Cerubidine

Bone Marrow: Cerubidine (daunorubicin) is a potent bone marrow suppressant. Suppression will occur in all patients given a therapeutic dose of this drug. Therapy with Cerubidine (daunorubicin) should not be started in patients with pre-existing drug-induced bone marrow suppression unless the benefit from such treatment warrants the risk. Persistent, severe myelosuppression may result in superinfection or hemorrhage.

Cardiac Effects: Special attention must be given to the potential cardiac toxicity of Cerubidine (daunorubicin) , particularly in infants and children. Pre-existing heart disease and previous therapy with doxorubicin are co-factors of increased risk of Cerubidine (daunorubicin) -induced cardiac toxicity and the benefit-to-risk ratio of Cerubidine (daunorubicin) therapy in such patients should be weighed before starting Cerubidine (daunorubicin) . In adults, at total cumulative doses less than 550 mg/m2, acute congestive heart failure is seldom encountered. However, rare instances of pericarditis-myocarditis, not dose-related, have been reported.

In adults, at cumulative doses exceeding 550 mg/m2, there is an increased incidence of drug-induced congestive heart failure. Based on prior clinical experience with doxorubicin, this limit appears lower, namely 400 mg/m2, in patients who received radiation therapy that encompassed the heart.

In infants and children, there appears to be a greater susceptibility to anthracycline-induced car-diotoxicity compared to that in adults, which is more clearly dose-related. Anthracycline therapy (including daunorubicin) in pediatric patients has been reported to produce impaired left ventricular systolic performance, reduced contractility, congestive heart failure or death. These conditions may occur months to years following cessation of chemotherapy. This appears to be dose-dependent and aggravated by thoracic irradiation. Long-term periodic evaluation of cardiac function in such patients should, thus, be performed. In both children and adults, the total dose of Cerubidine (daunorubicin) administered should also take into account any previous or concomitant therapy with other potentially cardiotoxic agents or related compounds such as doxorubicin.

There is no absolutely reliable method of predicting the patients in whom acute congestive heart failure will develop as a result of the cardiac toxic effect of Cerubidine (daunorubicin) . However, certain changes in the electrocardiogram and a decrease in the systolic ejection fraction from pre-treatment baseline may help to recognize those patients at greatest risk to develop congestive heart failure. On the basis of the electrocardiogram, a decrease equal to or greater than 30% in limb lead QRS voltage has been associated with a significant risk of drug-induced cardiomyopathy. Therefore, an electrocardiogram and/or determination of systolic ejection fraction should be performed before each course of Cerubidine (daunorubicin) . In the event that one or the other of these predictive parameters should occur, the benefit of continued therapy must be weighed against the risk of producing cardiac damage. Early clinical diagnosis of drug-induced congestive heart failure appears to be essential for successful treatment.

Evaluation of Hepatic and Renal Function: Significant hepatic or renal impairment can enhance the toxicity of the recommended doses of Cerubidine (daunorubicin) ; therefore, prior to administration, evaluation of hepatic function and renal function using conventional clinical laboratory tests is recommended (See DOSAGE AND ADMINISTRATION).

Pregnancy: Cerubidine (daunorubicin) may cause fetal harm when administered to a pregnant woman. An increased incidence of fetal abnormalities (parieto-occipital cranioschisis, umbilical hernias, or rachischisis) and abortions was reported in rabbits at doses of 0.05 mg/kg/day or approximately 1/100th of the highest recommended human dose on a body surface area basis. Rats showed an increased incidence of esophageal, cardiovascular and urogenital abnormalities as well as rib fusions at doses of 4 mg/kg/day or approximately 1/2 the human dose on a body surface area basis. Decreases in fetal birth weight and post-delivery growth rate were observed in mice. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Secondary Leukemias: There have been reports of secondary leukemias in patients exposed to topoi-somerase II inhibitors when used in combination with other antineoplastic agents or radiation therapy.

