DOXORUBICIN

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) 3-hydroxyacetyldaunorubicin
2) 14-hydroxydaunomycin
3) 14-hydroxydaunorubicin hydrochloride
4) ADM
5) ADR
6) Adriblastin
7) Adriblastina
8) Adriamycin
9) Adriamycin hydrochloride
10) DOXOrubicin hydrochloride
11) Doxoubicina
12) Doxorubicine
13) Doxorubicinium
14) DX
15) FI-106
16) NSC 123127
17) NDC 38242-874
18) KW-125
19) CAS 23214-92-8 (doxorubicin)
20) CAS 25316-40-9 (doxorubicin hydrochloride)

1.2.1) MOLECULAR FORMULA
1) C27-H29-N-O11-HCl (Prod Info ADRIAMYCIN intravenous injection, 2006)

Available Forms Sources

1) DOXOrubicin is available in the United States as 2 mg/mL IV solution (10 mg/5 mL, 20 mg/10 mL, 50 mg/25 mL, 150 mg/75 mL, 200 mg/100 mL) or 10, 20, 50, and 150 mg IV powder for solution (Prod Info doxorubicin HCl intravenous injection, 2013).
2) Liposomal DOXOrubicin is available as 2 mg/mL IV solution (single dose vials; 20 mg/10 mL and 50 mg/25 mL) (Prod Info DOXIL(R) intravenous injection, 2015a).

1) DOXOrubicin is an antineoplastic agent used in the treatment of a wide range of cancers, including leukemias, lymphoma, sarcomas, neuroblastoma, Wilms' tumor, and malignant neoplasms of the bladder, breast, lung, ovaries, gastric, and thyroid (Prod Info doxorubicin HCl intravenous injection, 2013). Liposomal DOXOrubicin is used to treat ovarian cancer, AIDS-related Kaposi's sarcoma, and multiple myeloma (Prod Info DOXIL(R) intravenous injection, 2015a).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: DOXOrubicin is an antineoplastic agent used in the treatment of a wide range of cancers, including leukemias, lymphomas, sarcomas, neuroblastoma, Wilms' tumor, and malignant neoplasms of the bladder, breast, lung, ovary, gastric, and thyroid. Liposomal DOXOrubicin is used to treat ovarian cancer, AIDS-related Kaposi's sarcoma, and multiple myeloma.
B) PHARMACOLOGY: DOXOrubicin is a cytotoxic anthracycline antibiotic thought to act on malignant cells by intercalating the cell nucleotide base and binding the cell membrane lipid. Intercalation blocks replication of nucleotide and action of DNA and RNA polymerases. It also interacts with topoisomerase II to form DNA-cleavable complexes, which is believed to be an important mechanism of its cytocidal activity. DOXOrubicin encapsulated in sterically-stabilized liposomes (Stealth(R) liposomes) has been shown to efficiently penetrate solid tumors. This is attributed in part to their small size and prolonged circulation time; a long blood-survival time appears required for sufficient uptake. Following distribution of liposomes to the tissue compartment, free DOXOrubicin is released, although the precise mechanism for this effect is unclear. DOXOrubicin is extensively metabolized in the liver.
C) TOXICOLOGY: DOXOrubicin interferes with DNA replication in rapidly dividing cells, such as bone marrow and gastrointestinal epithelium. Cardiac toxicity of DOXOrubicin may be related to free radical production.
D) EPIDEMIOLOGY: Overdose is rare.
E) WITH THERAPEUTIC USE

1) Delayed cardiomyopathy is the dose-limiting toxicity of DOXOrubicin. ACUTE: Acute cardiac toxicity usually presents as transient dysrhythmias, especially sinus tachycardia. These effects usually appear on an ECG as nonspecific ST-T changes, decreased QRS voltage, and a prolonged QT interval. Premature ventricular contractions, ventricular tachycardia, bradycardia, atrioventricular, and bundle-branch block have also been reported in patients receiving DOXOrubicin. Acute effects usually occur within 24 to 48 hours after a single dose or course of anthracycline therapy. SUBACUTE: DOXOrubicin-induced cardiotoxicity may occur late in the course of therapy or within 2 to 3 months after treatment discontinuation. A reduction in left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (eg, tachycardia, dyspnea, pulmonary edema, dependent edema, cardiomegaly, hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm) may also occur. DELAYED/LATE: The chronic cardiomyopathy related to the cumulative dose of DOXOrubicin is characterized by congestive heart failure. The risk of left ventricular failure increases rapidly following total cumulative doses above 550 mg/m(2). However, heart failure may also occur with lower (400 mg/m(2)) doses, especially in patients who have received radiotherapy to the mediastinal area or concomitant therapy with other cardiotoxic agents (eg, cyclophosphamide).
2) Bone marrow suppression is the acute dose-limiting toxicity. Nausea, vomiting, mucositis, and alopecia are common with therapeutic use. Secondary malignancies, primarily acute myelogenous leukemia and myelodysplastic syndrome have been reported.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Nausea, vomiting, diarrhea, stomatitis, and severe myelosuppression have been reported following DOXOrubicin overdose.
2) SEVERE TOXICITY: Severe bone marrow suppression, acute cardiomyopathy (ie, ECG changes, dysrhythmias, heart failure, hypotension), severe mucositis, vomiting, and diarrhea may develop.
3) INTRATHECAL INJECTION: Severe neurotoxicity (ie, paraparesis, coma, acute hydrocephalus), and death have been reported after unintentional intrathecal administration of DOXOrubicin.
4) EYE EXPOSURE: Splash exposures have caused self limited conjunctivitis and rarely corneal infiltrates and iritis.
5) DERMAL EXPOSURE: Generally causes no toxicity, or self limited irritation that resolves rapidly. DOXOrubicin is a vesicant; ulceration and skin necrosis can occur with extravasation.

0.2.20)

A) DOXOrubicin is classified as FDA pregnancy category D. There are no adequate and well-controlled studies with DOXOrubicin in pregnant women. Both successful pregnancies and adverse fetal outcome have been reported after DOXOrubicin was used as part of combination chemotherapy. Embryotoxic, teratogenic, or fetotoxic effects have been observed in animal reproductive studies of DOXOrubicin.

0.2.21)

A) DOXOrubicin has the potential to cause acute myelogenous leukemia and other neoplasms in children. DOXOrubicin-containing combination chemotherapy regimens have caused secondary acute myelogenous leukemia or myelodysplastic syndrome and DOXOrubicin liposome has been associated with secondary oral cancers.

Laboratory Monitoring

Treatment Overview

0.4.4)

A) Irrigate eyes with 0.9% saline or water. Perform an eye exam, including slit lamp, if irritation persists.

0.4.5)

A) OVERVIEW

1) Wash exposed skin well with soap and water and remove contaminated clothing.

0.4.6)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is symptomatic and supportive. Monitor for signs of congestive heart failure. Treat nausea and vomiting with several antiemetics of different classes. Administer dexrazoxane to prevent cardiomyopathy. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treatment is symptomatic and supportive. Monitor for signs of congestive heart failure. Dexrazoxane should be used for the prophylaxis of cardiomyopathy and to treat extravasation. Treat patients with heart failure with diuretics, digoxin or inotropic agents as indicated. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes.

C) INTRATHECAL INJECTION

1) Inadvertent intrathecal injection has been reported with DOXOrubicin in a small number of cases, resulting in severe neurologic toxicity. After an overdose, keep the patient upright and immediately drain at least 20 mL of CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 24 hours). Add fresh frozen plasma (25 mL FFP to 1 L NS or LR) or 5% albumin to the perfusate to enhance removal as DOXOrubicin is highly protein bound. Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.

D) DECONTAMINATION

1) Decontamination is not necessary in most situations as DOXOrubicin is administered IV. For dermal exposures, cleanse skin with soap and water, and for eye exposures, flush with water.

E) AIRWAY MANAGEMENT

1) Intubate if patient is unable to protect airway or if unstable dysrhythmias develop.

F) ANTIDOTE

1) There is no antidote, but dexrazoxane should be administered as soon as possible to prevent cardiotoxicity and to treat extravasation.

G) MYELOSUPPRESSION

1) Administer colony stimulating factors following a significant overdose as these patients are at risk for severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.

H) NEUTROPENIA

1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).

I) FEBRILE NEUTROPENIA

1) If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.

J) NAUSEA AND VOMITING

1) Treat severe nausea and vomiting with agents from several different classes. For example: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).

K) EXTRAVASATION

1) If extravasation occurs, stop the infusion. Disconnect the IV tubing, but leave the cannula or needle in place. Attempt to aspirate the extravasated drug from the needle or cannula. If possible, withdraw 3 to 5 mL of blood and/or fluids through the needle/cannula. Administer dexrazoxane (see dosing below). Elevate the affected area. Apply ice packs for 15 to 20 minutes at least 4 times daily for 3 days. Stop cooling procedures at least 15 minutes prior to and during dexrazoxane administration to allow sufficient blood flow. Administer analgesia for severe pain. If pain persists, there is concern for compartment syndrome, or injury is apparent, an early surgical consult should be considered. Close observation of the extravasated area is suggested. If tissue sloughing, necrosis or blistering occurs, treat as a chemical burn (ie, antiseptic dressings, silver sulfadiazine, antibiotics when applicable). Surgical or enzymatic debridement may be required. Risk of infection is increased in chemotherapy patients with reduced neutrophil count following extravasation. Consider culturing any open wounds. Monitor the site for the development of cellulitis, which may require antibiotic therapy.

a) DEXRAZOXANE: DOSE: The initial dose is 1000 mg/m(2) infused intravenously using a different venous access site over 1 to 2 hours on day 1 (MAX, 2000 mg). Treatment should occur within 6 hours of extravasation. Repeat the same dose 24 +/- 3 hours after extravasation on day 2 (MAX, 2000 mg) followed by a 500 mg/m(2) dose 48 +/- 3 hours after extravasation on day 3 (MAX, 1000 mg).

