyclines have been escalated. These leukemias can have a short 1- to 3- year latency period. An analysis of 7110 patients who received adjuvant treatment with epirubicin 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 cumulative doses as shown in Figure 6.

The occurrence of secondary acute myelogenous leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines. 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 the anthracyclines have been escalated. These leukemias can have a short 1- to 3- year latency period. An analysis of 7110 patients who received adjuvant treatment with epirubicin 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 cumulative doses as shown in Figure 6.

Figure 6. Risk of AML/MDS in 7110 Patients Treated with Epirubicin

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 (720 mg/m) or cyclophosphamide (6,300 mg/m), as shown in Table 4.

Epirubicin is mutagenic, clastogenic, and carcinogenic in animals (see next section, ).

**Table 4. Cumulative probability of AML/MDS in relation to cumulative doses of epirubicin and cyclophosphamide**
	Years from Treatment Start	Cumulative Probability of Developing AML/MDS % (95% CI)
	Cyclophosphamide Cumulative Dose ≤6,300 mg/m	Cyclophosphamide Cumulative Dose >6,300 mg/m
	Epirubicin Cumulative Dose ≤720 mg/m N=4760	Epirubicin Cumulative Dose >720 mg/m N=111	Epirubicin Cumulative Dose ≤720 mg/m N=890	Epirubicin Cumulative Dose >720 mg/m 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)

Carcinogenesis, Mutagenesis & Impairment of Fertility

Treatment-related acute myelogenous leukemia has been reported in women treated with epirubicin-based adjuvant chemotherapy regimens (see above section, ). Conventional long-term animal studies to evaluate the carcinogenic potential of epirubicin have not been conducted, but intravenous administration of a single 3.6 mg/kg epirubicin dose to female rats (about 0.2 times the maximum recommended human dose on a body surface area basis) approximately doubled the incidence of mammary tumors (primarily fibroadenomas) observed at 1 year. Administration of 0.5 mg/kg epirubicin intravenously to rats (about 0.025 times the maximum recommended human dose on a body surface area basis) every 3 weeks for ten doses increased the incidence of subcutaneous fibromas in males over an 18-month observation period. In addition, subcutaneous administration of 0.75 or 1.0 mg/kg/day (about 0.015 times the maximum recommended human dose on a body surface area basis) to newborn rats for 4 days on both the first and tenth day after birth for a total of eight doses increased the incidence of animals with tumors compared to controls during a 24-month observation period.

Epirubicin was mutagenic in vitro to bacteria (Ames test) either in the presence or absence of metabolic activation and to mammalian cells (HGPRT assay in V79 Chinese hamster lung fibroblasts) in the absence but not in the presence of metabolic activation. Epirubicin was clastogenic in vitro (chromosome aberrations in human lymphocytes) both in the presence and absence of metabolic activation and was also clastogenic in vivo (chromosome aberration in mouse bone marrow).

In fertility studies in rats, males were given epirubicin daily for 9 weeks and mated with females that were given epirubicin daily for 2 weeks prior to mating and through Day 7 of gestation. When 0.3 mg/kg/day (about 0.015 times the maximum recommended human single dose on a body surface area basis) was administered to both sexes, no pregnancies resulted. No effects on mating behavior or fertility were observed at 0.1 mg/kg/day, but male rats had atrophy of the testes and epididymis, and reduced spermatogenesis. The 0.1 mg/kg/day dose also caused embryolethality. An increased incidence of fetal growth retardation was observed in these studies at 0.03 mg/kg/day (about 0.0015 times the maximum recommended human single dose on a body surface area basis). Multiple daily doses of epirubicin to rabbits and dogs also caused atrophy of male reproductive organs. Single 20.5 and 12 mg/kg doses of intravenous epirubicin caused testicular atrophy in mice and rats, respectively (both approximately 0.5 times the maximum recommended human dose on a body surface area basis). A single dose of 16.7 mg/kg epirubicin caused uterine atrophy in rats.

Although experimental data are not available, epirubicin could induce chromosomal damage in human spermatozoa due to its genotoxic potential. Men undergoing treatment with epirubicin should use effective contraceptive methods. Epirubicin may cause irreversible amenorrhea (premature menopause) in premenopausal women.

