DAUNORUBICIN: 9,852 Adverse Event Reports & Safety Profile

DESCRIPTION Daunorubicin hydrochloride is the hydrochloride salt of an anthracycline cytotoxic antibiotic produced by a strain of Streptomyces coeruleorubidus . It is provided as a deep red sterile liquid in vials for intravenous administration only. Each mL contains 5 mg daunorubicin (equivalent to 5.34 mg of daunorubicin hydrochloride), 9 mg sodium chloride; sodium hydroxide and/or hydrochloric acid (to adjust pH), and water for injection, q.s. It has the following structural formula which may be described with the chemical name of (1S,3S)-3-Acetyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1-naphthacenyl 3-amino-2,3,6-trideoxy-α-L- lyxo -hexopyranoside hydrochloride. Its molecular formula is C 27 H 29 NO 10

• HCl with a molecular weight of 563.99. It is a hygroscopic crystalline powder. The pH of a 5 mg/mL aqueous solution is 3 to 4. daunorubicin-hcl-media-id-001

INDICATIONS AND USAGE Daunorubicin hydrochloride injection 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.

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 daunorubicin hydrochloride injection 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: Serum Bilirubin Serum Creatinine Dose Reduction 1.2 to 3 mg% — 25% >3 mg% — 50% — >3 mg% 50% Representative Dose Schedules and Combination for the Approved Indication of Remission Induction in Adult Acute Nonlymphocytic Leukemia: In Combination For patients under age 60, daunorubicin hydrochloride injection 45 mg/m 2 /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/m 2 /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, daunorubicin hydrochloride injection 30 mg/m 2 /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/m 2 /day IV infusion daily for 7 days for the first course and for 5 days for subsequent courses. This daunorubicin hydrochloride injection 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 Daunorubicin hydrochloride injection 25 mg/m 2 IV on day 1 every week, vincristine 1.5 mg/m 2 IV on day 1 every week, prednisone 40 mg/m 2 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 daunorubicin hydrochloride injection 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 Daunorubicin hydrochloride injection 45 mg/m 2 /day IV on days 1, 2, and 3 AND vincristine 2 mg IV on days 1, 8, and 15; prednisone 40 mg/m 2 /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. The sterile vial contents provide 20 mg or 50 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. Daunorubicin hydrochloride injection should not be administered mixed with other drugs or heparin. Storage and Handling Store unopened vials in refrigerator, 2° to 8°C (36° to 46°F). Store prepared solution for infusion at room temperature, 15° to 30°C (59° to 86°F) for up to 24 hours. Contains no preservative. Discard unused portion. Protect from light. If daunorubicin hydrochloride injection 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.

CONTRAINDICATIONS Daunorubicin hydrochloride injection is contraindicated in patients who have shown a hypersensitivity to it.

ADVERSE REACTIONS Dose-limiting toxicity includes myelosuppression and cardiotoxicity (see WARNINGS section). Other reactions include: Cutaneous Reversible alopecia occurs in most patients. Rash, contact dermatitis and urticaria have occurred rarely.

Gastrointestinal

Acute nausea and vomiting occur but are usually mild. Antiemetic therapy may be of some help. Mucositis may occur 3 to 7 days after administration. Diarrhea and abdominal pain have occasionally been reported. Local If extravasation occurs during administration, severe local tissue necrosis, severe cellulitis, thrombophlebitis, or painful induration can result.

Acute Reactions

Rarely, anaphylactoid reaction, fever, and chills can occur. Hyperuricemia may occur, especially in patients with leukemia, and serum uric acid levels should be monitored. To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals, Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

WARNINGS Bone Marrow Daunorubicin hydrochloride is a potent bone marrow suppressant. Suppression will occur in all patients given a therapeutic dose of this drug. Therapy with daunorubicin hydrochloride 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 daunorubicin hydrochloride, particularly in infants and children. Pre-existing heart disease and previous therapy with doxorubicin are co-factors of increased risk of daunorubicin-induced cardiac toxicity and the benefit-to-risk ratio of daunorubicin hydrochloride therapy in such patients should be weighed before starting daunorubicin hydrochloride. In adults, at total cumulative doses less than 550 mg/m 2 , 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/m 2 , 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/m 2 , in patients who received radiation therapy that encompassed the heart. In infants and children, there appears to be a greater susceptibility to anthracycline-induced cardiotoxicity 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 daunorubicin hydrochloride 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 daunorubicin hydrochloride. 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 daunorubicin hydrochloride. 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 daunorubicin hydrochloride; therefore, prior to administration, evaluation of hepatic function and renal function using conventional clinical laboratory tests is recommended (see DOSAGE AND ADMINISTRATION section ).

