Summary Of Exposure |
A) USES: Epirubicin and idarubicin are antineoplastic agents used to treat a wide variety of cancers, including breast, ovarian, and lung cancer, leukemia, and lymphoma. Intravesical valrubicin is used to treat BCG-refractory carcinoma in situ of the bladder.
B) PHARMACOLOGY: Anthracyclines interfere in replication of rapidly growing cancer cells by interfering with DNA/RNA replication. These drugs intercalate between base pairs in DNA/RNA, inhibiting synthesis; specifically they inhibit topoisomerase II, preventing relaxation of supercoiled DNA, and blocking transcription and replication. Anthracyclines create oxygen free radicals, damaging DNA and cell membranes.
C) TOXICOLOGY: These agents interfere with DNA replication in rapidly dividing cells, such as bone marrow and gastrointestinal epithelium. Cardiac toxicity of these agents may be related to free radical production.
D) EPIDEMIOLOGY: Overdose is rare.
E) WITH THERAPEUTIC USE
1) CARDIOMYOPATHY: EPIRUBICIN: Anthracycline-induced cardiac toxicity is manifested by early or delayed events. EARLY (ACUTE) ONSET: Mainly sinus tachycardia and/or ECG abnormalities (eg, non-specific ST-T wave changes). Dysrhythmias have included premature ventricular contractions, sinus tachycardia, bradycardia, bundle-branch block, and atrioventricular junctional premature beats. Acute cardiac effects are not predictive of late onset cardiomyopathy. Late or delayed toxicity usually develops within 2 to 3 months after the completion of treatment but may occur years later and is characterized by a specific cardiomyopathy (reduced left ventricular ejection fraction and or signs/symptoms of congestive heart failure). The toxicity is dependent on the cumulative dose of epirubicin. RISK FACTORS: A cumulative dose of 900 mg/m(2) or greater; pre-existing cardiovascular disease; prior or concomitant radiotherapy to the mediastinum and pericardial region; previous therapy with other anthracyclines; concomitant medications which suppress cardiac contractility. IDARUBICIN: Cardiomyopathy, congestive heart failure, and life-threatening dysrhythmias, including atrial fibrillation, chest pain, myocardial infarction, and reduction in left ventricular ejection fraction have been reported following idarubicin therapy. Cardiac toxicity was usually reversible and was reported in the setting of sepsis, anemia, and aggressive IV fluid administration.
2) The dose-limiting toxicity of these agents is myelosuppression, particularly leukopenia and neutropenia. Nadirs usually occur within 10 to 14 days, with recovery being evident by day 21. The following adverse effects have also been reported following therapeutic doses: nail changes, rash, urticaria, alopecia, extravasation (with epirubicin), nausea/vomiting, anorexia, diarrhea, stomatitis, abdominal pain, gastrointestinal bleeding, elevated liver enzymes (idarubicin), headache, dizziness, asthenia, malaise, and lethargy. VALRUBICIN: Bladder irritation (ie, dysuria, frequency, urgency, bladder spasm and pain) may occur after intravesical use of valrubicin.
F) WITH POISONING/EXPOSURE
1) Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.
2) MILD TO MODERATE TOXICITY: Nausea, vomiting, diarrhea, stomatitis, and myelosuppression may occur following an overdose. VALRUBICIN: Bladder irritation (dysuria, frequency, urgency, bladder spasm and pain) are expected after intravesical overdose of valrubicin. Myelosuppression may occur if valrubicin is administered systemically, or if patients with bladder rupture/perforation were exposed to high doses of valrubicin intravesically.
3) SEVERE TOXICITY: Severe myelosuppression (especially granulocytopenia), acute cardiomyopathy (ie, ECG changes, dysrhythmias), severe mucositis, vomiting, and diarrhea may develop.
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Vital Signs |
3.3.1) SUMMARY
A) WITH POISONING/EXPOSURE 1) A woman presented with hyperthermia after receiving a single 320 mg/m(2) dose of epirubicin.
3.3.3) TEMPERATURE
A) WITH POISONING/EXPOSURE 1) HYPERTHERMIA: A 63-year-old woman with breast cancer and liver metastasis developed hyperthermia, multiple organ failure, lactic acidosis, increased lactate dehydrogenase, and anuria after receiving a single 320 mg/m(2) dose of epirubicin. She died within 24 hours of receiving epirubicin (Prod Info ELLENCE(R) IV injection, 2007).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) CARDIOMYOPATHY 1) WITH THERAPEUTIC USE a) Cardiomyopathy has been reported with epirubicin and idarubicin administration (Prod Info ELLENCE(R) IV injection, 2007; Prod Info Idarubicin Hydrochloride IV injection, 2007) b) EPIRUBICIN 1) Anthracycline-induced cardiac toxicity is manifested by early or delayed events (Prod Info ELLENCE(R) IV injection, 2007; Cersosimo & Hong, 1986a). 2) EARLY/ACUTE ONSET a) MANIFESTATIONS: Mainly sinus tachycardia and/or ECG abnormalities (eg, non-specific ST-T wave changes). Dysrhythmias have included premature ventricular contractions, sinus tachycardia, bradycardia, bundle-branch block, and atrioventricular junctional premature beats (Prod Info ELLENCE(R) IV injection, 2007; Macchiarini et al, 1990; Martoni et al, 1990; Cersosimo & Hong, 1986a). T-wave flattening or inversion, ST-T wave depression, RS-T depression, negative U-wave, and depression of the QRS complex have also been reported (Cersosimo & Hong, 1986a). Acute cardiac effects are not predictive of late onset cardiomyopathy (Prod Info ELLENCE(R) IV injection, 2007).
3) LATE/DELAYED ONSET a) TIMING: Late or delayed toxicity usually develops within 2 to 3 months after the completion of treatment but may occur years later and is characterized by a specific cardiomyopathy (reduced left ventricular ejection fraction and or signs/symptoms of congestive heart failure). The toxicity is dependent on the cumulative dose of epirubicin (Prod Info ELLENCE(R) IV injection, 2007; Nielsen et al, 1990; Mouridsen et al, 1990; Neri et al, 1989a; Dardir et al, 1989; Cersosimo & Hong, 1986a). b) RISK FACTORS: A cumulative dose of 900 mg/m(2) or greater; pre-existing cardiovascular disease; prior or concomitant radiotherapy to the mediastinum and pericardial region; previous therapy with other anthracyclines; concomitant medications which suppress cardiac contractility (Prod Info ELLENCE(R) IV injection, 2007; Dardir et al, 1989). c) LITERATURE REPORTS 1) In a retrospective survey of 9144 patients (mostly with advanced stage solid tumors), the risk of developing congestive heart failure (CHF) increased with increasing cumulative doses of epirubicin. Following cumulative doses of 550 mg/m(2), 700 mg/m(2), and 900 mg/m(2), the estimated risk of developing CHF was 0.9%, 1.6% and 3.3%, respectively (Prod Info ELLENCE(R) IV injection, 2007).