L) DEXRAZOXANE

1) Dexrazoxane is used to prevent cardiomyopathy at therapeutic doses. There is no published clinical experience after overdose, but it should be administered as soon as possible if the DOXOrubicin overdose is recognized early. If the DOXOrubicin overdose is not recognized early, there is probably little benefit to administering dexrazoxane. The usual dose of dexrazoxane to prevent cardiomyopathy is 10 times the DOXOrubicin dose (ie, 500 mg/m(2) dexrazoxane for a 50 mg/m(2) dose of DOXOrubicin). Additive myelosuppression generally occurs at dexrazoxane doses above 1000 mg/m(2), so doses larger than this should generally be avoided.
2) For extravasation, the initial dose is 1000 mg/m(2) infused over 1 to 2 hours on day 1 (MAX, 2000 mg) and should be given within 6 hours of extravasation. Repeat the same dose 24 +/- 3 hours after extravasation on day 2 (MAX, 2000 mg) followed by a 500 mg/m(2) dose 48 +/- 3 hours after extravasation on day 3 (MAX, 1000 mg).

M) MUCOSITIS

1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. It has not been studied after overdose of chemotherapy agents. In patients with DOXOrubicin overdose, consider administering palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.

N) ENHANCED ELIMINATION

1) Dialysis is UNLIKELY to be of benefit due to high protein binding and large volume of distribution. Early use of hemoperfusion may increase the clearance of DOXOrubicin. Early plasma exchange would be expected remove significant amounts of liposomal DOXOrubicin, but there are no published overdose cases in which this has been performed.

O) PATIENT DISPOSITION

1) HOME CRITERIA: There is no data to support home management.
2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), cardiac function, and daily monitoring of CBC with differential until bone marrow suppression is resolved.
3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with DOXOrubicin overdose. Consult a cardiologist to manage patients with heart failure. May require surgical consult for extravasation.
4) TRANSFER CRITERIA: Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.

P) PITFALLS

1) Symptoms of overdose are similar to reported side effects of the medication. Symptoms in patients may be delayed (particularly myelosuppression and cardiomyopathy) so reliable follow up is imperative. Patients taking these medications may have severe co-morbidities and may be receiving other drugs with significant toxicity.

Q) PHARMACOKINETICS

1) Protein binding approximately 75%; Vd: 809 L/m(2) to 1214 L/m(2); the Vd for liposomal DOXOrubicin is considerably smaller; elimination half-life: 20 to 48 hours; liposomal DOXOrubicin: 45 to 55 hours. Extensive hepatic metabolism. Excretion: 50% feces, 40% bile and 5% to 12% renal.

R) DIFFERENTIAL DIAGNOSIS

1) Includes other agents that cause myelosuppression or cardiotoxicity.

S) RISK FACTORS

1) The primary risk factor for delayed cardiomyopathy is high cumulative doses of DOXOrubicin. Other risk factors include: mediastinal radiation, use of other cardiotoxic drugs, advanced age, preexisting heart disease, and hypertension. Patients with some of these risk factors may develop toxicity at lower cumulative doses. Women and patients who were treated at a younger age may also be at increased risk.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) OPTIC NEURITIS: In 4 studies of 753 patients with AIDS-related Kaposi's sarcoma who were treated with the recommended dose of 20 mg/m(2) every 2 to 3 weeks, adverse reactions, including optic neuritis, led to the discontinuation of treatment in 5% of patients. The cumulative dose was greater than 450 mg/m(2) in 26 (3%) of patients (Prod Info DOXIL(R) IV injection, 2008).

B) WITH POISONING/EXPOSURE

1) IRITIS AND CORNEAL CHANGES: Accidental instillation of DOXOrubicin into the external eye produced iritis and corneal changes in a 30-year-old nurse. The conjunctival infiltrate improved markedly following treatment with dexamethasone and homatropine eye drops. Photophobia persisted for 6 weeks. There were no changes in visual acuity or tension (Curran & Luce, 1989a; Wertenbaker, 1987).
2) CONJUNCTIVITIS may occur (Dorr & Fritz, 1980). Splash contact exposure to DOXOrubicin was followed by no reaction or rapidly resolving conjunctivitis in 13 of 15 cases in one study (Curran & Luce, 1989).
3) Excessive tearing may be noted (Dorr & Fritz, 1980).
4) ANIMAL STUDIES: In rabbit studies, instillation of 0.1% eyedrops caused irritation and corneal epithelial defects, and interstitial opacities when given 3 times a day for 3 days (Grant & Schuman, 1993).
5) CORNEAL INFILTRATE/IRITIS

a) CASE REPORT: Burning, tearing, and a sensation of numbness and strain were reported following splash contact of 0.5 mL of DOXOrubicin into the eye. Cellular infiltrates of the anterior corneal stroma were reported on slit lamp examination. Treatment for iritis was initiated with topical dexamethasone sodium phosphate (1 drop 4 times daily) and homatropine to dilate the pupil. Improved patient comfort and clinical were noted with this treatment. Some complaint of residual photophobia and mild aching of the pupil when it was not dilated was reported 6 weeks after the incident (Wertenbaker, 1987a).

6) CASE SERIES: In 2 of 15 cases of splash contact to DOXOrubicin, persistent photophobia and chronic inflammation occurred (Curran & Luce, 1989).

Cardiovascular

3.5.2)

A) CARDIOMYOPATHY

1) WITH THERAPEUTIC USE

a) ACUTE

1) Acute cardiac toxicity usually presents as transient dysrhythmias, especially sinus tachycardia. These effects usually appear on an ECG as nonspecific ST-T changes, decreased QRS voltage, and a prolonged QT interval. Premature ventricular contractions, ventricular tachycardia, bradycardia, atrioventricular, and bundle-branch block have also been reported in patients receiving DOXOrubicin. Acute left ventricular failure, pericarditis, and a fatal pericarditis-myocarditis syndrome have rarely been reported. Acute effects usually occur within 24 to 48 hours after a single dose or course of anthracycline therapy (Prod Info ADRIAMYCIN intravenous injection, 2006; Shan et al, 1996). Since most acute effects resolve spontaneously, further anthracycline treatment is NOT contraindicated (Prod Info ADRIAMYCIN intravenous injection, 2006; Cortes, 1975).
2) CASE REPORTS: A 36-year-old woman with metastatic leiomyosarcoma developed a syncopal attack that lasted a few seconds after receiving DOXOrubicin during the first cycle of chemotherapy. During the second cycle of chemotherapy, she experienced another transient syncopal attack. An ECG showed second degree possibly Mobitz type II atrioventricular block, and complete atrioventricular block lasting for 12 seconds. A permanent pacemaker was implanted and the chemotherapy regimen was changed to cisplatin and etoposide (Kilickap et al, 2005).

b) SUBACUTE

1) DOXOrubicin-induced cardiotoxicity may occur late in the course of therapy or within 2 to 3 months after treatment discontinuation. A reduction in left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (eg, tachycardia, dyspnea, pulmonary edema, dependent edema, cardiomegaly, hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm) may also occur (Prod Info ADRIAMYCIN intravenous injection, 2006).
2) Toxic myocarditis and pericarditis may occur within days or weeks of treatment, and may be fatal (Bristow, 1982).
3) Perimyocarditis occurs infrequently and is associated with single high doses of DOXOrubicin (Bristow, 1982).

c) DELAYED/LATE

1) The chronic cardiomyopathy related to the cumulative dose of DOXOrubicin is characterized by congestive heart failure that may be unresponsive to digitalis cardiac glycoside (Gilman et al, 1985). Symptoms of congestive heart failure may not appear in the patient for months or years following treatment (Freter et al, 1986). The risk of congestive heart failure increases rapidly at cumulative lifetime doses above 400 mg/m(2) (Prod Info ADRIAMYCIN intravenous injection, 2006). Heart failure may also occur after the discontinuation of anthracycline therapy (Prod Info DOXIL(R) IV injection, 2008). Complete clinical recovery has been reported in patients with well-documented severe left ventricular dysfunction due to DOXOrubicin (Saini et al, 1987).
2) LOWER DOSES: One study suggested that congestive heart failure begins at lower doses than previously indicated, such as 300 mg/m(2), and can be reversible or manageable (Swain, 1999). Likewise, a study of lung cancer patients given DOXOrubicin reported a decline in ejection fraction (between 16% to 45%) following doses of 91 to 180 mg/m(2) (average 143) of DOXOrubicin. However, only 5 of the 13 patients developed symptoms attributable to cardiac disease (Siddiqui & Burney, 1998).
3) INCIDENCE

a) The incidence of cardiac failure with DOXOrubicin has been estimated to be 3% to 4% with a cumulative dose of 450 mg/m(2) and up to 18% following a cumulative dose of 700 mg/m(2). Peak incidence occurs 1 to 3 months after the last dose, and has occurred as late as 20 years after treatment (Fisher & Marshall, 1999). In another study (n=2,631), the probability of congestive heart failure rose from 3% at a total dose of 400 mg/m(2) to 50% at 1000 mg/m(2) (von Hoff et al, 1979).
b) PEDIATRICS: Clinical cardiotoxicity developed in 1.6% (106 of 6493) of patients treated with an anthracycline and entered into Pediatric Oncology Group (POG) protocols between 1974 and 1990. Of the 106 children, 58 developed CHF, 43 developed changes in cardiac function which resulted in early termination of anthracycline therapy, and 5 died due to cardiac causes presumably related to treatment. Cardiac events occurred during therapy or within the first year in 95 of 106 children. Significant increases in risk were associated with black race, female sex, the presence of trisomy 21, Ewing's sarcoma, acute nonlymphocytic leukemia, T-cell leukemia, high cumulative dose of anthracycline (greater than 550 milligrams/square meter), and high, single doses (Krischer et al, 1997).