Liver Function

The major route of elimination of epirubicin is the hepatobiliary system (see ). Serum total bilirubin and AST levels should be evaluated before and during treatment with epirubicin. 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 ). Patients with severe hepatic impairment have not been evaluated; therefore, epirubicin should not be used in this patient population.

Renal Function

Serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary in patients with serum creatinine >5 mg/dL (see ). Patients undergoing dialysis have not been studied.

Tumor-Lysis Syndrome

As with other cytotoxic agents, epirubicin may induce hyperuricemia as a consequence of the extensive purine catabolism that accompanies drug-induced rapid lysis of highly chemosensitive neoplastic cells (tumor lysis syndrome). Other metabolic abnormalities may also occur. While not generally a problem in patients with breast cancer, physicians should consider the potential for tumor-lysis syndrome in potentially susceptible patients and should consider monitoring serum uric acid, potassium, calcium, phosphate, and creatinine immediately after initial chemotherapy administration. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor-lysis syndrome.

Pregnancy - Category D

Epirubicin may cause fetal harm when administered to a pregnant woman. Administration of 0.8 mg/kg/day intravenously of epirubicin to rats (about 0.04 times the maximum recommended single human dose on a body surface area basis) during Days 5 to 15 of gestation was embryotoxic (increased resorptions and post-implantation loss) and caused fetal growth retardation (decreased body weight), but was not teratogenic up to this dose. Administration of 2 mg/kg/day intravenously of epirubicin to rats (about 0.1 times the maximum recommended single human dose on a body surface area basis) on Days 9 and 10 of gestation was embryotoxic (increased late resorptions, post-implantation losses, and dead fetuses; and decreased live fetuses), retarded fetal growth (decreased body weight), and caused decreased placental weight. This dose was also teratogenic, causing numerous external (anal atresia, misshapen tail, abnormal genital tubercle), visceral (primarily gastrointestinal, urinary, and cardiovascular systems), and skeletal (deformed long bones and girdles, rib abnormalities, irregular spinal ossification) malformations. Administration of intravenous epirubicin to rabbits at doses up to 0.2 mg/kg/day (about 0.02 times the maximum recommended single human dose on a body surface area basis) during Days 6 to 18 of gestation was not embryotoxic or teratogenic, but a maternally toxic dose of 0.32 mg/kg/day increased abortions and delayed ossification. Administration of a maternally toxic intravenous dose of 1 mg/kg/day epirubicin to rabbits (about 0.1 times the maximum recommended single human dose on a body surface area basis) on Days 10 to 12 of gestation induced abortion, but no other signs of embryofetal toxicity or teratogenicity were observed. When doses up to 0.5 mg/kg/day epirubicin were administered to rat dams from Day 17 of gestation to Day 21 after delivery (about 0.025 times the maximum recommended single human dose on a body surface area basis), no permanent changes were observed in the development, functional activity, behavior, or reproductive performance of the offspring.

There are no adequate and well-controlled studies in pregnant women. Two pregnancies have been reported in women taking epirubicin. A 34-year-old woman, 28 weeks pregnant at her diagnosis of breast cancer, was treated with cyclophosphamide and epirubicin every 3 weeks for 3 cycles. She received the last dose at 34 weeks of pregnancy and delivered a healthy baby at 35 weeks. A second 34-year-old woman with breast cancer metastatic to the liver was randomized to FEC-50 but was removed from study because of pregnancy. She experienced a spontaneous abortion. If epirubicin 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. Women of childbearing potential should be advised to avoid becoming pregnant.

What are the precautions of epirubicin hydrochloride?

General

Epirubicin Injection is administered by intravenous infusion. Venous sclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Extravasation of epirubicin during the infusion may cause local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. It is recommended that epirubicin be slowly administered into the tubing of a freely running intravenous infusion. Patients receiving initial therapy at the recommended starting doses of 100–120 mg/m should generally have epirubicin infused over 15–20 minutes. For patients who require lower epirubicin starting doses due to organ dysfunction or who require modification of epirubicin doses during therapy, the epirubicin infusion time may be proportionally decreased, but should not be less than 3 minutes. (see ). If possible, veins over joints or in extremities with compromised venous or lymphatic drainage should be avoided. A burning or stinging sensation may be indicative of perivenous infiltration, and the infusion should be immediately terminated and restarted in another vein. Perivenous infiltration may occur without causing pain.