2) In an open study of 105 patients receiving epirubicin/paclitaxel-containing regimens for advanced breast cancer, the risk of developing congestive heart failure (CHF) was low, but increased substantially when cumulative epirubicin doses exceeded 990 mg/m(2). Patients (median age 51 years) with a baseline left ventricular ejection fraction (LVEF) of at least 50% received epirubicin (90 mg/m(2)) plus paclitaxel (135 to 225 mg/m(2)) (n=76) or gemcitabine (1000 mg/m(2) on days 1 and 4) plus epirubicin/paclitaxel (n=29) every 3 weeks for a maximum of 8 cycles. Patients were followed for a median duration of 17 months. Although no patients developed cardiotoxicity (grade 3) while receiving therapy, 9 (9%) patients developed symptomatic CHF accompanied by a decrease in LVEF substantially below 50% within 3 to 6 months following chemotherapy. Cumulative epirubicin doses in these patients were 1080 mg/m(2) (n=4), 720 mg/m(2) (n=2), 630 mg/m(2) (n=1) and 540 mg/m(2) (n=2). At least 1 cardiovascular risk factor was present in 54 patients, including prior adjuvant anthracycline chemotherapy, radiotherapy to the chest wall, hypertension, and diabetes. There was no significant association between these risks and the development of CHF following chemotherapy, but prior radiotherapy to the chest wall may enhance cardiac damage in patients receiving cumulative doses exceeding 990 mg/m(2) (Gennari et al, 1999).
3) In a retrospective study of 469 patients receiving epirubicin for advanced metastatic breast cancer, a cumulative dose greater than 950 mg/m(2) and previous irradiation to the left chest wall were important risk factors for the development of congestive heart failure (CHF). Based on Kaplan-Meier estimates, the risk of CHF was approximately 2%, 3%, and 4% at cumulative doses of 800 mg/m(2), 850 mg/m(2), and 900 mg/m(2) dose levels, respectively. The incidence rose dramatically to 15% at a cumulative dose level of 1000 mg/m(2). Factors not influencing risk for CHF included dosing schedule, mean dose-intensity, mean single-dose level, previous chemotherapy with cyclophosphamide, methotrexate, and fluorouracil, patient age, and overall chest wall irradiation. Overall, CHF occurred in 34 patients (7.2%), with a median onset of 57 days following the last dose of epirubicin. During a median follow-up time of 75 months, 13 patients died due to cardiac failure; median survival for this group of patients was 186 days. This was decreased to 125 days in 9 of 14 patients who received radiation to the left chest wall (Ryberg et al, 1998).
4) In one study, congestive heart failure occurred in 7 of 20 patients (35%) treated with epirubicin in cumulative doses of 1000 to 1563 mg/m(2); 4 of these patients died due to cardiotoxicity (Nielsen et al, 1990).
5) Heart failure has occurred with lower epirubicin doses (Nielsen et al, 1990), and studies have suggested that patients treated with cumulative epirubicin doses of 450 to 1000 mg/m(2) are at definite risk of heart failure (Nielsen et al, 1990; Dardir et al, 1989).
c) IDARUBICIN 1) Cardiomyopathy, congestive heart failure, and life-threatening dysrhythmias, including atrial fibrillation, chest pain, myocardial infarction, and reduction in left ventricular ejection fraction have been reported following idarubicin therapy. Cardiac toxicity was usually reversible and was reported in the setting of sepsis, anemia, and aggressive IV fluid administration (Prod Info Idarubicin Hydrochloride IV injection, 2007; Lopez et al, 1989; Harousseau et al, 1989; Lambertenghi-Deliliers et al, 1989; Wiernik et al, 1989; Madon et al, 1987a; Villani et al, 1989; Ganzina et al, 1986a; Vorobiof et al, 1988; Ganzina et al, 1986a). 2) In studies, ECG changes have consisted of ventricular and supraventricular extrasystoles, bundle branch block, t-wave flattening, and conduction defects. Fatal congestive heart failure has been reported in 1 pediatric patient (Madon et al, 1987a; Ganzina et al, 1986a; Harousseau et al, 1989; Vogler et al, 1989). 3) RISK FACTORS: Pre-existing cardiovascular disease; previous therapy with other cardiotoxic agents or anthracyclines at high cumulative doses; prior or concomitant radiotherapy to the mediastinum and pericardial region; treatment in patients with anemia, myelosuppression, infections, leukemic pericarditis and/or myocarditis; greater than 60 years of age (Prod Info Idarubicin Hydrochloride IV injection, 2007). 4) LITERATURE REPORTS a) IDARUBICIN VS DAUNORUBICIN: In comparative studies, the incidence of cardiotoxicity has been similar with idarubicin and daunorubicin during combined therapy with cytarabine (Wiernik et al, 1989; Vogler et al, 1989).
b) IDARUBICIN VS DOXORUBICIN: In 1 study comparing intravenous doxorubicin and oral idarubicin in patients with breast cancer, decreases in left ventricular ejection fraction and congestive heart failure (CHF) occurred more frequently with doxorubicin; CHF was observed in 4 of 37 doxorubicin treated patients but in none of 32 treated with idarubicin (Lopez et al, 1989).
c) In 2 studies, no significant cardiotoxic effects were reported in 126 patients with advanced malignancies after receiving idarubicin administered orally (cumulative dose of up to 540 mg/m(2)) or intravenously (cumulative dose of more than 65 mg/m(2)). In these studies, 10% to 20% of patients had previously received doxorubicin-containing chemotherapy (cumulative doses up to 540 mg/m(2)). These data support preclinical observations that idarubicin may be less cardiotoxic than other anthracyclines (Villani et al, 1989; Bertelli et al, 1988).
d) Acute myocardial infarction has been observed in at least 2 patients, one treated with oral idarubicin (Lowenthal et al, 1987; Wiernik et al, 1989).
2) WITH POISONING/EXPOSURE a) IDARUBICIN: Severe dysrhythmia developed in 1 patient following an idarubicin overdose. Very high doses of idarubicin may cause acute cardiac toxicity and a higher incidence of delayed cardiac failure (Prod Info Idarubicin Hydrochloride IV injection, 2007).