4) RISK FACTORS

a) The primary risk factor for delayed cardiomyopathy is high cumulative doses of DOXOrubicin. Other risk factors include: mediastinal radiation, use of other cardiotoxic drugs, advanced age, preexisting heart disease, and hypertension. Patients with some of these risk factors may develop toxicity at lower cumulative doses. Women and patients who were treated at a younger age may also be at increased risk (Shan et al, 1996).

5) CASE REPORT: A 26-year-old woman with DOXOrubicin-induced cardiac toxicity (congestive heart failure with decreased ejection fraction of 23%) developed a stroke approximately 5 months after the 4th cycle of a combination chemotherapy regimen (DOXOrubicin, bleomycin, vinblastine, and dexamethasone). She presented with a left-sided hemiplegia, and a head MRI revealed a cerebral infarction due to right middle cerebral artery occlusion (Kara et al, 2009).
6) CASE SERIES: Fatal heart failure occurred in one of 34 Kaposi's sarcoma patients treated with DOXOrubicin hydrochloride liposome 20 mg/m(2) every 3 weeks (total dose 76 mg); however, a contribution of HIV-related cardiomyopathy cannot be excluded (Harrison et al, 1995).

d) LIPOSOMAL DOXORUBICIN

1) In a clinical study of patients (n=250) with advanced breast cancer who received cumulative anthracycline doses between 450 to 500 mg/m(2) or between 500 to 550 mg/m(2), the risk of cardiac toxicity for patients treated with liposomal DOXOrubicin was 11%. Cardiotoxicity was defined as a decrease of more than 20% from the baseline if the left ventricular ejection fraction (LVEF) remained in the normal range, or a decrease greater than 10% if the resting LVEF became abnormal (less than the institutional lower limit of normal) (Prod Info DOXIL(R) IV injection, 2008).
2) In a randomized, multicenter, open-label study of 318 multiple myeloma patients, the incidence of heart failure events (ventricular dysfunction, cardiac failure, right ventricular heart failure, congestive cardiac failure, acute pulmonary edema and pulmonary edema) was 3% in each group. DOXOrubicin hydrochloride liposome (30 mg/m(2) over 1 hour) was administered on day 4 following bortezomib (1.3 mg/m(2) IV bolus on days 1, 4, 8 and 11) every 3 weeks. Left ventricular ejection fraction (LVEF) decrease was defined by an absolute decrease of greater than or equal to 15% over baseline or a decrease of greater than or equal to 5% below the institutional lower limit of normal. A reduction in LVEF was observed in 25 (8%) patients in the bortezomib arm and 42 (13%) patients in the DOXOrubicin hydrochloride liposome plus bortezomib arm (Prod Info DOXIL(R) IV injection, 2008).
3) In a small study (n=45) of women with metastatic breast cancer who received DOXOrubicin, only one patient developed cardiac toxicity who had a past history of mitoxantrone and mediastinal radiotherapy (Lyass et al, 2000).

e) RISK FACTORS

1) Patients with one or more of the following may be at substantially greater risk for developing cardiomyopathy (Prod Info DOXIL(R) IV injection, 2008; Perez, 2001; Singal & Iliskovic, 1998; Watts, 1991; DeVita et al, 1989; Unverferth, 1984; Bristow, 1982):

a) Mediastinal radiotherapy
b) Age greater than 70 years
c) Cumulative anthracycline dose greater than 400 mg/m(2)
d) Co-morbidity (ie, hypertension, liver disease, previous cardiac disease (coronary, valvular, or myocardial))
e) Whole-body hyperthermia
f) Use of other cytotoxic agents (eg, cyclophosphamide)

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A patient who was administered DOXOrubicin 333 mg/m(2) (a 10-fold overdose) died within 24 hours. Treatment was not reported. An autopsy showed lung edema, bilateral pleural effusions, and strikingly pale myocardium with a markedly dilated left ventricle (Curran, 1991).
b) Two of 12 patients developed heart failure following DOXOrubicin overdose (Curran, 1991).

B) MYOCARDIAL INFARCTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: Acute cardiac toxicity (severe chest pain and myocardial infarction) occurred in a 60-year-old man with preexisting heart disease receiving continuous infusion DOXOrubicin (9 mg/m(2)/day) and vincristine. Myocardial infarction occurred on 2 occasions, 48 and 72 hours after initiation of therapy (Carter & Bergin, 1986).

Respiratory

3.6.2)

A) COUGH

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN

1) In a randomized, open-label, multicenter study of 318 patients with multiple myeloma, 18% of patients developed cough after treatment with DOXOrubicin hydrochloride liposome (30 mg/m(2) administered on day 4 following bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 every 3 weeks) (Prod Info DOXIL(R) IV injection, 2008).
2) In a randomized, multicenter, open-label study of 239 ovarian cancer patients treated with DOXOrubicin hydrochloride liposome (50 mg/m(2) every 4 weeks) for a minimum of 4 courses, 9.6% of patients experienced increased cough (all grades) (Prod Info DOXIL(R) IV injection, 2008).

B) PNEUMONIA

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN: In a randomized, multicenter, open-label study of 239 ovarian cancer patients treated with DOXOrubicin hydrochloride liposome (50 mg/m(2) every 4 weeks) for a minimum of 4 courses, 1% to 10% of patients experienced pneumonia (Prod Info DOXIL(R) IV injection, 2008).

C) RESPIRATORY FINDING

1) WITH THERAPEUTIC USE

a) Severe systemic reactions including nasal congestion, tachypnea, and dyspnea have occurred following intravesicular instillation of DOXOrubicin (Crawford et al, 1986a).

Neurologic

3.7.2)

A) NEUROTOXICITY

1) WITH POISONING/EXPOSURE

a) INTRATHECAL ADMINISTRATION

1) CASE REPORT: A 12-year-old girl with acute lymphoblastic leukemia was inadvertently given 30 mg/m(2) of DOXOrubicin intrathecally, and developed encephalopathy with severe tetraventricular hydrocephalus within 2 weeks of exposure. A ventriculoperitoneal shunt was placed, and no residual neuropathy occurred (Trinkle & Wu, 1996; Arico et al, 1990).
2) CASE REPORT/INTRATHECAL: A 31-year-old woman with aggressive lymphoblastic lymphoma was inadvertently given 14.5 mg of DOXOrubicin intrathecally (instead of methotrexate), and developed hypoesthesia, paraparesis, and incontinence within a week of exposure, despite immediate cerebrospinal fluid exchange at a rate of 20 cm(3)/hour for a total of 500 cm(3) . The patient's clinical course progressed to complete flaccid paraplegia within 20 days. She was transferred to a rehab center and developed tetraventricular hydrocephaly likely due to adhesive arachnoiditis 7 weeks after exposure. The patient received 7 months of intensive rehab and was able to walk alone for short distances with crutches, and learned how to complete most of her prior activities of daily living (Jordan et al, 2004).

B) ASTHENIA

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN

1) In a randomized, multicenter, open-label study of 239 ovarian cancer patients treated with DOXOrubicin hydrochloride liposome (50 mg/m(2) every 4 weeks) for a minimum of 4 courses, 40.2% of patients experienced asthenia (Prod Info DOXIL(R) IV injection, 2008).
2) In a randomized, open-label, multicenter study of 318 patients with multiple myeloma, 22% of patients developed asthenia after treatment with DOXOrubicin hydrochloride liposome (30 mg/m(2) administered on day 4 following bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 every 3 weeks) (Prod Info DOXIL(R) IV injection, 2008).

C) FATIGUE

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN: In a randomized, multicenter, open-label study of 318 multiple myeloma patients, the incidence of fatigue was 36% in the DOXOrubicin hydrochloride liposome plus bortezomib group with 6% experiencing grade 3 fatigue and 1% experiencing grade 4 fatigue. DOXOrubicin hydrochloride liposome (30mg/m(2) over 1 hour) was administered on day 4 following bortezomib (1.3 mg/m(2) intravenous bolus on days 1, 4, 8 and 11) every 3 weeks. In the bortezomib arm, 28% of patients reported any grade of fatigue and 3% reported grade 3 fatigue (Prod Info DOXIL(R) IV injection, 2008).

D) HEADACHE

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN: In a randomized, multicenter, open-label study of 239 ovarian cancer patients treated with DOXOrubicin hydrochloride liposome (50 mg/m(2) every 4 weeks) for a minimum of 4 courses, 10.5% of patients experienced headache (Prod Info DOXIL(R) IV injection, 2008).