Facial flushing, as well as local erythematous streaking along the vein, may be indicative of excessively rapid administration. It may precede local phlebitis or thrombophlebitis.

Patients administered the 120-mg/m regimen of epirubicin as a component of combination chemotherapy should also receive prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole (e.g., Septra, Bactrim) or a fluoroquinolone (see , and ).

Epirubicin is emetigenic. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be considered before administration of epirubicin , particularly when given in conjunction with other emetigenic drugs.

As with other anthracyclines, administration of epirubicin after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation.

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.

Information for Patients

Patients should be informed of the expected adverse effects of epirubicin, including gastrointestinal symptoms (nausea, vomiting, diarrhea, and stomatitis) and potential neutropenic complications. Patients should consult their physician if vomiting, dehydration, fever, evidence of infection, symptoms of CHF, or injection-site pain occurs following therapy with epirubicin. Patients should be informed that they will almost certainly develop alopecia. Patients should be advised that their urine may appear red for 1 to 2 days after administration of epirubicin and that they should not be alarmed. Patients should understand that there is a risk of irreversible myocardial damage associated with treatment with epirubicin, as well as a risk of treatment-related leukemia. Because epirubicin may induce chromosomal damage in sperm, men undergoing treatment with epirubicin should use effective contraceptive methods. Women treated with epirubicin may develop irreversible amenorrhea, or premature menopause.

Laboratory Testing

See . Blood counts, including absolute neutrophil counts, and liver function should be assessed before and during each cycle of therapy with epirubicin. Repeated evaluations of LVEF should be performed during therapy.

Drug Interactions

Epirubicin when used in combination with other cytotoxic drugs may show on-treatment additive toxicity, especially hematologic and gastrointestinal effects.

Concomitant use of epirubicin with other cardioactive compounds that could cause heart failure (e.g., calcium channel blockers), requires close monitoring of cardiac function throughout treatment.

There are few data regarding the coadministration of radiation therapy and epirubicin. In adjuvant trials of epirubicin-containing CEF-120 or FEC-100 chemotherapies, breast irradiation was delayed until after chemotherapy was completed. This practice resulted in no apparent increase in local breast cancer recurrence relative to published accounts in the literature. A small number of patients received epirubicin-based chemotherapy concomitantly with radiation therapy but had chemotherapy interrupted in order to avoid potential overlapping toxicities. It is likely that use of epirubicin with radiotherapy may sensitize tissues to the cytotoxic actions of irradiation. Administration of epirubicin after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation.

Epirubicin is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect epirubicin metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity.

The administration of epirubicin immediately prior to paclitaxel or docetaxel does not affect the pharmacokinetics of epirubicin but does result in increases in the systemic exposure to epirubicin's inactive metabolites epirubicinol and 7-deoxy doxorubicin aglycone (see ). Administration of paclitaxel prior to epirubicin resulted in an increase in epirubicin AUC compared to when epirubicin was administered prior to paclitaxel.

Cimetidine increased the AUC of epirubicin by 50%. Cimetidine treatment should be stopped during treatment with epirubicin (see ).

Drug-Laboratory Test Interactions

There are no known interactions between epirubicin and laboratory tests.

Carcinogenesis, Mutagenesis & Impairment of Fertility

See .

Pregnancy

see .

Nursing Mothers

Epirubicin was excreted into the milk of rats treated with 0.50 mg/kg/day of epirubicin during peri- and postnatal periods. It is not known whether epirubicin 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, mothers should discontinue nursing prior to taking this drug.

Geriatric Use

Although a lower starting dose of epirubicin was not used in trials in elderly female patients, particular care should be taken in monitoring toxicity when epirubicin is administered to female patients ≥ 70 years of age. (See .)

Pediatric Use

The safety and effectiveness of epirubicin in pediatric patients have not been established in adequate and well-controlled clinical trials. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity and for chronic CHF.

What are the side effects of epirubicin hydrochloride?

On-Study Events

Integrated safety data are available from two studies (Studies MA-5 and GFEA-05, see ) evaluating epirubicin-containing combination regimens in patients with early breast cancer. Of the 1260 patients treated in these studies, 620 patients received the higher-dose epirubicin regimen (FEC-100/CEF-120), 280 patients received the lower dose epirubicin 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 5.

