Summary Of Exposure |
A) USES: Dexrazoxane is used to reduce the incidence and severity of anthracycline-induced (eg, doxorubicin) cardiomyopathy and is indicated for the treatment of extravasation injury secondary to IV anthracycline chemotherapy.
B) PHARMACOLOGY: Totect(TM): The mechanism is unknown. It has been proposed that dexrazoxane inhibits topoisomerase II reversibly, thereby diminishing tissue damage from extravasation of anthracycline. Zinecard(R): The mechanism of action of dexrazoxane hydrochloride's cardioprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of ethylenediamine tetra-acetic acid (EDTA) that readily penetrates cell membranes. It is believed to exert its cardioprotective effects by chelating iron following its intracellular hydrolysis. The reduction of the iron-doxorubicin complexes prevents free radical formation, which is thought to be at least partly responsible for the anthracycline-induced cardiotoxic effects.
C) EPIDEMIOLOGY: Overdose is rare.
D) WITH THERAPEUTIC USE
1) MOST COMMON (GREATER THAN 16%): Nausea, vomiting, fever, and injection site pain. OTHER EFFECTS: Fatigue, peripheral edema, diarrhea, abdominal pain, constipation, postoperative infection, dizziness, headache, alopecia, dyspnea, pneumonia, cough, vascular disorders, depression, insomnia, hyperamylasemia, coagulopathy, increased serum creatinine, elevated liver enzymes, and anorexia. Leukopenia, granulocytopenia, thrombocytopenia, and anemia have also been reported at therapeutic doses. Myelosuppressive effects are more common with dexrazoxane doses greater than 1000 mg/m(2).
E) WITH POISONING/EXPOSURE
1) Overdose data are limited. It is anticipated that overdose effects may be similar to adverse reactions observed with therapeutic use.
|
Vital Signs |
3.3.3) TEMPERATURE
A) WITH THERAPEUTIC USE 1) FEVER: In 2 clinical trials (n=80), pyrexia was reported in 21% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
|
Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) PERIPHERAL EDEMA 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), peripheral edema was reported in 10% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
B) CARDIOVASCULAR FINDING 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), cardiac disorders were reported in 5% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy. Vascular disorders were reported in 15% of patients (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
C) UNEXPECTED THERAPEUTIC EFFECT 1) WITH THERAPEUTIC USE a) Several studies have demonstrated the cardioprotective effect of dexrazoxane in patients receiving doxorubicin. Most studies have used a dosing ratio of 20:1 (dexrazoxane 1000 mg/m(2) per doxorubicin 50 mg/m(2)) (Speyer et al, 1990; Speyer et al, 1992).
|
Respiratory |
3.6.2) CLINICAL EFFECTS
A) DYSPNEA 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), dyspnea was reported in 8% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
B) PNEUMONIA 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), pneumonia was reported in 6% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
C) COUGH 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), cough was reported in 5% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
|
Neurologic |
3.7.2) CLINICAL EFFECTS
A) DIZZINESS 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), dizziness was reported in 11% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
B) FATIGUE 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), fatigue was reported in 13% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
C) HEADACHE 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), headache was reported in 6% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
|
Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) NAUSEA AND VOMITING 1) WITH THERAPEUTIC USE a) Nausea, vomiting, and anorexia are common adverse effects at therapeutic dose but are generally mild (Koeller et al, 1981; Holcenberg et al, 1986; Liesmann et al, 1981).
b) In 2 clinical studies (n=80), nausea, vomiting, and anorexia were reported in 43%, 19%, and 5% respectively, of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
B) ABDOMINAL PAIN 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), abdominal pain was reported in 6% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
C) CONSTIPATION 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), constipation was reported in 6% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
D) DIARRHEA 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), diarrhea was reported in 11% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
E) SERUM AMYLASE RAISED 1) WITH THERAPEUTIC USE a) Transient, asymptomatic elevations in serum amylase developed in 4 of 20 patients (20%) with leukemia in one study (Holcenberg et al, 1986) Von Hoff, 1998).
|
Hepatic |
3.9.2) CLINICAL EFFECTS
A) LIVER ENZYMES ABNORMAL 1) WITH THERAPEUTIC USE a) Transient, asymptomatic elevations of SGOT, SGPT, and bilirubin are common at therapeutic doses (Prod Info Totect(R) Kit intravenous infusion injection, 2013; Holcenberg et al, 1986; Liesmann et al, 1981).