E) DISORDER OF THE PERIPHERAL NERVOUS SYSTEM

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN: In a randomized, open-label, multicenter study of 318 patients with multiple myeloma, 42% of patients developed peripheral neuropathy after treatment with DOXOrubicin hydrochloride liposome (30 mg/m(2) administered on day 4 following bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 every 3 weeks) (Prod Info DOXIL(R) IV injection, 2008).

F) NEURALGIA

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN: In a randomized, open-label, multicenter study of 318 patients with multiple myeloma, 17% of patients developed neuralgia after treatment with DOXOrubicin hydrochloride liposome (30 mg/m(2) administered on day 4 following bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 every 3 weeks) (Prod Info DOXIL(R) IV injection, 2008).

G) PARESTHESIA

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN: In a randomized, open-label, multicenter study of 318 patients with multiple myeloma, 13% of patients developed paresthesia/dysesthesia after treatment with DOXOrubicin hydrochloride liposome (30 mg/m(2) administered on day 4 following bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 every 3 weeks) (Prod Info DOXIL(R) IV injection, 2008).

2) WITH POISONING/EXPOSURE

a) Transient peripheral numbness has been reported in patients following DOXOrubicin overdose (Curran, 1991).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea and vomiting are frequently reported with therapeutic doses of DOXOrubicin, within 4 to 8 hours of administration (Dorr & Fritz, 1980; Speth et al, 1988).
b) LIPOSOMAL DOXORUBICIN: In a randomized, multicenter, open-label study of 239 ovarian cancer patients treated with DOXOrubicin hydrochloride liposome (50 mg/m(2) every 4 weeks) for a minimum of 4 courses, 46% of patients experienced nausea (all grades) (Prod Info DOXIL(R) IV injection, 2008).

2) WITH POISONING/EXPOSURE

a) Nausea and vomiting have been reported following DOXOrubicin overdose (Uner et al, 2005).

B) DIARRHEA

1) WITH THERAPEUTIC USE

a) Diarrhea is frequently reported with therapeutic doses (Dorr & Fritz, 1980).
b) LIPOSOMAL DOXORUBICIN: In a randomized, multicenter, open-label study of 239 ovarian cancer patients treated with DOXOrubicin hydrochloride liposome (50 mg/m(2) every 4 weeks) for a minimum of 4 courses, 20.9% of patients experienced diarrhea (all grades) (Prod Info DOXIL(R) IV injection, 2008).

2) WITH POISONING/EXPOSURE

a) Diarrhea has been reported following DOXOrubicin overdose (Uner et al, 2005).

C) STOMATITIS

1) WITH THERAPEUTIC USE

a) Stomatitis and esophagitis are more common in patients receiving continuous infusions rather than intermittent bolus doses of DOXOrubicin (Smith, 1985). Mucositis (stomatitis and esophagitis) typically occurs 5 to 10 days after receiving the DOXOrubicin. It may be severe and result in a site for entrance of infections (Prod Info ADRIAMYCIN intravenous injection, 2006).
b) LIPOSOMAL DOXORUBICIN: Stomatitis appears to be dose-related with liposomal DOXOrubicin; symptoms are severe following doses of 60 to 70 mg/m(2) (Lyass et al, 2000).

2) WITH POISONING/EXPOSURE

a) Mucositis has been reported following DOXOrubicin overdose. Lesions heal slowly over 2 to 6 weeks (Uner et al, 2005; Curran, 1991).
b) CASE REPORTS: Two patients (a 58-year-old man and a 17-year-old girl) developed severe mucositis and bone marrow suppression after receiving DOXOrubicin overdoses of 540 mg as a single dose and 300 mg over 2 days, respectively. Both patients recovered following supportive care, including hemoperfusion (Back et al, 1995).

D) CONSTIPATION

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN: In a randomized, open-label, multicenter study of 318 patients with multiple myeloma, 31% of patients developed constipation after treatment with DOXOrubicin hydrochloride liposome (30 mg/m(2) administered on day 4 following bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 every 3 weeks) (Prod Info DOXIL(R) IV injection, 2008).

E) LOSS OF APPETITE

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN: In a randomized, multicenter, open-label study of 239 ovarian cancer patients treated with DOXOrubicin hydrochloride liposome (50 mg/m(2) every 4 weeks) for a minimum of 4 courses, 20.1% of patients experienced anorexia (all grades) (Prod Info DOXIL(R) IV injection, 2008).

F) ABDOMINAL PAIN

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN: In a randomized, open-label, multicenter study of 318 patients with multiple myeloma, 11% of patients developed abdominal pain after treatment with DOXOrubicin hydrochloride liposome (30 mg/m(2) administered on day 4 following bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 every 3 weeks) (Prod Info DOXIL(R) IV injection, 2008).

G) PANCREATITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: Acute pancreatitis occurred in a 24-year-old woman after receiving the second cycle of a chemotherapy regimen (cyclophosphamide 750 mg/m(2)/day IV, DOXOrubicin 50 mg/m(2)/day IV, vincristine 2 mg/IV, and prednisone 75 mg/day orally) for 5 days; this regimen was repeated every 21 days. Acute pancreatitis was observed upon rechallenge. The authors speculated that combination of these agents, rather than any single agent, was responsible (Puckett et al, 1982).

H) PROCTITIS

1) WITH THERAPEUTIC USE

a) Anal fissures or proctitis may occur with high doses of DOXOrubicin (Dorr & Fritz, 1980).

Hepatic

3.9.2)

A) ABNORMAL LIVER FUNCTION

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN: In 4 studies of 753 patients with AIDS-related Kaposi's sarcoma who were treated with the recommended dose of 20 mg/m(2) every 2 to 3 weeks, SGPT increase occurred in 1% to 5% of patients. The cumulative dose was greater than 450 mg/m(2) in 26 (3%) of patients (Prod Info DOXIL(R) IV injection, 2008). In other clinical trials, no hepatotoxicity was reported in patients with Kaposi's sarcoma (Poizot-Martin et al, 1994) or other cancer patients (Uziely et al, 1995).
b) Subclinical hepatic toxicity (liver enzymes abnormalities) was noted in 77% of women receiving adjuvant chemotherapy and 82% of women being treated for metastatic breast cancer with combination chemotherapy including DOXOrubicin. The authors suggested that mild abnormalities detected during chemotherapy were insufficient evidence of metastasis and should be considered a manifestation of drug toxicity (Larroquette et al, 1986).
c) CASE SERIES: Toxic hepatitis manifested by elevated liver enzymes was reported in 6 patients with acute leukemia treated with DOXOrubicin and vincristine. Light microscopy of liver biopsy specimens showed variable degrees of hepatocellular degeneration and necrosis with inflammatory reaction compatible with toxic hepatitis. A chronologic relationship between the administration of DOXOrubicin and serum abnormalities was noted. Infection, transfusion reactions, leukemic infiltration and viral hepatitis were ruled out (Aviles et al, 1984).
d) CASE REPORTS: In one study, three case reports of hepatic injury in nurses following years of handling cytostatic drugs (bleomycin, vincristine, cyclophosphamide, DOXOrubicin, dacarbazine, fluorouracil, and methotrexate) was described. All patients had neurological symptoms associated with elevated serum alanine aminotransferase and alkaline phosphatase levels, and liver biopsy revealed portal hepatitis with piecemeal necrosis in one, and hepatic fibrosis and fat accumulation in the others. It is suggested that handling of cytostatic agents may insidiously produce hepatic damage and possibly irreversible fibrosis (Sotaniemi et al, 1983).
e) CASE REPORT: A 54-year-old woman with metastatic breast cancer developed veno-occlusive disease of the liver following chemotherapy with mitomycin C and DOXOrubicin (Craft & Pembrey, 1987).

B) HEPATORENAL SYNDROME

1) WITH THERAPEUTIC USE

a) CASE REPORT: Hepatorenal failure was described in a 38-year-old man with AIDS-related Kaposi's sarcoma 6 weeks after the second dose of DOXOrubicin hydrochloride liposome (10 mg every 2 weeks); the patient died of hepatorenal failure 2 months later. Necropsy revealed hepatic fibrosis with necrosis of lobuli and bile duct proliferations (Hengge et al, 1993a). This patient had a history of chronic hepatitis B and an increase in replication of hepatitis B virus was demonstrated during week 6, which may have been contributory. It is suggested that, at worst, this case represents an idiosyncratic reaction to DOXOrubicin hydrochloride liposome, augmented by viral replication, as opposed to a major toxicity of the formulation (Coker et al, 1993).

C) ALKALINE PHOSPHATASE RAISED

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN: In 4 studies of 753 patients with AIDS-related Kaposi's sarcoma who were treated with the recommended dose of 20 mg/m(2) every 2 to 3 weeks, an increase in alkaline phosphatase occurred in 7.8% of patients. The median time on study was 127 days (range 1 to 811 days) and median cumulative dose was 120 mg/m(2) (range 3.3 to 798.6 mg/m(2)). The cumulative dose was greater than 450 mg/m(2) in 26 (3%) of patients (Prod Info DOXIL(R) IV injection, 2008).

