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Basic Drug Info
Drug Name:RUBEX
Manufacturer:Bristol-Myers Squibb Company
Other Info:3351DIM-08 51-004726-04 1085217A2Revised: May 2001



Clinical Trials:


Indications and Usage
RUBEX (doxorubicin hydrochloride for injection, USP) has been used successfully to produce regression in disseminated neoplastic conditions such as acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilms’ tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin’s disease, malignant lymphoma and bronchogenic carcinoma in which the small cell histologic type is the most responsive compared to other cell types.
Disease regression -- A decrease in the size of a tumor or in the extent of cancer in the body.

Acute lymphocytic leukemia -- acute leukemia in which lymphoblasts and their progenitor cells predominate; the most common childhood cancer and accounts for 20 percent of adult acute leukemia; common ALL antigen (CALLA) expressed in most cases.

Precursor Cell Lymphoblastic Leukemia Lymphoma -- A neoplasm characterized by abnormalities of the lymphoid cell precursors leading to excessive lymphoblasts in the marrow and other organs. It is the most common cancer in children and accounts for the vast majority of all childhood leukemias.

Leukemia, Myelocytic, Acute -- acute leukemia arising from myeloid tissue in which the granular, polymorphonuclear leukocytes and their precursors predominate.

Nephroblastoma -- pediatric nephroblastoma originating from embryonic kidney stem cells; usually affects children before the fifth year, but may occur in the fetus or rarely in later life; caused by defects in one or more tumor suppressor genes.

Central neuroblastoma --

Neuroblastoma -- A common neoplasm of early childhood arising from neural crest cells in the sympathetic nervous system, and characterized by diverse clinical behavior, ranging from spontaneous remission to rapid metastatic progression and death. This tumor is the most common intraabdominal malignancy of childhood, but it may also arise from thorax, neck, or rarely occur in the central nervous system. Histologic features include uniform round cells with hyperchromatic nuclei arranged in nests and separated by fibrovascular septa. Neuroblastomas may be associated with the opsoclonus-myoclonus syndrome. (From DeVita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2099-2101; Curr Opin Oncol 1998 Jan;10(1):43-51)

Bone Sarcoma -- A malignant mesenchymal tumor arising from the bone.

Breast Carcinoma -- (brest KAN-ser) Cancer that forms in tissues of the breast, usually the ducts (tubes that carry milk to the nipple) and lobules (glands that make milk). It occurs in both men and women, although male breast cancer is rare.

Epithelial ovarian cancer -- (ep-ih-THEE-lee-ul) Cancer that occurs in the cells lining the ovaries.

Ovarian Carcinoma --

transitional cell carcinoma -- A malignant neoplasm derived from transitional epithelium, occurring chiefly in the urinary bladder, ureters or renal pelves (especially if well differentiated), frequently papillary. Transitional cell carcinomas are graded 1 to 3 or 4 according to the degree of anaplasia, grade 1 appearing histologically benign but being liable to recurrence. (Stedman, 25th ed)

Thyroid carcinoma -- A carcinoma arising from the thyroid gland. It is usually an adenocarcinoma and includes the following main subtypes: follicular, papillary, medullary, poorly differentiated, and anaplastic. --2003

Stomach Carcinoma -- A malignant epithelial tumor of the stomach mucosa. The vast majority of gastric carcinomas are adenocarcinomas, arising from the gastric glandular epithelium. --2002

Hodgkins Disease -- A malignant disease characterized by progressive enlargement of the lymph nodes, spleen, and general lymphoid tissue. In the classical variant, giant usually multinucleate Hodgkin's and REED-STERNBERG CELLS are present; in the nodular lymphocyte predominant variant, lymphocytic and histiocytic cells are seen.

Lymphoma -- A general term for various neoplastic diseases of the lymphoid tissue.

Bronchogenic Carcinoma -- Malignant neoplasm arising from the epithelium of the BRONCHI. It represents a large group of epithelial lung malignancies which can be divided into two clinical groups: SMALL CELL LUNG CANCER and NON-SMALL-CELL LUNG CANCER.

Contraindications

Doxorubicin therapy should not be started in patients who have marked myelosuppression induced by previous treatment with other antitumor agents or by radiotherapy.

Doxorubicin treatment is contraindicated in patients who received previous treatment with complete cumulative doses of doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenes.
Myelosuppression -- A condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. Myelosuppression is a side effect of some cancer treatments.

Warnings

Special attention must be given to the cardiotoxicity induced by doxorubicin.

Irreversible myocardial toxicity, manifested in its most severe form by life-threatening or fatal congestive heart failure, may occur either during therapy or months to years after termination of therapy.

The probability of developing impaired myocardial function, based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (LVEF) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m2 of doxorubicin, 3 to 5% at a dose of 400 mg/m2, 5 to 8% at a dose of 450 mg/m2 and 6 to 20% at a dose of 500 mg/m2 given in a schedule of a bolus injection once every 3 weeks (data on file at Pharmacia & Upjohn).

In a retrospective review by Von Hoff et al, the probability of developing congestive heart failure was reported to be 5/168 (3%) at a cumulative dose of 430 mg/m2 of doxorubicin, 8/110 (7%) at 575 mg/m2 and 3/14 (21%) at 728 mg/m2.

The cumulative incidence of CHF was 2.2%.

In a prospective study of doxorubicin in combination with cyclophosphamide, fluorouracil and/or vincristine in patients with breast cancer or small cell lung cancer, the cumulative incidence of congestive heart failure was 5 to 6%.

The probability of CHF at various cumulative doses of doxorubicin was 1.5% at 300 mg/m2, 4.9% at 400 mg/m2, 7.7% at 450 mg/m2 and 20.5% at 500 mg/m2. Cardiotoxicity may occur at lower doses in patients with prior mediastinal irradiation, concurrent cyclophosphamide therapy exposure at an early age and advanced age.

Data also suggest that pre-existing heart disease is a co-factor for increased risk of doxorubicin cardiotoxicity.

In such cases, cardiac toxicity may occur at doses lower than the respective recommended cumulative dose of doxorubicin.

Studies have suggested that concomitant administration of doxorubicin and calcium channel entry blockers may increase the risk of doxorubicin cardiotoxicity.

The total dose of doxorubicin administered to the individual patient should also take into account previous or concomitant therapy with related compounds such as daunorubicin, idarubicin and mitoxantrone.

Cardiomyopathy and/or congestive heart failure may be encountered several months or years after discontinuation of doxorubicin therapy. The risk of congestive heart failure and other acute manifestations of doxorubicin cardiotoxicity in pediatric patients may be as much or lower than in adults.

Pediatric patients appear to be at particular risk for developing delayed cardiac toxicity in that doxorubicin induced cardiomyopathy impairs myocardial growth as pediatric patients mature, subsequently leading to possible development of congestive heart failure during early adulthood.

As many as 40% of pediatric patients may have subclinical cardiac dysfunction and 5 to 10% of pediatric patients may develop congestive heart failure on long term follow-up.

This late cardiac toxicity may be related to the dose of doxorubicin.

The longer the length of follow-up the greater the increase in the detection rate. Treatment of doxorubicin induced congestive heart failure includes the use of digitalis, diuretics, after load reducers such as angiotensin I converting enzyme (ACE) inhibitors, low salt diet, and bed rest.

Such intervention may relieve symptoms and improve the functional status of the patient.

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