B) CHEST PAIN 1) WITH THERAPEUTIC USE a) VALRUBICIN: Chest pain occurred in 3% of patients with transitional cell carcinoma of the bladder who received intravesical valrubicin (n=230). Multiple weekly valrubicin doses (dose range, 200 to 900 mg) were administered to 205 patients; additionally, 179 of these patients received the approved dosage schedule of 800 mg once weekly for multiple weeks (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) HEADACHE 1) WITH THERAPEUTIC USE a) EPIRUBICIN 1) Headache has been reported in some patients treated with epirubicin (Prod Info ELLENCE(R) IV injection, 2007; Cersosimo & Hong, 1986a).
b) VALRUBICIN 1) Headache occurred in 4% of patients with transitional cell carcinoma of the bladder who received intravesical valrubicin (n=230). Multiple weekly valrubicin doses (dose range, 200 to 900 mg) were administered to 205 patients; additionally, 179 of these patients received the approved dosage schedule of 800 mg once weekly for multiple weeks (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
B) DIZZINESS 1) WITH THERAPEUTIC USE a) EPIRUBICIN 1) Dizziness has been reported in some patients treated with epirubicin (Prod Info ELLENCE(R) IV injection, 2007; Cersosimo & Hong, 1986a).
b) VALRUBICIN 1) Dizziness occurred in 3% of patients with transitional cell carcinoma of the bladder who received intravesical valrubicin (n=230). Multiple weekly valrubicin doses (dose range, 200 to 900 mg) were administered to 205 patients; additionally, 179 of these patients received the approved dosage schedule of 800 mg once weekly for multiple weeks (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
C) ASTHENIA 1) WITH THERAPEUTIC USE a) VALRUBICIN 1) Asthenia occurred in 4% of patients with transitional cell carcinoma of the bladder who received intravesical valrubicin (n=230). Multiple weekly valrubicin doses (dose range, 200 to 900 mg) were administered to 205 patients; additionally, 179 of these patients received the approved dosage schedule of 800 mg once weekly for multiple weeks (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
D) MALAISE 1) WITH THERAPEUTIC USE a) VALRUBICIN 1) Malaise occurred in 4% of patients with transitional cell carcinoma of the bladder who received intravesical valrubicin (n=230). Multiple weekly valrubicin doses (dose range, 200 to 900 mg) were administered to 205 patients; additionally, 179 of these patients received the approved dosage schedule of 800 mg once weekly for multiple weeks (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
E) LETHARGY 1) WITH THERAPEUTIC USE a) EPIRUBICIN 1) Lethargy has been reported in some patients treated with epirubicin (Prod Info ELLENCE(R) IV injection, 2007; Cersosimo & Hong, 1986a).
F) DISORDER OF THE PERIPHERAL NERVOUS SYSTEM 1) WITH THERAPEUTIC USE a) EPIRUBICIN: Peripheral neuropathy has been described with high doses of epirubicin in some studies (Macchiarini et al, 1990).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) NAUSEA AND VOMITING 1) WITH THERAPEUTIC USE a) EPIRUBICIN 1) Nausea and vomiting have been reported in 20% to 100% of patients treated with epirubicin, with higher incidences generally occurring with higher doses (Prod Info ELLENCE(R) IV injection, 2007; Carmo-Pereira et al, 1991; Macchiarini et al, 1990; Hortobagyi et al, 1989; Mouridsen et al, 1987; Cersosimo & Hong, 1986a; Jain et al, 1985).
b) IDARUBICIN 1) Nausea and vomiting are observed with intravenous and oral idarubicin therapy (Ganzina et al, 1986a; Bonfante et al, 1983; Lopez et al, 1986; Bastholt et al, 1989; Madon et al, 1987a; Lambertenghi-Deliliers et al, 1989).
c) VALRUBICIN 1) Nausea and vomiting developed in up to 5% of patients with transitional cell carcinoma of the bladder who received intravesical valrubicin (n=230). Multiple weekly valrubicin doses (dose range, 200 to 900 mg) were administered to 205 patients; additionally, 179 of these patients received the approved dosage schedule of 800 mg once weekly for multiple weeks (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
2) Gastrointestinal symptoms, including abdominal pain, nausea, vomiting, diarrhea, and flatulence, have been reported occasionally (5% or less) following intravesical administration. These effects may be drug-related because many have also occurred with intraperitoneal instillation (greater systemic absorption). Gastrointestinal symptoms subside 1 to 7 days after instillation (Markman et al, 1996).
3) After intraperitoneal doses of 200 to 600 mg/m(2), nausea, abdominal pain, and vomiting have occurred in approximately 65% of patients (Markman et al, 1996).
2) WITH POISONING/EXPOSURE a) IDARUBICIN: Severe gastrointestinal toxicity may occur following idarubicin overdose (Prod Info Idarubicin Hydrochloride IV injection, 2007).
B) LOSS OF APPETITE 1) WITH THERAPEUTIC USE a) EPIRUBICIN: Anorexia has been observed in up to 50% of patients in some studies. An incidence of 1.8% to 2.9% for all grades (no grade 3/4 events) of anorexia has been reported in two studies evaluating epirubicin-containing regimens in breast cancer patients (Prod Info ELLENCE(R) IV injection, 2007; Mouridsen et al, 1987).
C) DIARRHEA 1) WITH THERAPEUTIC USE a) EPIRUBICIN 1) Diarrhea is a less frequent gastrointestinal adverse effect, generally occurring in less than 25% of patients treated (Prod Info ELLENCE(R) IV injection, 2007; Blackstein et al, 1990; Hortobagyi et al, 1989; Mouridsen et al, 1987; Cersosimo & Hong, 1986a).
b) IDARUBICIN 1) Diarrhea has been reported with idarubicin therapy (Bonfante et al, 1983; Hurteloup & Ganzina, 1986a; Ganzina et al, 1986a).
2) In patients with advanced solid malignancies, diarrhea was observed in 11% of patients treated with intravenous idarubicin 15 mg/m(2) every 3 weeks. Diarrhea occurred in 9% and 22% of patients following oral doses of 36 and 48 mg/m(2) (Lambertenghi-Deliliers et al, 1989; Harousseau et al, 1989a; Madon et al, 1987a; Ganzina et al, 1986a).
c) VALRUBICIN 1) Diarrhea occurred in 3% of patients with transitional cell carcinoma of the bladder who received intravesical valrubicin (n=230). Multiple weekly valrubicin doses (dose range, 200 to 900 mg) were administered to 205 patients; additionally, 179 of these patients received the approved dosage schedule of 800 mg once weekly for multiple weeks (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
2) Gastrointestinal symptoms, including abdominal pain, nausea, vomiting, diarrhea, and flatulence, have been reported occasionally (5% or less) following intravesical administration. These effects may be drug-related because many have also occurred with intraperitoneal instillation (greater systemic absorption). Gastrointestinal symptoms subside 1 to 7 days after instillation (Markman et al, 1996).