Genitourinary

3.10.2)

A) CYSTITIS

1) WITH THERAPEUTIC USE

a) Significant local toxicity occurred following intravesical instillation of DOXOrubicin in patients with bladder carcinoma. Bladder irritation ranging from mild dysuria and urinary frequency to frank chemical cystitis occurred in up to 30% of patients. Hematuria and bladder spasms also occurred in a significant number of patients (Garnick et al, 1984; Jauhiainen et al, 1986).
b) CASE REPORT: Chemical pericystitis occurred in a 60-year-old man who had undergone transurethral resection of a bladder tumor and subsequent intravesical instillation of DOXOrubicin. The patient had a high fever lasting 18 days, lower abdominal pain, and mild hydronephrosis. Extravasation of DOXOrubicin through the resected and thinned region of the bladder wall seemed to be responsible for this complication. The lesion improved spontaneously without sequelae (Yoshimura et al, 1986).

Hematologic

3.13.2)

A) MYELOSUPPRESSION

1) WITH THERAPEUTIC USE

a) Myelosuppression may occur with DOXOrubicin and is one of the dose-limiting toxicities. Reversible leukopenia and/or granulocytopenia (neutropenia) are the most common acute dose-limiting toxicity. The nadir occurs between 10 and 14 days with recovery by the 21st day. Thrombocytopenia and anemia occur in the same period as leukopenia, but are less common (Prod Info ADRIAMYCIN intravenous injection, 2006).
b) Myelosuppression after DOXOrubicin hydrochloride liposome has usually been mild or moderate in patients with solid tumor (without HIV infection), and less than observed with conventional formulations (Uziely et al, 1995; Gabizon et al, 1994a; Allen, 1994a). With regimens of 20 to 80 mg/m(2) every three weeks, white blood cell and granulocyte nadirs exceeded 2000/mcL in most patients, and platelet counts remained above 100,000/mcL; anemia was mild (Uziely et al, 1995).

B) ANEMIA

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN

1) In 4 studies of 720 patients with AIDS-related Kaposi's sarcoma who were treated with the recommended dose of 20 mg/m(2) every 2 to 3 weeks, anemia (hemoglobin less than 10 g/dL) occurred in up to 55.4% of patients. Anemia defined as hemoglobin less than 8 g/dL, occurred in 18.2% of patients. Patients received a variety of other potentially myelotoxic drugs (Prod Info DOXIL(R) IV injection, 2008).
2) In a randomized, open-label, multicenter study of 318 patients with multiple myeloma, 25% of patients developed anemia after treatment with DOXOrubicin hydrochloride liposome (30 mg/m(2) administered on day 4 following bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 every 3 weeks) (Prod Info DOXIL(R) IV injection, 2008).

C) NEUTROPENIA

1) WITH THERAPEUTIC USE

a) DOXORUBICIN: Reversible leukopenia and/or granulocytopenia (neutropenia) are the most common acute dose-limiting toxicity. The nadir occurs between 10 and 14 days with recovery by the 21st day (Prod Info ADRIAMYCIN intravenous injection, 2006).
b) LIPOSOMAL DOXORUBICIN

1) Mild myelosuppression in the form of leukopenia/neutropenia was reported in a small study (n=45) of metastatic breast cancer patients (Lyass et al, 2000).
2) In 4 studies of 720 patients with AIDS-related Kaposi's sarcoma who were treated with the recommended dose of 20 mg/m(2) every 2 to 3 weeks, neutropenia (ANC less than 500/mm(3)) occurred in 13.3% of patients (Prod Info DOXIL(R) IV injection, 2008).
3) In a randomized, open-label, multicenter study of 318 patients with multiple myeloma, 10% of patients developed grade 4 neutropenia after treatment with DOXOrubicin hydrochloride liposome (30 mg/m(2) administered on day 4 following bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 every 3 weeks) (Prod Info DOXIL(R) IV injection, 2008).

2) WITH POISONING/EXPOSURE

a) Following an overdose, an earlier onset of leukopenia and slower resolution may be observed.

1) CASE REPORT: A 58-year-old man developed neutropenia (absolute neutrophil count, less than 0.5 x 10(9)/L) and thrombocytopenia (platelets less than 25 x 10(9)/L) 5 days after receiving DOXOrubicin 300 mg/m(2) (540 mg). Hematologic toxicity lasted for 11 days (Back et al, 1995).
2) CASE REPORTS: A 17-year-old girl developed moderately severe mucositis and bone marrow suppression after receiving DOXOrubicin 300 mg over 2 days. She recovered following supportive care, including hemoperfusion (Back et al, 1995).

D) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN: In three open-label, clinical studies of 176 patients with metastatic ovarian cancer receiving DOXOrubicin hydrochloride liposome at a dose of 50 mg/m(2), leukopenia (WBC less than 4000 mm(3)) occurred in 42.2% of patients. In general, leukopenia is transient. DOXOrubicin hydrochloride liposome was infused over 1 hour every 3 to 4 weeks for 3 to 6 cycles or longer. In a randomized, multicenter, open-label study of 474 patients with epithelial ovarian cancer, leukopenia (WBC less than 4000 mm(3)) occurred in 36.8% of patients. Patients received either DOXOrubicin hydrochloride liposome 50 mg/m(2) infused over 1 hour every 4 weeks, or topotecan 1.5 mg/m(2) infused daily for 5 consecutive days every 3 weeks (Prod Info DOXIL(R) IV injection, 2008).

2) WITH POISONING/EXPOSURE

a) Leukopenia may occur following an overdose (Prod Info ADRIAMYCIN intravenous injection, 2006; Curran, 1991).

E) THROMBOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN

1) In a randomized, open-label, multicenter study of 318 patients with multiple myeloma, 33% of patients developed thrombocytopenia after treatment with DOXOrubicin hydrochloride liposome (30 mg/m(2) administered on day 4 following bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 every 3 weeks) (Prod Info DOXIL(R) IV injection, 2008).
2) In 4 studies of 720 patients with AIDS-related Kaposi's sarcoma who were treated with the recommended dose of 20 mg/m(2) every 2 to 3 weeks, thrombocytopenia (platelets less than 150,000/mm(3)) occurred in 60.9% of patients. Thrombocytopenia (platelets less than 25,000/mm(3)) occurred in 4.2% of patients. The cumulative dose was greater than 450 mg/m(2) in 26 (3%) of patients (Prod Info DOXIL(R) IV injection, 2008).

2) WITH POISONING/EXPOSURE

a) Thrombocytopenia may occur following an overdose (Prod Info ADRIAMYCIN intravenous injection, 2006).

F) PANCYTOPENIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 23-year-old woman with diffuse large-cell lymphoma received cumulative doses of cyclophosphamide 6000 mg, DOXOrubicin 420 mg, and vincristine 12 mg over 6 consecutive days (instead of 6 cycles), and developed nausea, vomiting, abdominal pain, diarrhea, paralytic ileus, pancytopenia, fever, neuropathies (due to vincristine therapy), blurred vision, and neurogenic bladder. Following supportive care, including antibiotic therapy, granulocyte colony stimulating factor, and platelet transfusion, she recovered and was discharged after 25 days (Uner et al, 2005).
b) Pancytopenia occurred in all overdoses reported to the manufacturer (Curran, 1991).

G) HEMOLYTIC ANEMIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 58-year-old man with G6PD A-deficiency developed a decrease in hemoglobin (10.6 grams/dL, reticulocytes 4.1%) and was Coombs test negative with numerous Heinz bodies present on supravital staining 3 days following an IV injection of 150 mg DOXOrubicin. No rechallenge was done (Doll, 1983).

Dermatologic

3.14.2)

A) SKIN NECROSIS

1) WITH THERAPEUTIC USE

a) EXTRAVASATION

1) Severe ulceration and necrosis may occur following extravasation of DOXOrubicin (Prod Info ADRIAMYCIN intravenous injection, 2006; Dorr et al, 1989; Lokich & Moore, 1986; Reed et al, 1985; Reilly et al, 1977; Tan et al, 1973; Wang et al, 1971).
2) LIPOSOMAL DOXORUBICIN: In limited experience, extravasation of DOXOrubicin hydrochloride liposome has not produced tissue damage or necrosis, which is in contrast to the severe local inflammation and ulceration reported with DOXOrubicin extravasation. DOXOrubicin hydrochloride liposome extravasation reactions have been limited to mild erythema and/or edema (Madhavan & Northfelt, 1995).
3) CASE REPORT: One study reported extravasation of an unknown amount of DOXOrubicin (2.1 mg/mL) and vincristine (0.1 mg/mL) into the medial aspect of the right upper arm in a 56-year-old patient without producing severe acute symptomatology. Local swelling and redness were not apparent until 2 weeks after the infusion was completed. Surgical debridement was required at 2 and 3 weeks after the incident, followed by a split thickness skin graft (Dorr et al, 1989).

B) HAND-FOOT SYNDROME IN SICKLE CELL ANEMIA

1) WITH THERAPEUTIC USE

a) Although it may occur earlier, hand-foot syndrome (HFS) was generally observed after 2 or 3 cycles of treatment. The reaction is usually mild and resolves in 1 to 2 weeks, but dose modification may be necessary to manage HFS. In some patients, HFS is severe and debilitating, requiring the cessation of treatment (Prod Info DOXIL(R) IV injection, 2008).
b) In a randomized, multicenter, open-label study of 239 ovarian cancer patients treated with DOXOrubicin hydrochloride liposome (50 mg/m(2) every 4 weeks) for a minimum of 4 courses, 50.6% of patients experienced hand-foot syndrome (HFS). Grade 3 (blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing) or grade 4 (diffuse or local process causing infectious complications, or a bedridden state or hospitalization) HFS was reported in 23.8% of patients. Treatment was discontinued in 10 patients (4.2%) due to HFS or other skin toxicity (Prod Info DOXIL(R) IV injection, 2008).
c) CASE REPORT: Two patients with AIDS-related Kaposi's sarcoma developed hand-foot syndrome after receiving liposomal DOXOrubicin. Following the discontinuation of DOXOrubicin, their symptoms resolved (Gordon et al, 1995).
d) LIPOSOMAL DOXORUBICIN: Palmar-plantar erythema and mucositis have been associated more frequently with liposomal formulations during therapeutic use (von Moos et al, 2008; S Sweetman , 2001).