**Table 5. Clinically Relevant Acute Adverse Events in Patients with Early Breast Cancer**
FEC & CEF = cyclophosphamide + epirubicin + 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.
	Event	% of Patients
	FEC-100/CEF-120(N=620)	FEC-50(N=280)	CMF(N=360)
	Grades 1–4	Grades ¾	Grades 1–4	Grades 3/4	Grades 1–4	Grades 3/4
Hematologic
Endocrine
Body as a Whole
Gastrointestinal
Infection
Ocular
Skin

Delayed Events

Table 6 describes the incidence of delayed adverse events in patients participating in the MA-5 and GFEA-05 trials.

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

**Table 6. 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	2.1 1.5	1.40.4	0.8 0.3
Leukemia	0.8	0	0.3

Overview of Acute and Delayed Toxicities

See .

A dose-dependent mucositis (mainly oral stomatitis, less often esophagitis) may occur in patients treated with epirubicin. 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; prophylactic use of antiemetics should be considered before therapy (see ).

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; signs and symptoms of these reactions may vary from skin rash and pruritus to fever, chills, and shock.

See .

See .

See .

What should I look out for while using epirubicin hydrochloride?

Patients should not be treated with epirubicin Injection if they have any of the following conditions: baseline neutrophil count < 1500 cells/mm; severe myocardial insufficiency, recent myocardial infarction, severe arrhythmias; previous treatment with anthracyclines up to the maximum cumulative dose; hypersensitivity to epirubicin, other anthracyclines, or anthracenediones; or severe hepatic dysfunction (see and ).

Epirubicin injection should be administered only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Before beginning treatment with epirubicin, patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) of prior cytotoxic treatment. Also, initial treatment with epirubicin should be preceded by a careful baseline assessment of blood counts; serum levels of total bilirubin, AST, and creatinine; and cardiac function as measured by left ventricular ejection function (LVEF). Patients should be carefully monitored during treatment for possible clinical complications due to myelosuppression. Supportive care may be necessary for the treatment of severe neutropenia and severe infectious complications. Monitoring for potential cardiotoxicity is also important, especially with greater cumulative exposure to epirubicin.

What might happen if I take too much epirubicin hydrochloride?

A 36-year-old man with non-Hodgkin's lymphoma received a daily 95 mg/m dose of Epirubicin Injection for 5 consecutive days. Five days later, he developed bone marrow aplasia, grade 4 mucositis, and gastrointestinal bleeding. No signs of acute cardiac toxicity were observed. He was treated with antibiotics, colony-stimulating factors, and antifungal agents, and recovered completely. A 63-year-old woman with breast cancer and liver metastasis received a single 320 mg/m dose of epirubicin. She was hospitalized with hyperthermia and developed multiple organ failure (respiratory and renal), with lactic acidosis, increased lactate dehydrogenase, and anuria. Death occurred within 24 hours after administration of epirubicin. Additional instances of administration of doses higher than recommended have been reported at doses ranging from 150 to 250 mg/m. The observed adverse events in these patients were qualitatively similar to known toxicities of epirubicin. Most of the patients recovered with appropriate supportive care.

If an overdose occurs, supportive treatment (including antibiotic therapy, blood and platelet transfusions, colony-stimulating factors, and intensive care as needed) should be provided until the recovery of toxicities. Delayed CHF has been observed months after anthracycline administration. Patients must be observed carefully over time for signs of CHF and provided with appropriate supportive therapy.

How should I store and handle epirubicin hydrochloride?

Store the kit at 2°-8°C (36°-46°F) and protect from light.ArrayStore the kit at 2°-8°C (36°-46°F) and protect from light.ArrayEpirubicin injection is available in polypropylene single-use CYTOSAFE™ vials containing 2 mg epirubicin hydrochloride per mL as a sterile, preservative-free, ready-to-use solution in the following strengths:50 mg/25 mL single-use vial NDC 15210-404-28200 mg/100 mL single-use vial NDC 15210-404-29Epirubicin injection is available in polypropylene single-use CYTOSAFE™ vials containing 2 mg epirubicin hydrochloride per mL as a sterile, preservative-free, ready-to-use solution in the following strengths:50 mg/25 mL single-use vial NDC 15210-404-28200 mg/100 mL single-use vial NDC 15210-404-29Epirubicin injection is available in polypropylene single-use CYTOSAFE™ vials containing 2 mg epirubicin hydrochloride per mL as a sterile, preservative-free, ready-to-use solution in the following strengths:50 mg/25 mL single-use vial NDC 15210-404-28200 mg/100 mL single-use vial NDC 15210-404-29

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Epirubicin pharmacokinetics are linear over the dose range of 60 to 150 mg/m 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 at doses of 60 to 150 mg/m in patients with solid tumors are shown in Table 1. 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.