D) STOMATITIS 1) WITH THERAPEUTIC USE a) EPIRUBICIN 1) Mucositis, mainly stomatitis, has occurred in up to 60% of patients treated with conventional epirubicin doses (Prod Info ELLENCE(R) IV injection, 2007; Anon, 1991; Mouridsen et al, 1987; Cersosimo & Hong, 1986a; Jain et al, 1985).
b) IDARUBICIN 1) Stomatitis has been reported with idarubicin therapy (Bonfante et al, 1983; Hurteloup & Ganzina, 1986a; Ganzina et al, 1986a).
2) In patients with advanced solid malignancies, stomatitis was observed in 11% of patients treated with intravenous idarubicin 15 mg/m(2) every 3 weeks (Madon et al, 1987a; Ganzina et al, 1986a; Lambertenghi-Deliliers et al, 1989; Harousseau et al, 1989a).
2) WITH POISONING/EXPOSURE a) EPIRUBICIN: A 36-year-old man with non-Hodgkin's lymphoma developed bone marrow aplasia, grade 4 mucositis, and gastrointestinal bleeding 5 days after receiving epirubicin (95 mg/m(2) daily) for 5 days. He recovered after receiving antibiotics, colony-stimulating factors, and antifungal therapy (Prod Info ELLENCE(R) IV injection, 2007).
E) ABDOMINAL PAIN 1) WITH THERAPEUTIC USE a) VALRUBICIN 1) Abdominal pain occurred in 5% of patients with transitional cell carcinoma of the bladder who received intravesical valrubicin (n=230). Multiple weekly valrubicin doses (dose range, 200 to 900 mg) were administered to 205 patients; additionally, 179 of these patients received the approved dosage schedule of 800 mg once weekly for multiple weeks (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
2) Gastrointestinal symptoms, including abdominal pain, nausea, vomiting, diarrhea, and flatulence, have been reported occasionally (5% or less) following intravesical administration. These effects may be drug-related because many have also occurred with intraperitoneal instillation (greater systemic absorption). Gastrointestinal symptoms subside 1 to 7 days after instillation (Markman et al, 1996).
3) After intraperitoneal doses of 200 to 600 mg/m(2), nausea, abdominal pain, and vomiting have occurred in approximately 65% of patients. Additionally, vomiting and abdominal pain were reported as severe in about 10% of patients (Markman et al, 1996).
F) GASTROINTESTINAL HEMORRHAGE 1) WITH THERAPEUTIC USE a) IDARUBICIN 1) Gastrointestinal hemorrhage has been reported with intravenous idarubicin as single-agent therapy or in combination with cytarabine (Wiernik et al, 1989; Madon et al, 1987a).
2) In one comparative clinical trial, serious hemorrhage was observed in 30% and 17% of patients treated with the intravenous combinations of idarubicin/cytarabine and daunorubicin/cytarabine, respectively(Wiernik et al, 1989).
2) WITH POISONING/EXPOSURE a) EPIRUBICIN: A 36-year-old man with non-Hodgkin's lymphoma developed bone marrow aplasia, grade 4 mucositis, and gastrointestinal bleeding 5 days after receiving epirubicin (95 mg/m(2) daily) for 5 days. He recovered after receiving antibiotics, colony-stimulating factors, and antifungal therapy (Prod Info ELLENCE(R) IV injection, 2007).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) TOXIC LIVER DISEASE 1) WITH THERAPEUTIC USE a) IDARUBICIN 1) Elevation of hepatic liver enzymes (bilirubin, transaminases, alkaline phosphatase) has been described with oral and intravenous idarubicin administration as single-agent therapy and in combination with cytarabine (Harousseau et al, 1989a; Berman et al, 1989; Harousseau et al, 1989; Wiernik et al, 1989; Lowenthal et al, 1987; Ganzina et al, 1986a; Carella et al, 1985a).
2) Hepatic function tests generally return to normal within 1 month (Lambertenghi-Deliliers et al, 1989).
3) Severe changes in hepatic function (equivalent to World Health Organization grade IV) occurred in less than 5% of patients (Prod Info Idarubicin Hydrochloride IV injection, 2007).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) URINARY SYMPTOMS 1) WITH THERAPEUTIC USE a) VALRUBICIN 1) In clinical studies, approximately 88% of patients with transitional cell carcinoma of the bladder (n=170) who received valrubicin 800 mg intravesically once weekly for multiple weeks reported local bladder symptoms (eg, urinary frequency, dysuria, urinary urgency, bladder spasm, hematuria, cystitis, nocturia, bladder pain); however, 45% of patients reported having some of these symptoms prior to treatment. These local bladder symptoms usually occurred around the time of the valrubicin instillation and resolved within 1 to 7 days (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
2) The ethanol content of the commercial formulation may contribute to bladder complications (Greenberg et al, 1997).
2) WITH POISONING/EXPOSURE a) VALRUBICIN: Bladder irritation (ie, dysuria, frequency, urgency, bladder spasm and pain) may occur after intravesical overdose of valrubicin (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
B) PROTEINURIA 1) WITH THERAPEUTIC USE a) EPIRUBICIN: Proteinuria has been reported in some patients treated with high doses (140 mg/m(2)) of epirubicin (Macchiarini et al, 1990).
C) URINARY TRACT INFECTIOUS DISEASE 1) WITH THERAPEUTIC USE a) VALRUBICIN: In clinical trials, 15% of patients reported urinary tract infections following intravesical administration of valrubicin (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
D) BLOOD IN URINE 1) WITH THERAPEUTIC USE a) VALRUBICIN 1) In clinical studies, 29% of patients with transitional cell carcinoma of the bladder (n=170) who received valrubicin 800 mg intravesically once weekly for multiple weeks reported hematuria; however, 11% of patients reported having hematuria prior to treatment. Additionally, gross hematuria was reported in 1% of patients following intravesical valrubicin and in no patients prior to treatment. Local bladder symptoms, including hematuria, usually occurred around the time of the valrubicin instillation and resolved within 1 to 7 days (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
2) Microscopic hematuria occurred in 3% of patients with transitional cell carcinoma of the bladder who received intravesical valrubicin (n=230). Multiple weekly valrubicin doses (dose range, 200 to 900 mg) were administered to 205 patients; additionally, 179 of these patients received the approved dosage schedule of 800 mg once weekly for multiple weeks (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
E) MULTIPLE ORGAN FAILURE 1) WITH POISONING/EXPOSURE a) EPIRUBICIN: A 63-year-old woman with breast cancer and liver metastasis developed hyperthermia, multiple organ failure (respiratory and renal), lactic acidosis, increased lactate dehydrogenase, and anuria after receiving a single 320 mg/m(2) dose of epirubicin. She died within 24 hours of receiving epirubicin (Prod Info ELLENCE(R) IV injection, 2007).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) MYELOSUPPRESSION 1) WITH THERAPEUTIC USE a) EPIRUBICIN: Patients who received 100 to 120 mg/m(2) of epirubicin in combination with fluorouracil and cyclophosphamide for adjuvant treatment of breast cancer experienced grade 3 and 4 neutropenia (67.2%), leukopenia (58.6%), anemia (5.8%), thrombocytopenia (5.4%), and rarely secondary acute myelogenous leukemia (Prod Info ELLENCE(R) IV injection, 2007).