1) CASE REPORT: A 43-year-old woman developed intertrigo-like eruption after receiving the fourth dose of pegylated liposomal DOXOrubicin (40 mg /m(2) IV every 4 weeks). She presented with palmar-plantar erythematous skin lesions with severe desquamation. Three days later, she also experienced erythematous patches over axillae and groin, severe neuropathic pain, allodynia, and hyperalgesia (Sanchez Henarejos et al, 2009).

C) ERUPTION

1) WITH THERAPEUTIC USE

a) In a randomized, multicenter, open-label study of 239 ovarian cancer patients treated with DOXOrubicin hydrochloride liposome (50 mg/m(2) every 4 weeks) for a minimum of 4 courses, 28.5% of patients experienced rash (Prod Info DOXIL(R) IV injection, 2008).
b) Three cases of cutaneous eruptions associated with the use of liposomal DOXOrubicin have been documented. All were patients with metastatic ovarian carcinoma. Approximately 3 to 4 weeks after treatment with liposomal DOXOrubicin all developed erythematous macular/papular to plaque cutaneous eruptions, with a vesicular component in one of the patients. The cutaneous lesions involved the trunk and extremities. All were successfully treated with topical steroids with or without other antipruritic agents. Histologic findings in all three patients consisted of a biopsy showing an interface dermatitis with numerous apoptotic/dyskeratotic cells within the epidermis with involvement of the intra-epidermal sweat ducts and the infundibulum of hair follicles. Because of the prolonged latent period from drug exposure to cutaneous eruption, direct cytotoxic effects can be discarded as a cause of the eruptions. The authors of this report suggested that these eruptions represented a chemotherapy induced host-versus-altered-host reaction (Skelton et al, 2002).

2) WITH POISONING/EXPOSURE

a) Rash with desquamation has been reported in patients following DOXOrubicin overdose (Curran, 1991).
b) In one study, skin splash contact with DOXOrubicin resulted in no reaction or rapidly resolving local reactions in 24 cases (Curran & Luce, 1989).

D) ALOPECIA

1) WITH THERAPEUTIC USE

a) Alopecia has been reported in patients receiving DOXOrubicin (Prod Info DOXIL(R) IV injection, 2008).

E) NAIL FINDING

1) WITH THERAPEUTIC USE

a) Hyperpigmentation of the nail beds and skin may occur (Dorr & Fritz, 1980).
b) CASE SERIES: Nail discoloration (white or red-brown), painful nails, and pressure sensitive nails were reported in 4 patients being treated with the combination of DOXOrubicin and mitoxantrone (Van Belle et al, 1989).

2) WITH POISONING/EXPOSURE

a) Cracked nails has been reported in patients following DOXOrubicin overdose (Curran, 1991).

F) INJECTION SITE REACTION

1) WITH THERAPEUTIC USE

a) An erythematous streak forms up the vein from the injection site and may be associated with pruritus and urticaria. This reaction is reported to be of short duration (about 1 hour) with or without the use of antihistamines (Dorr & Fritz, 1980).
b) INTRA-ARTERIAL INJECTION: Four patients developed extensive erythema over the chest wall associated with DOXOrubicin 25 to 35 mg/m(2) given as a 6 hour intra-arterial infusion on 2 successive days into the internal mammary artery. The reaction occurred within 48 hours of the start of the treatment. Progression of the reaction to superficial ulceration occurred in one patient. Hemi-diaphragm and phrenic nerve paralysis were noted in 2 patients. Pleural effusion occurred in one of these patients secondary to the nerve paralysis (Twelves et al, 1990).

Musculoskeletal

3.15.2)

A) BACKACHE

1) WITH THERAPEUTIC USE

a) LIPOSOMAL DOXORUBICIN: In a randomized, multicenter, open-label study of 239 ovarian cancer patients treated with DOXOrubicin hydrochloride liposome (50 mg/m(2) every 4 weeks) for a minimum of 4 courses, 11.7% of patients experienced back pain (Prod Info DOXIL(R) IV injection, 2008).

Immunologic

3.19.2)

A) ACUTE ALLERGIC REACTION

1) WITH THERAPEUTIC USE

a) DOXORUBICIN FLARE is an erythematous streaking near the site of infusion. The flare is a benign local allergic reaction that may be confused or mistaken for extravasation (Van Sloten & Aisner, 1984).
b) Systemic reactions may occur following intravesical instillation of DOXOrubicin. Hypersensitivity reactions have been reported following intravesical instillation (Crawford et al, 1986; Birch & Crisp, 1988).
c) Although rare, systemic allergic reactions to DOXOrubicin have been observed and include diffuse urticarial skin eruptions, transient pruritus of the upper extremities, marked angioedema of the eyelids and tongue, difficulty swallowing, and respiratory distress. Reactions have occurred within minutes and resolved with the use of IV antihistamines and steroids (Arena & Sherlock, 1990; Birch & Crisp, 1988a; Solimando & Wilson, 1984; Collins, 1984; Souhami & Feld, 1978).

Reproductive

3.20.1)

3.20.2)

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) MALFORMATIONS

1) Administration of DOXOrubicin (total, 325 mg) and cyclophosphamide (total, 2.1 g) with cobalt during the first trimester of pregnancy resulted in the birth of a small neonate with imperforate anus and rectovaginal fistula, which were corrected by surgery. Findings from chromosomal analyses were normal. The authors suggest that cytotoxic drug therapy during the first trimester of pregnancy is associated with a very small risk of malformations (Murray et al, 1984).

C) ANIMAL STUDIES

1) DOXORUBICIN HCl

a) In rats, DOXOrubicin was teratogenic and embryotoxic following doses of 0.8 mg/kg/day (about 0.07 times the human dose based on body surface area). Between 6- and 9-day gestation was the most susceptible period of treatment, with teratogenicity and embryotoxicity (esophageal and intestinal atresia, tracheoesophageal fistula, hypoplasia of the urinary bladder, and cardiovascular anomalies) observed following doses of 1.25 mg/kg/day and greater. In rabbits, DOXOrubicin was embryotoxic and abortifacient following doses of 0.4 mg/kg/day (about 0.07 times the human dose based on body surface area) given during the period of organogenesis (Prod Info doxorubicin HCl intravenous injection, 2013).

3.20.3)

A) PREGNANCY CATEGORY

1) DOXOrubicin is classified by the manufacturer as FDA pregnancy category D (Prod Info doxorubicin HCl intravenous injection, 2013).

B) COMBINATION THERAPY

1) Both successful pregnancies and adverse fetal outcome have been reported after DOXOrubicin was used as part of combination chemotherapy (Aviles et al, 1991; Murray et al, 1984; Zemlickis et al, 1992).
2) CASE SERIES: A total of 160 patients who received anthracyclines during pregnancy for leukemia or solid tumors were analyzed. Most patients received either DOXOrubicin (n=99; 62%) or daunorubicin (n=50; 31%) during the study period, along with other chemotherapeutic agents: antimetabolites (37%) alkylating agents (20%), mitotic spindle poisons (20%) or others in 90% of patients. The median duration of treatment with DOXOrubicin and daunorubicin were 12 and 5 weeks, respectively. The duration of exposure was not associated with the occurrence of severe fetal toxicity, but the risk of severe fetal toxicity increased 30-fold when the dose per cycle of DOXOrubicin exceeded 70 mg/m(2) per cycle (p=0.037). Fetal outcome was normal in 123 cases, with fetal death reported in 15 cases (6 cases were directly associated with maternal death). During the study, five malformations developed and were all associated with combination regimens (ie, antimetabolites or alkylating agents along with either daunorubicin (3 cases) or DOXOrubicin (2 cases). The effects were variable and affected any organ. Spontaneous abortion was reported in 4 cases with 2 cases occurring in the first trimester. Drug therapy during the second and third trimester was associated with anthracycline-induced toxicities (eg, cardiac toxicity). Nine cases of prematurity occurred after exposure during the second trimester, with respiratory distress (73%), ventricular hemorrhage (18%), and enterocolitis (9%) reported the most frequently (Germann et al, 2004).
3) DOXOrubicin, cytarabine, and thioguanine were used to treat a patient diagnosed with acute myelogenous leukemia at 23 weeks gestation. Good fetal movement and a fetal heartbeat were noted at the time of diagnosis. Treatment was initiated at 24 weeks gestation and lasted 7 days. Nine days after completion of therapy, the patient had a stillbirth. No abnormalities were noted; however, the infant had multiple areas of bruising and petechiae suggesting thrombocytopenia secondary to bone marrow suppression (Zemlickis et al, 1992).
4) In a case-control study, occupational exposure to cyclophosphamide, DOXOrubicin, and vincristine in the first trimester of pregnancy was associated with a significant increase in fetal loss in nurses (Selevan et al, 1985).