Extravasation at Injection Site: Extravasation of Cerubidine (daunorubicin) at the site of intravenous administration can cause severe local tissue necrosis. (See ADVERSE REACTIONS)

Dosage Forms & Strengths

injectable solution

• 5mg/mL

powder for injection

• 20mg

Acute Nonlymphocytic Leukemia

In combination with cytarabine 100 mg/m²/day IV for 7 days first course, for 5 days subsequent courses 

<60 years old: 45 mg/m² IVP days 1, 2, 3 first course; days 1, 2 subsequent courses

>60 years old: 30 mg/m² IVP days 1, 2, 3 first course; days 1, 2 subsequent courses

Monitor: Cardiac, renal, hepatic function

Acute Lymphocytic Leukemia

45 mg/m² IVP days 1, 2, 3 

Monitor: Cardiac, renal, hepatic function

Renal Impairment

>3 mg/dL serum creatinine: Administer 50% regular dose

Hepatic Impairment

< 1.2 mg/dL serum bilirubin: Dose adjustment not necessary

1.2-3 mg/dL serum bilirubin: 75% of regular dose

> 3 mg/dL serum bilirubin: 50% of regular dose

Administration

Limit lifetime dose to <550 mg/m² (including doses of related drugs) to reduce risk of cardiotoxicity (400 mg/m² for patients who received irradiation of cardiac region)

Dosage Forms & Strengths

injectable solution

• 5mg/mL

powder for injection

• 20mg

Acute Nonlymphocytic Leukemia

<2 years old or <0.5 m² BSA: 1 mg/kg IVP qWeek 

>2 years old or >0.5 m² BSA: 25 mg/m² IVP qWeek

Monitor: Cardiac, renal, hepatic function

Acute Lymphocytic Leukemia

<2 years old or <0.5 m² BSA: 1 mg/kg IVP qWeek

>2 years old or >0.5 m² BSA: 25 mg/m² IVP qWeek 

Monitor: Cardiac, renal, hepatic function

Administration

Limit lifetime dose for children 2 years old or older to 300 mg/sq.meter, and for children <2 years old to 10 mg/kg to avoid irreversible cardiotoxicity

>10%

Nausea

Vomiting

Arrhythmias

Discoloration of urine

Alopecia

1-10%

Injection site skin flare

Hyperuricemia

GI ulceration

Diarrhea

<1%

Arrythmia

Cardiomyopathy

Bilirubin increased

Pruritus

Urticaria

Frequency Not Defined

Fever

CHF

Flushing

Stomatitis

Myelosuppression

Rash

Hyperpigmentation of previously radiated areas

Transverse pigmentation of fingernails and toenails

Fertility impairment

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Cerubidine falls into category D. It has been shown that use of cerubidine in pregnant women caused some babies to be born with problems. However, in some serious situations, the benefit of using this medication may be greater than the risk of harm to the baby.

Daunorubicin is injected into a vein through an IV. A healthcare provider will give you this injection.

Before you receive each dose of daunorubicin, your heart function may need to be checked with an electrocardiograph or ECG (sometimes called an EKG). Your kidney and liver function may also need to be checked.

Tell your caregivers if you feel any burning, pain, or swelling around the IV needle when daunorubicin is injected.

Skin accidentally exposed to daunorubicin should be rinsed thoroughly with soap and warm water.

Daunorubicin can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests.

Daunorubicin is sometimes given together with certain other medicines. If you are using a combination of medicines, it is important that you receive each one at the proper time. If you are taking some of these medicines by mouth, ask your health care professional to help you plan a way to take them at the right times.

While you are receiving daunorubicin, your doctor may want you to drink extra fluids so that you will pass more urine. This will help prevent kidney problems and keep your kidneys working well.

This medicine often causes nausea and vomiting. However, it is very important that you continue to receive it, even if you begin to feel ill. Ask your health care professional for ways to lessen these effects.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

Mechanism of Action

Cerubidine has antimitotic and cytotoxic activity through a number of proposed mechanisms of action. Cerubidine forms complexes with DNA by intercalation between base pairs. It inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. Single strand and double strand DNA breaks result.