b) VALRUBICIN: The dose-limiting toxicity of valrubicin is myelosuppression, particularly leukopenia and neutropenia, starting within 1 week of exposure. Nadirs usually occur within 14 days, with recovery being evident by the third week. Valrubicin 600 mg/m(2) is the maximum tolerated dose in humans by either intraperitoneal or intravenous routes (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
2) WITH POISONING/EXPOSURE a) EPIRUBICIN: A 36-year-old man with non-Hodgkin's lymphoma developed bone marrow aplasia, grade 4 mucositis, and gastrointestinal bleeding 5 days after receiving epirubicin (95 mg/m(2) daily) for 5 days. He recovered after receiving antibiotics, colony-stimulating factors, and antifungal therapy (Prod Info ELLENCE(R) IV injection, 2007).
b) IDARUBICIN: Severe and prolonged myelosuppression may occur following idarubicin overdose (Prod Info Idarubicin Hydrochloride IV injection, 2007).
c) VALRUBICIN: Myelosuppression may occur if valrubicin is administered systemically, or if patients with bladder rupture/perforation were exposed to high doses of valrubicin intravesically (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
B) ANEMIA 1) WITH THERAPEUTIC USE a) EPIRUBICIN 1) Anemia occurs less frequently than leukopenia. Hemoglobin levels of less than 8 g/dL have been reported in 11% to 30% of patients receiving conventional doses (Cersosimo & Hong, 1986a) and in 33% receiving high doses (140 mg/m(2)) (Macchiarini et al, 1990). However, effects of the drug on erythrocytes have not been described in most trials, suggesting that anemia did not occur or was not considered clinically significant (Cersosimo & Hong, 1986a).
b) IDARUBICIN 1) Decreases in hemoglobin have been observed with oral and intravenous idarubicin therapy, and occur in up to 100% of patients treated intravenously (Ganzina et al, 1986a; Lopez et al, 1989; Berman et al, 1983).
2) In one comparative study in breast cancer patients, the incidence of anemia with oral idarubicin (34%) was similar to that observed with intravenous doxorubicin (45%) (Lopez et al, 1989).
3) In other studies, median decreases in hemoglobin of 1.8 g/dL were observed in all patients treated with intravenous idarubicin 15 mg/m(2) every 3 weeks.. These decreases occurred at day 15 without evidence of hemolysis or hemorrhage. At doses of 18 mg/m(2), the median decrease in hemoglobin was 3 g/dL. With oral idarubicin, median decreases in hemoglobin levels of 2 g/dL were seen with doses of 50 mg/m(2) every 3 weeks (Ganzina et al, 1986a).
c) VALRUBICIN 1) Anemia occurred in 2% of patients with transitional cell carcinoma of the bladder who received intravesical valrubicin (n=230). Multiple weekly valrubicin doses (dose range, 200 to 900 mg) were administered to 205 patients; additionally, 179 of these patients received the approved dosage schedule of 800 mg once weekly for multiple weeks (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
C) LEUKOPENIA 1) WITH THERAPEUTIC USE a) EPIRUBICIN 1) The dose-limiting toxicity of epirubicin is myelosuppression, particularly leukopenia and neutropenia (Prod Info ELLENCE(R) IV injection, 2007). Leukopenia, defined as decreases in white blood cell count below 4000/mcL, was observed in 13% to 66% of patients in phase II trials (Cersosimo & Hong, 1986a). However, higher incidences (100%) have been reported with high-dose therapy (Macchiarini et al, 1990; Wils et al, 1990; Martoni et al, 1990). Nadirs usually occur within 10 to 14 days, with recovery being evident by day 21 (Prod Info ELLENCE(R) IV injection, 2007; Cersosimo & Hong, 1986a; Bonfante et al, 1982).
b) IDARUBICIN 1) Leukopenia occurs in most patients treated with intravenous idarubicin (Ganzina et al, 1986a; Madon et al, 1987a; Carella et al, 1985a; Mittelman et al, 1987; Weiss et al, 1986). This is the primary dose-limiting toxicity of the drug and is dose-related (Ganzina et al, 1986a).
2) When combined with cytarabine in patients with leukemia, the incidence of leukopenia has been similar with idarubicin and daunorubicin, although the duration of marrow suppression has been longer with idarubicin. Patients treated with idarubicin/cytarabine spent a mean of 24 days with a leukocyte count of less than 1000/mcL as compared to 18 days in the daunorubicin/cytarabine group; this difference was statistically significant (Wiernik et al, 1989). The degree of leukopenia has been similar with oral idarubicin (86%) and intravenous doxorubicin (89%) in breast cancer patients (Lopez et al, 1989).
3) Following oral or intravenous administration of idarubicin every 3 weeks in patients with advanced solid malignancies, leukopenia was observed more frequently than thrombocytopenia, and was dose-related. With intravenous doses of 7.5, 10.5, and 13.5 mg/m(2), leukopenia (white blood cell count less than 4000/m(3) was observed in 67%, 85%, and 100% of patients, respectively. In patients receiving oral therapy, incidences of leukopenia were 20%, 17%, 40%, and 62% with doses of 21, 27, 36, and 48 mg/m(2), respectively. Leukocyte count nadirs with both routes of administration occurred on approximately the 14th day of therapy, and were followed by complete recovery by day 21 in most patients. No drug-related deaths were observed (Bonfante et al, 1983).
c) VALRUBICIN 1) The dose-limiting toxicity of valrubicin is myelosuppression, particularly leukopenia and neutropenia, starting within 1 week of exposure. Nadirs usually occur within 14 days, with recovery being evident by the third week (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
2) Severe leukopenia was reported in a patient with a perforated bladder approximately 2 weeks following the intravesical administration of valrubicin 800 mg (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
D) THROMBOCYTOPENIC DISORDER 1) WITH THERAPEUTIC USE a) EPIRUBICIN 1) Thrombocytopenia (platelet counts less than 110,000/mcL) has occurred in 8% to 25% of patients in most studies; times to nadir and recovery have been similar to leukopenia (Cersosimo & Hong, 1986a).
b) IDARUBICIN 1) Thrombocytopenia is observed with oral and intravenous idarubicin, but occurs less frequently than leukopenia (Ganzina et al, 1986a; Bonfante et al, 1983; Lopez et al, 1989; Weiss et al, 1986).