C) DOXORUBICIN HCl LIPOSOME

1) There are no adequate or well controlled studies of DOXOrubicin hydrochloride liposome use during human pregnancy. During animal studies, embryotoxicity was reported in both rats and rabbits. Abortifacient effects were also reported in rabbits. Adequate contraception is required during treatment and for at least 6 months after treatment in male and female patients of reproductive potential. If pregnancy occurs, or use is required during pregnancy, apprise patient of the potential for fetal harm (Prod Info DOXIL(R) intravenous injection, 2015).

D) LACK OF EFFECT

1) DOXOrubicin or DOXOrubicinol were not found in amniotic fluid of a pregnant woman treated at 20 weeks gestation (Roboz et al, 1979).

E) ANIMAL STUDIES

1) DOXORUBICIN HCl

a) RABBITS: In rabbits, DOXOrubicin was embryotoxic and abortifacient following doses of 0.4 mg/kg/day (about 0.07 times the human dose based on body surface area) given during the period of organogenesis (Prod Info doxorubicin HCl intravenous injection, 2013).

2) DOXORUBICIN HCl LIPOSOME

a) During animal studies, embryotoxicity (ie, embryofetal death, reduced live litter size) was reported with administration of DOXOrubicin hydrochloride liposome 1 mg/kg/day in rats. Embryotoxicity and abortifacient effects were reported in rabbits who were administered DOXOrubicin hydrochloride liposome at a dose of 0.5 mg/kg/day (Prod Info DOXIL(R) intravenous injection, 2015).

3.20.4)

A) BREAST MILK

1) DOXOrubicin has been detected in the breast milk of at least 1 lactating mother. Because potential harm to a nursing infant exists, either breastfeeding or DOXOrubicin hydrochloride should be discontinued considering the need for treatment of the mother (Prod Info doxorubicin HCl intravenous injection, 2013). It is contraindicated by the American Academy of Pediatrics because of potential concerns of immune suppression, carcinogenesis, neutropenia, and unknown effects on growth (Briggs et al, 1998). Even if the drug does not enter the breast milk, the increased energy and nutrient requirements for milk production could negatively impact the mother's recovery (Dillon et al, 1997).
2) CASE REPORT: Distribution of DOXOrubicin into human milk was examined in a 31-year-old woman who was treated for ovarian cancer 7 months postpartum. DOXOrubicin (70 mg/m(2); total dose 90 mg) was given as a 15 minute IV infusion. DOXOrubicin concentrations in milk usually exceeded those detected in concomitant plasma samples. Highest milk:plasma concentration ratio was observed 24 hrs after drug administration (4.43:1). AUC values were approximately the same for milk and plasma. The AUC for DOXOrubicinol, the major metabolite found in plasma and milk, was approximately 10 times higher in milk than plasma. Peak plasma concentration of DOXOrubicinol was 0.15 mcmol, observed at 0.5 hr; maximum concentration in milk was 0.20 mcmol (111 mcg/L) measured at 24 hr. However, the total amount of anthracycline delivered in milk was negligible (maximum concentration of active anthracycline 0.24 mg/L) (Egan et al, 1985).

B) DOXORUBICIN HCl LIPOSOME

1) Lactation studies with DOXOrubicin hydrochloride liposome have not been conducted. It is unknown whether DOXOrubicin hydrochloride liposome is excreted into human milk, and the effects on the nursing infant from exposure to the drug in milk have not been determined. Because many drugs are excreted in human milk and the potential for serious toxicity in a nursing infant exists, it is recommended to either discontinue nursing or DOXOrubicin hydrochloride liposome, considering the importance of the drug to the mother (Prod Info DOXIL(R) intravenous injection, 2015).

3.20.5)

A) OLIGOSPERMIA AND AZOOSPERMIA

1) Oligospermia, azoospermia, and permanent loss of fertility may occur in men receiving DOXOrubicin hydrochloride. Sperm counts have been reported to return to normal levels in some men but this may occur only after several years following discontinuation (Prod Info doxorubicin HCl intravenous injection, 2013).

B) AMENORRHEA AND INFERTILITY

1) Amenorrhea, premature menopause, and infertility may occur in women of reproductive potential who have received DOXOrubicin hydrochloride. Depending on age at treatment, recovery of menses and ovulation is possible (Prod Info doxorubicin HCl intravenous injection, 2013).

C) ANIMAL STUDIES

1) Male rats developed testicular atrophy, diffuse degeneration of the seminiferous tubules, and oligospermia or hypospermia after receiving a single IV dose of DOXOrubicin 0.1 mg/kg (0.01 times the human dose based on body surface). In addition, DOXOrubicin-induced DNA damage in spermatozoa was observed in rabbits and dominant lethal mutations were seen in mice (Prod Info doxorubicin HCl intravenous injection, 2013).
2) A decrease in fertility was observed in female rats administered DOXOrubicin hydrochloride at doses of 0.05 and 0.2 mg/kg/day (approximately 0.005 and 0.02 times, respectively, the recommended human dose based on body surface area) (Prod Info doxorubicin HCl intravenous injection, 2013).

Carcinogenicity

3.21.2)

3.21.3)

A) SECONDARY CARCINOMA

1) DOXOrubicin-containing combination chemotherapy regimens have caused secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). In 2 separate studies of DOXOrubicin hydrochloride in the adjuvant treatment of patients with breast cancer, the cumulative incidence at 5 years was 0.2% and 1.5% at 10 years. These leukemias usually occur within 1 to 3 years of treatment (Prod Info doxorubicin HCl intravenous injection, 2013).
2) In postmarketing surveillance, secondary oral cancers, primarily squamous cell carcinoma, have been reported during long-term (ie, more than 1 year) DOXOrubicin hydrochloride liposome therapy and up to 6 years after treatment cessation (Prod Info DOXIL(R) intravenous injection, 2015).
3) Although causality cannot be established, secondary acute myelogenous leukemia, with fatalities, has been reported with DOXOrubicin hydrochloride liposome therapy in postmarketing surveillance (Prod Info DOXIL(R) intravenous injection, 2015).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Pancytopenia is expected after overdose. Neutrophil nadir is generally 10 to 14 days after a therapeutic dose. Monitor patient for signs of bleeding.
B) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
C) Monitor vital signs and serial ECGs; institute continuous cardiac monitoring. Evaluate for evidence of cardiomyopathy and congestive heart failure. Echocardiogram or radionucleotide studies may be useful.
D) Monitor serum electrolytes, renal function, and hepatic enzymes.
E) Evaluate patients for signs and symptoms of mucositis.

4.1.2)

A) HEMATOLOGIC

1) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Pancytopenia is expected after overdose. Neutrophil nadir is generally 10 to 14 days after a therapeutic dose.

4.1.4)

A) OTHER

1) MONITORING

a) Endomyocardial biopsy is useful in monitoring anthracycline-induced myocardial injury, along with echocardiography or multigated radionuclide scans. If cardiac injury is present, the benefit of therapy and risk of myocardial injury needs to be evaluated (Prod Info DOXIL(R) IV injection, 2008).
b) NONINVASIVE CARDIAC MONITORING: Radionuclide evaluation of ejection fractions of left ventricular contraction was reported to be more reliable than electrocardiography, echocardiography, or systolic time intervals in evaluating for cardiomyopathy (Ganz et al, 1996; Bristow, 1982).
c) CARDIAC CATHETERIZATION: Abnormal ejection fractions may warrant right heart catheterization and myocardial biopsy to determine if the patient may receive additional courses of DOXOrubicin (Bristow, 1982).
d) LIMITATIONS: One study contends that monitoring of the ejection fraction does NOT provide adequate information for the management of cardiomyopathy. The poor sensitivity and specificity of left ventricular ejection fraction by radionuclide angiography may limit its usefulness (Lipshultz et al, 1999).
e) DOPPLER ECHOCARDIOGRAPHY: Abnormal left ventricular diastolic filling pattern in patients with long-term DOXOrubicin therapy was reported to be easily identified by doppler echocardiography (Marchandise et al, 1989).

Methods

1) DOXOrubicin blood levels are not readily available and not useful in guiding initial management.

Treatment

Life Support

Patient Disposition

6.3.2)

6.3.2.1) ADMISSION CRITERIA/PARENTERAL

A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), cardiac function, and daily monitoring of CBC with differential until bone marrow suppression is resolved.

6.3.2.2) HOME CRITERIA/PARENTERAL

A) There is no data to support home management.

6.3.2.3) CONSULT CRITERIA/PARENTERAL

A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with DOXOrubicin overdose. Consult a cardiologist to manage patients with heart failure. May require surgical consult for extravasation.

6.3.2.4) PATIENT TRANSFER/PARENTERAL

A) Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

Oral Exposure

6.5.1)

A) Decontamination is not necessary in most situations as DOXOrubicin is administered IV. For dermal exposures, clean skin with soap and water, and for eye exposures, flush with water.

6.5.3)

A) SUPPORT

1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

6.8.2)

A) IRITIS

1) Accidental instillation of DOXOrubicin into the eye has produced iritis and corneal changes. Patients with significant iritis should be referred to an ophthalmologist.
2) DEXAMETHASONE SODIUM PHOSPHATE: Instill one drop into affected eye 4 times daily (Wertenbaker, 1987a).
3) HOMATROPINE: Pharmacologically dilate the pupil (Wertenbaker, 1987a).
4) Dexamethasone and homatropine improved symptoms in a 30-year-old woman who developed iritis and corneal infiltrates following accidental splash contact with approximately 0.5 mL of DOXOrubicin (2 mg/mL) (Wertenbaker, 1987a).