B) INCREASED BILIRUBIN LEVEL 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), a grade 2 to 4 increase in bilirubin was reported in 11% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
|
Genitourinary |
3.10.2) CLINICAL EFFECTS
A) SERUM CREATININE RAISED 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), a grade 2 to 4 increase in creatinine was reported in 14% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
|
Hematologic |
3.13.2) CLINICAL EFFECTS
A) MYELOSUPPRESSION 1) WITH THERAPEUTIC USE a) Myelosuppressive effects are more common with dexrazoxane doses greater than 1000 mg/m(2) (Prod Info Zinecard(R), dexrazoxane, 1995). Leukopenia is most common, thrombocytopenia may also occur and anemia is least common (Holcenberg et al, 1986; Liesmann et al, 1981; Koeller et al, 1981).
b) Dexrazoxane may contribute to myelosuppression caused by chemotherapy. Leukopenia, granulocytopenia, and thrombocytopenia were more severe at nadir in patients receiving dexrazoxane and FAC (fluorouracil, doxorubicin, and cyclophosphamide) than in patients who received FAC without dexrazoxane. Recovery counts were similar for both groups of patients ((Prod Info Zinecard(R) intravenous injection, 2012; Koeller et al, 1981a; Liesmann et al, 1981a).
c) Patients receiving fluorouracil, doxorubicin and cyclophosphamide (FAC) with dexrazoxane experienced more severe leukopenia, granulocytopenia and thrombocytopenia at nadir than patients receiving FAC without dexrazoxane. Recovery counts were similar for both groups of patients (Liesmann et al, 1981; Koeller et al, 1981).
B) LEUKOPENIA 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), a grade 2 to 4 decrease in white blood cells was reported in 73% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
C) NEUTROPENIA 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), a grade 2 to 4 decrease in neutrophils was reported in 61% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
D) THROMBOCYTOPENIC DISORDER 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), a grade 2 to 4 decrease in platelets was reported in 26% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
E) DECREASED HEMOGLOBIN 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), a grade 2 to 4 decrease in hemoglobin was reported in 43% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
F) BLOOD COAGULATION PATHWAY FINDING 1) WITH THERAPEUTIC USE a) Prolonged PT and PTT developed in three of 48 patients in one study. One patient developed decreased fibrinogen levels and two others developed decreases in specific clotting factors (Holcenberg et al, 1986).
|
Dermatologic |
3.14.2) CLINICAL EFFECTS
A) ALOPECIA 1) WITH THERAPEUTIC USE a) Alopecia may develop at therapeutic doses (Holcenberg et al, 1986; Liesmann et al, 1981).
b) In 2 clinical studies (n=80), alopecia was reported in 14% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
B) SKIN NECROSIS 1) WITH THERAPEUTIC USE a) Cutaneous and subcutaneous necrosis, and panniculitis have been reported in a 42-year-old woman who received dexrazoxane by infusion into a peripheral right forearm vein followed by intravenous injection of doxorubicin through a different venous line in the same arm. She developed severe forearm pain followed by swelling and erythema (Lossos & Ben-Yehuda, 1999).
b) In another case report including 2 patients, extravasation of dexrazoxane did not cause a cutaneous reaction in either patient (Koeller et al, 1981).
C) INJECTION SITE PAIN 1) WITH THERAPEUTIC USE a) In 2 clinical trials (n=80), injection site pain was reported in 16% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
|
Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) MUSCULOSKELETAL FINDING 1) WITH THERAPEUTIC USE a) In 2 clinical studies (n=80), musculoskeletal and connective tissue disorders were reported in 13% of patients receiving 1 to 3 doses of dexrazoxane hydrochloride for extravasation from intravenous anthracycline chemotherapy (Prod Info Totect(R) Kit intravenous infusion injection, 2013).
|
Reproductive |
3.20.1) SUMMARY
A) Dexrazoxane is classified as a FDA pregnancy category D. While there are no human data, in animal studies dexrazoxane has caused embryo deaths and malformations and agenesis in skeletal and organ systems, respectively.
3.20.2) TERATOGENICITY
A) LACK OF INFORMATION 1) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info Zinecard(R) intravenous injection, 2012; Prod Info Totect(TM) intravenous injection, 2009) .
B) ANIMAL STUDIES 1) RATS: In pregnant rats, doses of 8 mg/kg (about one-twentieth (Totect(TM) to one-tenth (Zinecard(R)) of the human dose on a mg/m(2) basis) were embryotoxic and teratogenic when given daily during organogenesis. Teratogenic effects included imperforate anus, microphthalmia, and anophthalmia (Prod Info Zinecard(R) intravenous injection, 2012; Prod Info Totect(TM) intravenous injection, 2009).