2) Following the administration of idarubicin every 3 weeks in patients with advanced solid malignancies, thrombocytopenia (platelet count less than 100,000/m(3) was reported in 33% and 75% of patients treated with intravenous idarubicin in doses of 15 and 18 mg/m(2), respectively. With oral doses of 27, 48, and 60 mg/m(2), thrombocytopenia was seen in 17%, 25%, and 20% of patients, respectively. Platelet nadirs with both routes of administration occurred on approximately the 14th day of therapy, and were followed by complete recovery by day 21 in most patients. No drug-related deaths were observed (Bonfante et al, 1983).
3) When combined with cytarabine in patients with leukemia, the incidence of thrombocytopenia were similar with idarubicin and daunorubicin, although the duration of marrow suppression has been longer with idarubicin. Patients treated with idarubicin/cytarabine spent a mean of 27 days with a platelet count of less than 50,000/mcL as compared to 19 days in the daunorubicin/cytarabine group; this difference was statistically significant (Wiernik et al, 1989). The degree of thrombocytopenia has been similar with oral idarubicin (17%) and intravenous doxorubicin (18%) in breast cancer patients (Lopez et al, 1989).
E) NEUTROPENIA 1) WITH THERAPEUTIC USE a) IDARUBICIN 1) In a multicenter efficacy trial, patients over 70 years of age with metastatic hormone-resistant breast cancer were given oral idarubicin (20 mg/m(2)/week). Of the 26 patients enrolled in the study, 11 patients developed grade 3 to 4 neutropenia. The trial was stopped when 2 of those patients developed septicemia and died (only 1 of these patients was neutropenic when sepsis developed); a third patient died of congestive heart failure (Freyer et al, 2004).
b) VALRUBICIN 1) The dose-limiting toxicity of valrubicin is myelosuppression, particularly leukopenia and neutropenia, starting within 1 week of exposure. Nadirs usually occur within 14 days, with recovery being evident by the third week (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
2) Severe neutropenia was reported in a patient with a perforated bladder approximately 2 weeks following the intravesical administration of valrubicin 800 mg. Monitor CBC weekly for 3 weeks if valrubicin is administered following a suspected bladder rupture or perforation (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
3) Dose-related neutropenia has occurred frequently with intraperitoneal instillation (grade 3 or 4 in over 60% of patients receiving 600 mg/m(2)). Sepsis has been observed. However, neutrophil counts normalized by day 21, enabling repeat doses without interruption (Markman et al, 1996).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) NAIL CHANGES 1) WITH THERAPEUTIC USE a) EPIRUBICIN 1) Nail changes have been reported with the administration of epirubicin (Prod Info ELLENCE(R) IV injection, 2007).
b) IDARUBICIN 1) Pigmentary-changes of the nails has been reported with anthracyclines, including idarubicin, and appear to be related to increased melanin deposition. One case report describes a 20-year-old man with acute myelocytic leukemia who received induction chemotherapy with idarubicin 22 mg for 3 days, cytarabine 180 mg for 7 days, and intrathecal methotrexate on day 1. Hyperpigmentation of the nails was noted following the first course of therapy, and again following the second induction course. However, the bands of pigmentation had completely resolved 5 months after the administration of the last dose of idarubicin (Borecky et al, 1997).
B) ERUPTION 1) WITH THERAPEUTIC USE a) EPIRUBICIN 1) Rash and urticaria have been reported with the administration of epirubicin (Prod Info ELLENCE(R) IV injection, 2007).
2) CASE REPORT: A 58-year-old man developed generalized erythema of the face, trunk, upper and lower limbs 2 days after receiving intravesical instillations of epirubicin in combination with mitomycin C for superficial bladder carcinoma (Okumura et al, 2009).
b) IDARUBICIN 1) Skin rashes have been observed occasionally with idarubicin (Stuart et al, 1988).
2) Urticaria and a bullous erythrodermatous rash of the palms and soles have occurred. Local reactions including hives at the injection site have also been reported. (Prod Info Idarubicin Hydrochloride IV injection, 2007).
c) VALRUBICIN 1) Rash occurred in 3% of patients with transitional cell carcinoma of the bladder who received intravesical valrubicin (n=230). Multiple weekly valrubicin doses (dose range, 200 to 900 mg) were administered to 205 patients; additionally, 179 of these patients received the approved dosage schedule of 800 mg once weekly for multiple weeks (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
C) ALOPECIA 1) WITH THERAPEUTIC USE a) EPIRUBICIN 1) Alopecia has been reported with the administration of epirubicin (Prod Info ELLENCE(R) IV injection, 2007).
2) In studies, alopecia developed in 25% to 100% of patients treated with epirubicin (average incidence, 70%) (Prod Info ELLENCE(R) IV injection, 2007; Cersosimo & Hong, 1986a; Mouridsen et al, 1987; Jain et al, 1985; Macchiarini et al, 1990).
b) IDARUBICIN 1) In studies, alopecia developed in 25% to 30% of patients treated with oral and intravenous idarubicin administration (Weiss et al, 1986; Hurteloup & Ganzina, 1986a; Bonfante et al, 1983; Lopez et al, 1989; Lopez et al, 1986; Ganzina et al, 1986a).
D) PHOTOSENSITIVITY 1) WITH THERAPEUTIC USE a) EPIRUBICIN 1) Photosensitivity has been reported with the administration of epirubicin (Prod Info ELLENCE(R) IV injection, 2007).
E) EXTRAVASATION INJURY 1) WITH THERAPEUTIC USE a) EPIRUBICIN 1) Extravasation injury has been reported with the administration of epirubicin (Prod Info ELLENCE(R) IV injection, 2007; Cersosimo & Hong, 1986a).
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) BACKACHE 1) WITH THERAPEUTIC USE a) VALRUBICIN: Back pain occurred in 3% of patients with transitional cell carcinoma of the bladder who received intravesical valrubicin (n=230). Multiple weekly valrubicin doses (dose range, 200 to 900 mg) were administered to 205 patients; additionally, 179 of these patients received the approved dosage schedule of 800 mg once weekly for multiple weeks (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
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Reproductive |
3.20.1) SUMMARY
A) Epirubicin and idarubicin are classified as FDA pregnancy category D. Valrubicin is classified as FDA pregnancy category C. There are no adequate and well-controlled studies in pregnant women. Both successful pregnancies and adverse fetal outcome have been reported. Embryonic, teratogenic, and fetotoxic effects have been observed in animal reproductive studies. Due to the potential for serious adverse effects to the infant from exposure to these agents, breastfeeding during chemotherapy is not recommended.