Non-Clinical Toxicology

Patients should not be treated with epirubicin Injection if they have any of the following conditions: baseline neutrophil count < 1500 cells/mm; severe myocardial insufficiency, recent myocardial infarction, severe arrhythmias; previous treatment with anthracyclines up to the maximum cumulative dose; hypersensitivity to epirubicin, other anthracyclines, or anthracenediones; or severe hepatic dysfunction (see and ).

Epirubicin injection should be administered only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Before beginning treatment with epirubicin, patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) of prior cytotoxic treatment. Also, initial treatment with epirubicin should be preceded by a careful baseline assessment of blood counts; serum levels of total bilirubin, AST, and creatinine; and cardiac function as measured by left ventricular ejection function (LVEF). Patients should be carefully monitored during treatment for possible clinical complications due to myelosuppression. Supportive care may be necessary for the treatment of severe neutropenia and severe infectious complications. Monitoring for potential cardiotoxicity is also important, especially with greater cumulative exposure to epirubicin.

Epirubicin when used in combination with other cytotoxic drugs may show on-treatment additive toxicity, especially hematologic and gastrointestinal effects.

Concomitant use of epirubicin with other cardioactive compounds that could cause heart failure (e.g., calcium channel blockers), requires close monitoring of cardiac function throughout treatment.

There are few data regarding the coadministration of radiation therapy and epirubicin. In adjuvant trials of epirubicin-containing CEF-120 or FEC-100 chemotherapies, breast irradiation was delayed until after chemotherapy was completed. This practice resulted in no apparent increase in local breast cancer recurrence relative to published accounts in the literature. A small number of patients received epirubicin-based chemotherapy concomitantly with radiation therapy but had chemotherapy interrupted in order to avoid potential overlapping toxicities. It is likely that use of epirubicin with radiotherapy may sensitize tissues to the cytotoxic actions of irradiation. Administration of epirubicin after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation.

Epirubicin is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect epirubicin metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity.

The administration of epirubicin immediately prior to paclitaxel or docetaxel does not affect the pharmacokinetics of epirubicin but does result in increases in the systemic exposure to epirubicin's inactive metabolites epirubicinol and 7-deoxy doxorubicin aglycone (see ). Administration of paclitaxel prior to epirubicin resulted in an increase in epirubicin AUC compared to when epirubicin was administered prior to paclitaxel.

Cimetidine increased the AUC of epirubicin by 50%. Cimetidine treatment should be stopped during treatment with epirubicin (see ).

Epirubicin Injection is administered by intravenous infusion. Venous sclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Extravasation of epirubicin during the infusion may cause local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. It is recommended that epirubicin be slowly administered into the tubing of a freely running intravenous infusion. Patients receiving initial therapy at the recommended starting doses of 100–120 mg/m should generally have epirubicin infused over 15–20 minutes. For patients who require lower epirubicin starting doses due to organ dysfunction or who require modification of epirubicin doses during therapy, the epirubicin infusion time may be proportionally decreased, but should not be less than 3 minutes. (see ). If possible, veins over joints or in extremities with compromised venous or lymphatic drainage should be avoided. A burning or stinging sensation may be indicative of perivenous infiltration, and the infusion should be immediately terminated and restarted in another vein. Perivenous infiltration may occur without causing pain.

Facial flushing, as well as local erythematous streaking along the vein, may be indicative of excessively rapid administration. It may precede local phlebitis or thrombophlebitis.

Patients administered the 120-mg/m regimen of epirubicin as a component of combination chemotherapy should also receive prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole (e.g., Septra, Bactrim) or a fluoroquinolone (see , and ).

Epirubicin is emetigenic. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be considered before administration of epirubicin , particularly when given in conjunction with other emetigenic drugs.

As with other anthracyclines, administration of epirubicin after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation.

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.

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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