Cerubidine may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA.

Cerubidine possesses an antitumor effect against a wide spectrum of animal tumors, either grafted or spontaneous.

Pharmacokinetics

Following intravenous injection of Cerubidine, plasma levels of daunorubicin decline rapidly, indicating rapid tissue uptake and concentration. Thereafter, plasma levels decline slowly with a half-life of 45 minutes in the initial phase and 18.5 hours in the terminal phase. By 1 hour after drug administration, the predominant plasma species is daunorubicinol, an active metabolite, which disappears with a half-life of 26.7 hours.

Cerubidine is rapidly and widely distributed in tissues, with highest levels in the spleen, kidneys, liver, lungs, and heart. The drug binds to many cellular components, particularly nucleic acids. There is no evidence that Cerubidine crosses the blood-brain barrier, but the drug apparently crosses the placenta.

Cerubidine is extensively metabolized in the liver and other tissues, mainly by cytoplasmic aldo-keto reductases, producing daunorubicinol, the major metabolite which has antineoplastic activity. Approximately 40% of the drug in the plasma is present as daunorubicinol within 30 minutes and 60% in 4 hours after a dose of daunorubicin. Further metabolism via reduction cleavage of the glycosidic bond, 4-O demethylation, and conjugation with both sulfate and glucuronide have been demonstrated. Simple glycosidic cleavage of daunorubicin or daunorubicinol is not a significant metabolic pathway in man. Twenty-five percent of an administered dose of Cerubidine is eliminated in an active form by urinary excretion and an estimated 40% by biliary excretion.

Special Populations

Although appropriate studies with Cerubidine have not been performed in the pediatric population, cardiotoxicity may be more frequent and occur at lower cumulative doses in children.

Although appropriate studies with Cerubidine have not been performed in the geriatric population, cardiotoxicity may be more frequent in the elderly. Caution should also be used in patients who have inadequate bone marrow reserves due to old age. In addition, elderly patients are more likely to have age-related renal function impairment, which may require reduction of dosage in patients receiving Cerubidine.

Doses of Cerubidine should be reduced in patients with hepatic and renal impairment. Patients with serum bilirubin concentrations of 1.2 to 3 mg/dL should receive 75% of the usual daily dose and patients with serum bilirubin concentrations greater than 3 mg/dL should receive 50% of the usual daily dose. Patients with serum creatinine concentrations of greater than 3 mg/dL should receive 50% of the usual daily dose. (See WARNINGS, Evaluation of Hepatic and Renal Function).

Clinical Studies

In the treatment of adult acute nonlymphocytic leukemia, Cerubidine, used as a single agent, has produced complete remission rates of 40 to 50%, and in combination with cytarabine, has produced complete remission rates of 53 to 65%.

The addition of Cerubidine to the two-drug induction regimen of vincristine-prednisone in the treatment of childhood acute lymphocytic leukemia does not increase the rate of complete remission. In children receiving identical CNS prophylaxis and maintenance therapy (without consolidation), there is prolongation of complete remission duration (statistically significant, p<0.02) in those children induced with the three drug (Cerubidine-vincristine-prednisone) regimen as compared to two drugs. There is no evidence of any impact of Cerubidine on the duration of complete remission when a consolidation (intensification) phase is employed as part of a total treatment program.

In adult acute lymphocytic leukemia, in contrast to childhood acute lymphocytic leukemia, Cerubidine during induction significantly increases the rate of complete remission, but not remission duration, compared to that obtained with vincristine, prednisone, and L-asparaginase alone. The use of Cerubidine in combination with vincristine, prednisone, and L-asparaginase has produced complete remission rates of 83% in contrast to a 47% remission in patients not receiving Cerubidine.

Cerubidine in combination with other approved anticancer drugs is indicated for remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults and for remission induction in acute lymphocytic leukemia of children and adults.

Cerubidine is contraindicated in patients who have shown a hypersensitivity to it.

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