2) RABBITS: In pregnant rabbits, daily doses of 20 mg/kg (about one-fourth (Totect(TM)) to one-half (Zinecard(R)) of the human dose on a mg/m(2) basis) given during organogenesis showed embryotoxicity and teratogenicity, including skeletal deformities; subcutaneous, eye, and cardiac hemorrhages; and agenesis of the gallbladder and intermediate lung lobe (Prod Info Zinecard(R) intravenous injection, 2012; Prod Info Totect(TM) intravenous injection, 2009).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY 1) Dexrazoxane is classified as a FDA pregnancy category D (Prod Info Zinecard(R) intravenous injection, 2012; Prod Info Totect(TM) intravenous injection, 2009).
B) ANIMAL STUDIES 1) RATS: Maternal toxicity was reported in pregnant rats at doses of 2 mg/kg (one-fortieth the human dose of Zinecard(R) on a mg/m(2) basis) administered daily during organogenesis (Prod Info Zinecard(R) intravenous injection, 2012).
2) RABBITS: Maternal toxicity was reported in pregnant rabbits at doses of 5 mg/kg (approximately one-tenth the human dose of Zinecard(R) on a mg/m(2) basis) administered daily during organogenesis (Prod Info Zinecard(R) intravenous injection, 2012).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) BREASTMILK 1) It is not known whether dexrazoxane or its metabolites are excreted in human milk, and the potential for adverse effects in the nursing infant from exposure to the drug is unknown. Due to the lack of human safety information, a decision should be made whether to discontinue nursing or discontinue therapy after taking into consideration the importance of the drug to the mother (Prod Info Zinecard(R) intravenous injection, 2012; Prod Info Totect(TM) intravenous injection, 2009).
3.20.5) FERTILITY
A) ANIMAL STUDIES 1) RATS, DOGS: Doses of 8 mg/kg of dexrazoxane in rats (about one-twentieth of the human dose for Totect(TM) and one-tenth of the human dose for Zinecard(R) on a mg/m(2) basis) given daily during organ formation impaired the fertility of mature offspring of both sexes. Over 6 weeks, testicular atrophy occurred in rats with weekly doses as low as 30 mg/kg (about one-fifth the human dose for Totect(TM) and one-third of the human dose for Zinecard(R) on a mg/m(2) basis), and in 13 weeks in dogs with doses as low as 20 mg/kg weekly (about one-half the human dose for Totect(TM) and equal to the human dose for Zinecard(R) on a mg/m(2) basis) (Prod Info Zinecard(R) intravenous injection, 2012; Prod Info Totect(TM) intravenous injection, 2009).
|
Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) Secondary malignancies such as acute myeloid leukemia and myelodysplastic syndrome have been reported in pediatric patients who received dexrazoxane in combination with chemotherapy. Razoxane (of which dexrazoxane is the S(+) enantiomer) use has also resulted in secondary malignancies, primarily acute myeloid leukemia, in patients who were receiving doses up to 480 g and duration of treatment up to 319 weeks. Cutaneous basal cell or squamous cell carcinoma (6 to 8 cases), as well as a case each of T- and B-cell lymphoma, have also been reported in patients treated with razoxane.
3.21.3) HUMAN STUDIES
A) LEUKEMIA 1) Secondary malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have been reported in pediatric patients who received dexrazoxane in combination with chemotherapy (Prod Info Zinecard(R) intravenous injection, 2012).
2) Secondary malignancies (primarily acute myeloid leukemia) have been reported in patients treated chronically with oral razoxane (razoxane being a racemic mixture), of which dexrazoxane is the S(+) enantiomer. Cumulative doses of razoxane resulting in secondary malignancies ranged from 26 to 480 g with a duration of treatment from 42 to 319 weeks (Prod Info Zinecard(R) intravenous injection, 2012).
B) CARCINOMA 1) Six to eight cases of cutaneous basal cell or squamous cell carcinoma, one case of T-cell lymphoma, and one case of B-cell lymphoma have been reported in patients treated with razoxane (Prod Info Zinecard(R) intravenous injection, 2012).
3.21.4) ANIMAL STUDIES
A) MALIGNANCIES 1) RATS: The long-term use of razoxane, a racemic mixture of which dexrazoxane is the S(+) enantiomer, was associated with the development of malignancies in rats, and possibly mice, in a study by the National Cancer Institute (Prod Info Zinecard(R) intravenous injection, 2012; Prod Info Totect(TM) intravenous injection, 2009).
|
Genotoxicity |
A) Dexrazoxane was found to be mutagenic and clastogenic (Prod Info Totect(TM) intravenous injection, 2009). Although dexrazoxane was not mutagenic in the Ames test, the drug was found to be clastogenic to human lymphocytes in vitro and to mouse bone marrow erythrocytes in vivo (Prod Info Zinecard(R) intravenous injection, 2012; Prod Info Totect(TM) intravenous injection, 2009).
|