3.20.2) TERATOGENICITY
A) LACK OF INFORMATION 1) CHEMOTHERAPY AGENTS a) The teratogenic potential of chemotherapeutic agents is difficult to assess because of the relatively small number of reports, variation in dosages, routes of administration, timing of administration with respect to gestational age, and the variety of combinations of drugs administered. Although fetal exposure to chemotherapy throughout all trimesters of pregnancy has been reported to not induce abnormalities, there is no assurance that deleterious fetal effects will not occur. Exposure during the first trimester is still considered by the majority of practitioners as the most critical for abnormal fetal development (Glantz, 1994).
B) ANIMAL STUDIES 1) EPIRUBICIN a) When epirubicin 2 mg/kg/day IV (approximately 0.1 times the maximum recommended single human dose) was given to rats on day 9 and 10 of gestation, congenital anomalies, such as anal atresia, misshapen tail, abnormal genital tubercle, gastrointestinal, urinary, and cardiovascular malformations, and skeletal malformations (deformed long bones, girdles, rib abnormalities, irregular spinal ossification) were observed. Rabbits given epirubicin 0.2 mg/kg/day (approximately 0.02 times the maximum recommended single human dose) from day 6 to 18 of gestation, did not exhibit teratogenic effects (Prod Info ELLENCE(R) IV injection, 2007).
2) IDARUBICIN a) Teratogenicity occurred in rats administered idarubicin 1.2 mg/m(2)/day (1/10th the human dose), which was nontoxic to dams (Prod Info Idarubicin Hydrochloride IV injection, 2007).
3) VALRUBICIN a) Teratogenicity has been reported in animal studies. Valrubicin 12 mg/kg IV given to rats daily during fetal development resulted in fetal malformations. Doses of 24 mg/kg (approximately 1/3rd the human intravesical dose on a mg/m(2) basis) resulted in multiple, severe alterations of the skull and skeleton of the developing fetuses (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) Epirubicin and idarubicin are classified by the manufacturers as FDA pregnancy category D (Prod Info ELLENCE(R) IV injection, 2007; Prod Info Idarubicin Hydrochloride IV injection, 2007)
2) Valrubicin is classified by the manufacturer as FDA pregnancy category C (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009)
B) EPIRUBICIN 1) CASE REPORT: A case of unintentional pregnancy during epirubicin treatment is reported by the manufacturer. A 34-year-old woman was treated with FEC-50 (5-fluorouracil, epirubicin, and cyclophosphamide) during the first trimester of pregnancy. The infant was spontaneously aborted (Prod Info ELLENCE(R) IV injection, 2007).
C) IDARUBICIN 1) CASE REPORT: One fetal fatality following maternal exposure to idarubicin occurred during the second trimester (Reynoso & Huerta, 1994; Prod Info Idarubicin Hydrochloride IV injection, 2007).
2) CASE REPORT: A 23-year-old woman at 22 weeks gestation was diagnosed with acute lymphoblastic leukemia and received induction polychemotherapy which included idarubicin. Elective delivery at 28 weeks was performed prior to consolidation therapy. Despite obvious birth complications related to prematurity (e.g., respiratory distress syndrome, necrotizing enterocolitis, and grade II ventricular hemorrhage), the neonate had acute cardiac failure (during the first 3 days of life) which the authors attributed to chemotherapy, especially idarubicin. At 18 months, the child had a delay in language acquisition, but neurologic function appeared normal (Achtari & Hohlfeld, 2000).
3) CASE REPORT: An infant, born to a woman who received idarubicin and cytosine arabinoside (Ara-C) during the second and third trimesters of pregnancy, had no structural congenital abnormalities at birth. The mother was diagnosed with acute myeloid leukemia during gestational week 21. She received idarubicin 10 mg/m(2) on days 1, 3, and 5, and Ara-C 100 mg/m(2) on days 1 through 10. Consolidation therapy with Ara-C 1000 mg/m(2) every 12 hours on days 1 through 6 was initiated in gestational week 27. The infant was delivered at a gestational age of 33 weeks; observed adverse effects in the newborn included: prematurity, growth retardation, mildly disturbed transaminases, and erythroblastosis, all of which were self-limiting and presented no permanent sequelae (Claahsen et al, 1998).
D) VALRUBICIN 1) Valrubicin can cause fetal harm when administered systemically to a pregnant woman, or after perforation of the urinary bladder during therapy (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
E) LACK OF EFFECT 1) EPIRUBICIN a) CASE REPORT: One case report described a 33-year old patient treated with 5 courses of FEC regimen (5-fluorouracil 600 mg/m(2), epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks) during the first 28 weeks of pregnancy, who subsequently delivered a healthy infant at week 35 of gestation. She was not pregnant when she was diagnosed with locally advanced malignant neoplasm of the left breast. After complaining of dilatation of the abdomen and bloating, an ultrasound showed pregnancy of 28 weeks gestation. The 2070 g infant was delivered by cesarian section without any complications, and was developing normally at 1 year of age (Andreadis et al, 2004).
b) CASE REPORT: A case of unintentional pregnancy during epirubicin treatment is reported by the manufacturer. A 34-year-old patient at 28 weeks gestation was started on epirubicin and cyclophosphamide for breast cancer. She received treatment every three weeks for three cycles. Her last dose was administered at 34 weeks, and she delivered a healthy infant at 35 weeks (Prod Info ELLENCE(R) IV injection, 2007).
F) ANIMAL STUDIES 1) EPIRUBICIN a) Epirubicin 0.8 mg/kg/day IV (approximately 0.04 times the maximum recommended single human dose) given to rats from day 5 to 15 of gestation resulted in increased fetal resorption and loss and decreased body weight. When 2 mg/kg/day IV (approximately 0.1 times the maximum recommended single human dose) was given to rats on day 9 and 10 of gestation, similar embryotoxicity, retarded fetal growth, and decreased placental weight were observed. In rabbits, doses of 0.32 mg/kg/day were maternally toxic and resulted in delayed ossification and increased abortions. Increasing the dose to 1 mg/kg/day on days 10 to 12 of gestation increased spontaneous abortion in rabbits (Prod Info ELLENCE(R) IV injection, 2007).