Pregnancy

Daunorubicin hydrochloride 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 topoisomerase II inhibitors when used in combination with other antineoplastic agents or radiation therapy. Extravasation at Injection Site Extravasation of daunorubicin hydrochloride at the site of intravenous administration can cause severe local tissue necrosis. (see ADVERSE REACTIONS section)

PRECAUTIONS General Therapy with daunorubicin hydrochloride requires close patient observation and frequent complete blood-count determinations. Cardiac, renal, and hepatic function should be evaluated prior to each course of treatment. Appropriate measures must be taken to control any systemic infection before beginning therapy with daunorubicin hydrochloride. Daunorubicin hydrochloride may transiently impart a red coloration to the urine after administration, and patients should be advised to expect this.

Laboratory Tests

Daunorubicin hydrochloride may induce hyperuricemia secondary to rapid lysis of leukemic cells. As a precaution, allopurinol administration is usually begun prior to initiating antileukemic therapy. Blood uric acid levels should be monitored and appropriate therapy initiated in the event that hyperuricemia develops. Carcinogenesis, Mutagenesis, Impairment of Fertility Daunorubicin hydrochloride, when injected subcutaneously into mice, causes fibrosarcomas to develop at the injection site. When administered to mice thrice weekly intraperitoneally, no carcinogenic effect was noted after 18 months of observation. In male rats administered daunorubicin thrice weekly for 6 months, at 1/70th the recommended human dose on a body surface area basis, peritoneal sarcomas were found at 18 months. A single IV dose of daunorubicin administered to rats at 1.6 fold the recommended human dose on a body surface area basis caused mammary adenocarcinomas to appear at 1 year. Daunorubicin was mutagenic in vitro (Ames assay, V79 hamster cell assay), and clastogenic in vitro (CCRFCEM human lymphoblasts) and in vivo (SCE assay in mouse bone marrow) tests. In male dogs at a daily dose of 0.25 mg/kg administered intravenously, testicular atrophy was noted at autopsy. Histologic examination revealed total aplasia of the spermatocyte series in the seminiferous tubules with complete aspermatogenesis.

Pregnancy

Category D (See WARNINGS section)

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from daunorubicin, mothers should be advised to discontinue nursing during daunorubicin therapy.

Elderly

See CLINICAL PHARMACOLOGY , Special Populations , Geriatric Patients section.

Pediatric Use

See CLINICAL PHARMACOLOGY , Special Populations , Pediatric Patients section and WARNINGS , Cardiac Effects section.

Drug Interactions

Use of daunorubicin in a patient who has previously received doxorubicin increases the risk of cardiotoxicity. Daunorubicin hydrochloride should not be used in patients who have previously received the recommended maximum cumulative doses of doxorubicin or daunorubicin hydrochloride. Cyclophosphamide used concurrently with daunorubicin hydrochloride may also result in increased cardiotoxicity. Dosage reduction of daunorubicin hydrochloride may be required when used concurrently with other myelosuppressive agents. Hepatotoxic medications, such as high-dose methotrexate, may impair liver function and increase the risk of toxicity.

Drug Interactions Use of daunorubicin in a patient who has previously received doxorubicin increases the risk of cardiotoxicity. Daunorubicin hydrochloride should not be used in patients who have previously received the recommended maximum cumulative doses of doxorubicin or daunorubicin hydrochloride. Cyclophosphamide used concurrently with daunorubicin hydrochloride may also result in increased cardiotoxicity. Dosage reduction of daunorubicin hydrochloride may be required when used concurrently with other myelosuppressive agents. Hepatotoxic medications, such as high-dose methotrexate, may impair liver function and increase the risk of toxicity.