Cerubidine® (Daunorubicin HCL)

Daunorubicin HCL - Cerubidine®

Usual Diluents

Preparation: 1
The contents of a vial should be reconstituted with 4 mL of Sterile Water for Injection and agitated gently until the material has completely dissolved. The sterile vial contents provide 20 mg of daunorubicin, with 5 mg of daunorubicin per mL. The desired dose is withdrawn into a syringe containing 10 mL to 15 mL of 0.9% Sodium Chloride Injection, USP and then injected into the tubing or sidearm in a rapidly flowing IV infusion of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP. Cerubidine should not be administered mixed with other drugs or heparin.1  May further dilute in 100 - 250 mL D5W or NS.

Storage and Handling: 1
Store unreconstituted powder at controlled room temperature, 15° to 30° C (59° to 86° F). The reconstituted solution is stable for 24 hours at room temperature and 48 hours under refrigeration. It should be protected from exposure to sunlight. Protect from light. Retain in carton until time of use.

Other:  Further dilution in D5W, LR, or NS is stable at room temperature (25°C) for up to 4 weeks if protected from light.2

Administration:
Administer as slow I.V. push over 1 to 5 minutes into the tubing of a rapidly infusing I.V. solution of D5W or NS or dilute in 100 mL of D5W or NS and infuse over 15 to 30 minutes.2

CLINICAL PHARMACOLOGY

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
General
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.

Distribution
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.

Metabolism and Elimination
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.

INDICATIONS AND USAGE
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.

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

DOSAGE AND ADMINISTRATION
Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit.

Principles
In order to eradicate the leukemic cells and induce a complete remission, a profound suppression of the bone marrow is usually required. Evaluation of both the peripheral blood and bone marrow is mandatory in the formulation of appropriate treatment plans.

It is recommended that the dosage of Cerubidine be reduced in instances of hepatic or renal impairment. For example, using serum bilirubin and serum creatinine as indicators of liver and kidney function, the following dose modifications are recommended:

Representative Dose Schedules and Combination for the Approved Indication of Remission Induction in Adult Acute Nonlymphocytic Leukemia

In Combination
For patients under age 60, Cerubidine 45 mg/m2/day IV on days 1, 2, and 3 of the first course and on days 1, 2 of subsequent courses AND cytosine arabinoside 100 mg/m2/day IV infusion daily for 7 days for the first course and for 5 days for subsequent courses.

For patients 60 years of age and above, Cerubidine 30 mg/m2/day IV on days 1, 2, and 3 of the first course and on days 1, 2 of subsequent courses AND cytosine arabinoside 100 mg/m2/day IV infusion daily for 7 days for the first course and for 5 days for subsequent courses. This Cerubidine dose-reduction is based on a single study and may not be appropriate if optimal supportive care is available.

The attainment of a normal-appearing bone marrow may require up to three courses of induction therapy. Evaluation of the bone marrow following recovery from the previous course of induction therapy determines whether a further course of induction treatment is required.

Representative Dose Schedule and Combination for the Approved Indication of Remission Induction in Pediatric Acute Lymphocytic Leukemia

In Combination
Cerubidine 25 mg/m2 IV on day 1 every week, vincristine 1.5 mg/m2 IV on day 1 every week, prednisone 40 mg/m2 PO daily. Generally, a complete remission will be obtained within four such courses of therapy; however, if after four courses the patient is in partial remission, an additional one or, if necessary, two courses may be given in an effort to obtain a complete remission.

In children less than 2 years of age or below 0.5 m2 body surface area, it has been recommended that the Cerubidine dosage calculation should be based on weight (1 mg/kg) instead of body surface area.

Representative Dose Schedules and Combination for the Approved Indication of Remission Induction in Adult Acute Lymphocytic Leukemia

In Combination
Cerubidine 45 mg/m2/day IV on days 1, 2, and 3 AND vincristine 2 mg IV on days 1, 8, and 15; prednisone 40 mg/m2/day PO on days 1 through 22, then tapered between days 22 to 29; L-asparaginase 500 IU/kg/day x 10 days IV on days 22 through 32.

Preparation:
The contents of a vial should be reconstituted with 4 mL of Sterile Water for Injection and agitated gently until the material has completely dissolved. The sterile vial contents provide 20 mg of daunorubicin, with 5 mg of daunorubicin per mL. The desired dose is withdrawn into a syringe containing 10 mL to 15 mL of 0.9% Sodium Chloride Injection, USP and then injected into the tubing or sidearm in a rapidly flowing IV infusion of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP. Cerubidine should not be administered mixed with other drugs or heparin.

Storage and Handling
Store unreconstituted powder at controlled room temperature, 15° to 30° C (59° to 86° F). The reconstituted solution is stable for 24 hours at room temperature and 48 hours under refrigeration. It should be protected from exposure to sunlight. Protect from light. Retain in carton until time of use.

If Cerubidine contacts the skin or mucosae, the area should be washed thoroughly with soap and water. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

HOW SUPPLIED
Cerubine (daunorubicin HCl) for Injection, is available in butyl-rubber-stoppered vials, each containing 21.4 mg daunorubicin hydrochloride (equivalent to 20 mg of daunorubicin) and 100 mg of mannitol, as a sterile reddish lyophilized powder. When reconstituted with 4 mL of Sterile Water for Injection, USP, each mL contains 5 mg daunorubicin activity.

NDC 55390-281-10 20 mg, single dose vials; carton of 10.

2) Solimando, Dominic A. Drug Information Handbook for Oncology: A Complete Guide to Combination Chemotherapy Regimens, 8th ed. Hudson, OH: Lexi-Comp, Inc.; 2010.

Proper handling and disposal: Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA, March 15,1985. National Study Commission on Cytotoxic Exposure Recommendations for Handling Cytotoxic Agents. Available from Louis R Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied HealthSciences, 179 Longwood Avenue, Boston, Massachusetts 02115. Clinical Oncological Society of Australia: Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia 1:426-428, 1983. Jones RB, et al: Safe handling of chemotherapeutic agents: A report from the Mount Sinai Medical Center, Ca A Cancer Joumal for Clinicians Sept/Oct, 258-263, 1983. American Society of Hospital Pharmacists technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 47:1033-1049, 1990. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines),Am J Health-Syst Pharm, 15:1669-1685