2) IDARUBICIN a) Embryotoxicity occurred in rats administered idarubicin at a dose of 1.2 mg/m(2)/day (1/10th the human dose), which was nontoxic to dams. Embryotoxicity occurred in rabbits administered idarubicin at a dose of 2.4 mg/m(2)/day (2/10th the human dose), which was toxic to dams (Prod Info Idarubicin Hydrochloride IV injection, 2007).
3) VALRUBICIN a) Embryotoxicity has been reported in animal studies. Valrubicin doses of 24 mg/kg (approximately 1/3rd the human intravesical dose on a mg/m(2) basis) resulted in an increase in fetal resorptions and a decrease in viable fetuses (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) LACK OF INFORMATION 1) EPIRUBICIN a) No reports describing the use of epirubicin during human lactation or measuring the amount, if any, of the drug excreted into milk have been located. Until more data are available, nursing should be discontinued during chemotherapy (Prod Info ELLENCE(R) IV injection, 2007).
2) IDARUBICIN a) The effects on the nursing infant from exposure to chemotherapy drugs in milk are unknown. Until more data are available, nursing should be discontinued during chemotherapy (Prod Info Idarubicin Hydrochloride IV injection, 2007).
3) VALRUBICIN a) It is unknown whether valrubicin is excreted in human milk; however, valrubicin is highly lipophilic and any exposure of infants could pose serious health risks. Breastfeeding should be discontinued prior to initiation of therapy with valrubicin (Prod Info VALSTAR(TM) intravesical instillation sterile solution, 2009).
B) ANIMAL STUDIES 1) Epirubicin was found in the milk of rats administered 0.5 mg/kg/day prior to and following pregnancy (Prod Info ELLENCE(R) IV injection, 2007).
3.20.5) FERTILITY
A) ANIMAL STUDIES 1) EPIRUBICIN a) When epirubicin 0.3 mg/kg/day (approximately 0.015 times the maximum recommended human dose on a body surface area basis) was administered daily to male and female rats during the mating cycle through day 7 of gestation, no pregnancies resulted. At a dose of 0.1 mg/kg/day, male rats developed atrophy of the testes, epididymis, and reduced spermatogenesis. Embryolethality was observed at a dose of 0.1 mg/kg/day and an increased incidence of fetal growth retardation was observed at a dose of 0.03 mg/kg/day (approximately 0.0015 times the maximum recommended human dose on a body surface area basis). Uterine atrophy was observed following a single epirubicin dose of 16.7 mg/kg. Male rabbits and dogs administered multiple daily doses of epirubicin experienced atrophy of the reproductive organs. A single 20.5 mg/kg dose administered to mice and 12 mg/kg administered to rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis) resulted in testicular atrophy (Prod Info ELLENCE(R) IV injection, 2007).
2) IDARUBICIN a) Idarubicin caused testicular atrophy (with inhibition of spermiogenesis and sperm maturation with few or no mature sperm) in male dogs given idarubicin doses of 1.8 mg/m(2)/day 3 times a week (approximately 1/7 of the weekly human dose on a body surface area basis) for 13 weeks. Effects were not readily reversible after an 8-week recovery period (Prod Info Idarubicin Hydrochloride IV injection, 2007).
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) At the time of this review, the manufacturer does not report any carcinogenic potential of valrubicin in humans. However, epirubicin-based adjuvant chemotherapy has caused acute myelogenous leukemia in women. Idarubicin was found to be carcinogenic in experimental models.
3.21.3) HUMAN STUDIES
A) EPIRUBICIN 1) Epirubicin-based adjuvant chemotherapy has caused acute myelogenous leukemia in women (Prod Info ELLENCE(R) intravenous injection , 2014).
2) The development of secondary acute myelogenous leukemia has been reported in breast cancer patients (n=7110) treated with adjuvant epirubicin-containing regimens. The cumulative risk of secondary acute myelogenous leukemia or myelodysplastic syndrome (AML/MDS) in patients who received adjuvant epirubicin therapy as a component of polychemotherapy regimens was approximately 0.27% (95% CI, 0.14 to 0.40) at 3 years, 0.46% (95% CI, 0.28 to 0.65) at 5 years, and 0.55% (95% CI, 0.33 to 0.78) at 8 years. Higher epirubicin doses were associated with an increased risk of the development of AML/MDS (Prod Info ELLENCE(R) intravenous injection , 2014).
3.21.4) ANIMAL STUDIES
A) EPIRUBICIN 1) No long-term animal studies of epirubicin have been conducted; however, the incidence of mammary tumors, particularly fibroadenomas, approximately doubled when a single epirubicin 3.6 mg/kg IV dose (approximately 0.2 times the maximum human dose based on body surface area) was administered to female rats. An increased incidence in subcutaneous fibromas was observed in male rats when epirubicin 0.5 mg/kg IV (approximately 0.025 times the maximum human dose based on body surface area) was administered every 3 weeks for 10 doses over an 18-month period. In a 24-month study, an increased incidence of animal tumors was observed in newborn rats administered subcutaneous epirubicin for 4 days (on the first and tenth day) at a dose of 0.75 or 1 mg/kg/day (approximately 0.015 times the maximum human dose based on body surface area) for a total of 8 doses compared with controls (Prod Info ELLENCE(R) intravenous injection , 2014).
B) IDARUBICIN 1) No long-term studies of idarubicin have been conducted; however, carcinogenic effects were observed in female Sprague-Dawley rats (Prod Info Idamycin PFS(R) intravenous injection solution, 2014).
C) VALRUBICIN 1) The carcinogenic potential of valrubicin has not been examined; however, the drug damaged DNA in vitro (Prod Info VALSTAR(R) intravesical instillation solution, 2015).
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Genotoxicity |
A) EPIRUBICIN
1) Epirubicin was mutagenic or clastogenic in the Ames test with or without metabolic activation, HGPRT assay in V79 Chinese hamster lung fibroblast in the absence of metabolic activation, in vitro chromosome aberration in human lymphocytes with or without metabolic activation, and the in vivo chromosome aberration in mouse bone marrow (Prod Info ELLENCE(R) intravenous injection , 2014).
B) IDARUBICIN
1) Idarubicin was mutagenic in bacterial systems, mammalian cells, and female Sprague-Dawley rats (Prod Info Idamycin PFS(R) intravenous injection solution, 2014).
C) VALRUBICIN
1) Valrubicin was mutagenic or clastogenic in the following tests: in vitro assays in Salmonella typhimurium and Escherichia coli, and chromosomal aberration assay in CHO cells (Prod Info VALSTAR(R) intravesical instillation solution, 2015).
2) Valrubicin is positive for DNA damage in vitro (Prod Info VALSTAR(R) intravesical instillation solution, 2015).
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