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

6.9.1)

A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

1) Dialysis is UNLIKELY to be of benefit due to high protein binding and large volume of distribution.

1) SUMMARY: Early use of hemoperfusion may increase the clearance of DOXOrubicin.
2) CASE REPORT: A patient received two 4-hour Amberlite hemoperfusions after receiving DOXOrubicin 230 mg/m(2) (300 mg; a 10-fold overdose) and completely recovered within 2 weeks (Curran, 1991). Hemoperfusion clearance was not determined.

a) DOXOrubicin is highly protein-bound; however, if hemoperfusion is initiated within minutes of an overdose, a reduction in serum concentrations might be achieved (Curran, 1991).

3) Hemoperfusion was used to treat 2 patients with DOXOrubicin overdose. Both patients recovered, but hemoperfusion clearance rates were not reported (Back et al, 1995).
4) ANIMAL STUDY: In a study done in dogs, DOXOrubicin was removed from the body with a total body clearance enhanced 20 fold during hemoperfusion with 2% acrylic hydrocel-coated charcoal hemoperfusion at a blood flow rate of 100 mL/minute (Winchester et al, 1980).

1) Early plasma exchange would be expected remove significant amounts of liposomal DOXOrubicin, but there are no published overdose cases in which this has been performed.

Abstracts

Case Reports

1) INTRATHECAL

a) A 31-year-old woman with aggressive lymphoblastic lymphoma was inadvertently given 14.5 mg of DOXOrubicin intrathecally (instead of methotrexate) and developed hypoesthesia, paraparesis, and incontinence within 1 week of exposure, despite immediate cerebrospinal fluid exchange at a rate of 20 cm(3)/hr for a total of 500 cm(3). The patient's clinical course progressed to complete flaccid paraplegia within 20 days. She was transferred to a rehab center and developed tetraventricular hydrocephaly likely due to adhesive arachnoiditis 7 weeks after exposure. During her 7-month stay in a rehab center, the patient completed a comprehensive multidisciplinary rehab program, after which she was able to walk alone for 10 meters with two crutches and improved her Barthel-score for activities of daily living from 25/100 (at admission) to 90/100 (Jordan et al, 2004).

2) ORAL

a) A 79-year-old woman was given a vial of DOXOrubicin and instructed to take it to a clinic for administration. She misunderstood the instructions and took the vial home with her, removed the vial cap with pliers, and ingested the unreconstituted powder. No adverse reactions were reported (Curran & Luce, 1989).

3) OCULAR

a) In a series of 15 cases of accidental ocular exposure to DOXOrubicin, 2 cases developed persistent photophobia and chronic inflammation. In the other 13 cases, either no reaction occurred or a rapidly resolving conjunctivitis was observed (Curran & Luce, 1989).

4) DERMAL

a) In a series of 23 cases of accidental dermal exposure to DOXOrubicin, either no reaction occurred or a rapidly resolving local reaction was observed (Curran & Luce, 1989).

1) INTRATHECAL

a) CASE REPORT: A 12-year-old girl with acute lymphoblastic leukemia was inadvertently given 30 mg/m(2) of DOXOrubicin intrathecally, and developed encephalopathy with severe tetraventricular hydrocephalus within 2 weeks of exposure. A ventriculoperitoneal shunt was placed, and no residual neuropathy occurred (Trinkle & Wu, 1996; Arico et al, 1990).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) DOXORUBICIN HYDROCHLORIDE

1) (single agent) 60 to 75 mg/m(2) IV every 21 days (Prod Info doxorubicin HCl intravenous injection, 2013)
2) (in combination with other chemotherapy agents) 40 to 75 mg/m(2) IV every 21 to 28 days(Prod Info doxorubicin HCl intravenous injection, 2013)

a) adjuvant treatment of breast cancer: 60 mg/m(2) IV bolus on day 1 of each 21-day cycle, in combination with cyclophosphamide for 4 cycles (Prod Info doxorubicin HCl intravenous injection, 2013)

B) DOXORUBICIN HYDROCHLORIDE LIPOSOME

1) The recommended dose is 20 to 50 mg/m(2) IV every 3 to 4 weeks (Prod Info DOXIL(R) intravenous injection, 2013).

7.2.2)

A) DOXORUBICIN HYDROCHLORIDE

1) (single agent) 60 to 75 mg/m(2) IV every 21 days (Prod Info doxorubicin HCl intravenous injection, 2013)
2) (in combination with other chemotherapy agents) 40 to 75 mg/m(2) IV every 21 to 28 days (Prod Info doxorubicin HCl intravenous injection, 2013)

B) DOXORUBICIN HYDROCHLORIDE LIPOSOME

1) The safety and effectiveness in children have not been established (Prod Info DOXIL(R) intravenous injection, 2013).

Minimum Lethal Exposure

Maximum Tolerated Exposure

1) One study reported the incidence of cardiomyopathy based on the total dose of DOXOrubicin (Minow et al, 1975):

a) Less than 500 mg/m(2): less than 1%
b) 501 to 600 mg/m(2): about 11%
c) Greater than 600 mg/m(2): greater than 30%

1) CASE SERIES: A series of 12 patients who received inadvertent DOXOrubicin overdoses (3 to 10 times the intended dose) were reported to the manufacturer. All patients developed leukopenia or pancytopenia, 7 developed mucositis, 2 developed heart failure, and 5 died. Other effects reported were cracked nails, peripheral numbness, desquamating rash, a single seizure, and increased serum creatinine (Curran, 1991).
2) CASE REPORT: Two patients (a 58-year-old man and a 17-year-old girl) survived DOXOrubicin overdoses of 540 mg as a single dose and 300 mg over 2 days, respectively. Complications included severe mucositis and bone marrow suppression (Back et al, 1995).

1) CASE REPORT: No adverse effects were observed in a 79-year-old woman who inadvertently ingested the unreconstituted powder from 1 vial of DOXOrubicin (Curran & Luce, 1989).

1) CASE REPORT: A 12-year-old girl with acute lymphoblastic leukemia was inadvertently given 30 mg/m(2) of DOXOrubicin intrathecally, and developed encephalopathy with severe tetraventricular hydrocephalus within 2 weeks of exposure. A ventriculoperitoneal shunt was placed, and no residual neuropathy occurred (Trinkle & Wu, 1996; Arico et al, 1990).
2) CASE REPORT: A 31-year-old woman with aggressive lymphoblastic lymphoma was inadvertently given 14.5 mg of DOXOrubicin intrathecally (instead of methotrexate), and developed hypoesthesia, paraparesis, and incontinence within a week of exposure, despite immediate cerebrospinal fluid exchange at a rate of 20 cm(3)/hour for a total of 500 cm(3) . The patient's clinical course progressed to complete flaccid paraplegia within 20 days. She was transferred to a rehab center and developed tetraventricular hydrocephaly likely due to adhesive arachnoiditis 7 weeks after exposure. The patient received 7 months of intensive rehab and was able to walk alone for short distances with crutches, and learned how to complete most of her prior activities of daily living (Jordan et al, 2004).

1) CASE SERIES: In a series of 23 cases of dermal exposure to DOXOrubicin, either no reaction occurred or a rapidly resolving local reaction was observed (Curran & Luce, 1989).

1) CASE SERIES: In a series of 15 cases of ocular exposure to DOXOrubicin, two developed persistent photophobia and chronic inflammation and the other 13 either had no reaction or rapidly resolving conjunctivitis (Curran & Luce, 1989).

Toxicity Information

7.7.1)

A) LD50- (INTRAPERITONEAL)MOUSE:

1) 10700 mcg/kg (RTECS, 2006)

B) LD50- (ORAL)MOUSE:

1) 570 mg/kg (RTECS, 2006)

C) LD50- (INTRAPERITONEAL)RAT:

1) 10510 mcg/kg (RTECS, 2006)

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Animal Toxicology

References

General Bibliography

10)

11)

12)

13)

14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24)

25)

26)

27)

28)

29)

30)

31)

32)

33)

34)

35)

36)

37)

38)

39)

40)

41)

42)

43)

44)

45)

46)

47)

48)

49)

50)

51)

52)

53)

54)

55)

56)

57)

58)

59)

60)

61)

62)

63)

64)

65)

66)

67)

68)

69)

70)

71)

72)

73)

74)

75)

76)

77)

78)

79)

80)

81)

82)

83)

84)

85)

86)

87)

88)

89)

90)

91)

92)

93)

94)

95)

96)

97)

98)

99)

100)

101)

102)

103)

104)

105)

106)

107)

108)

109)

110)

111)

112)

113)

114)

115)

116)

117)

118)

119)

120)

121)

122)

123)

124)

125)

126)

127)

128)

129)

130)

131)

132)

133)

134)

135)

136)

137)

138)

139)

140)

141)

142)

143)

144)

145)

146)

147)

148)

149)

150)

151)

152)

153)

154)

155)

156)

157)

158)

159)

160)

161)

162)

163)

164)

165)

166)

167)

168)

169)

170)

171)

172)

173)

FeedBack

DOXORUBICIN

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Hematologic

Dermatologic

Musculoskeletal

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

General Bibliography