VA Class:AN200

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• DAUNOrubicin Citrate

• DAUNOrubicin Hydrochloride

Chemical Name:

• (7S,9S)-9-acetyl-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione

Molecular Formula:

• C₂₇H₂₉NO₁₀

Daunorubicin is an anthracycline glycoside antineoplastic antibiotic produced by Streptomyces coeruleorubidus .

Leukemias

Acute Myeloid Leukemia

Daunorubicin hydrochloride is used in combination with other antineoplastic agents for the treatment of acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL) in adults.125,127,154 Cytarabine with either daunorubicin or idarubicin is a regimen of choice for remission induction in AML.127,154 Induction regimens are used to rapidly reduce the tumor burden in order to achieve complete remission, which generally is defined as less than 5% leukemic blast cells in the bone marrow, and normalization of peripheral blood counts (including hemoglobin concentration, hematocrit, granulocyte count, and platelet count), and absence of any evidence of extramedullary disease.149,154 Optimal postremission therapy has not been established, but current approaches include consolidation chemotherapy with cytarabine-based regimens similar to standard induction regimens, consolidation chemotherapy with high-dose cytarabine-based regimens (for younger adults), high-dose chemotherapy or chemoradiotherapy with autologous bone marrow rescue, or high-dose marrow-ablative therapy with allogeneic bone marrow rescue.127,154 There is no evidence of benefit from prolonged administration of chemotherapy in the treatment of AML, and most current treatment regimens in the US no longer employ maintenance therapy.154

The 2-drug regimen of daunorubicin hydrochloride and cytarabine generally results in a complete response rate of approximately 65% in patients with previously untreated AML.154 There is some evidence that dose intensity of cytarabine as a component of induction therapy may affect disease-free survival.154,156,157,158,159 (See Acute Myeloid Leukemia under Uses: Conventional Cytarabine, in Cytarabine 10:00.) Some clinicians have used thioguanine in addition to intensive therapy with daunorubicin and cytarabine for remission induction.154

Patients with AML who have complete remission of disease following induction therapy generally receive consolidation chemotherapy.154 The optimal regimen has not been established, but consolidation chemotherapy typically consists of a cytarabine-based regimen similar to that used in induction therapy administered over a short-term period.154 Consolidation therapy has ranged in duration from one to 4 or more cycles,154,157,160,161 but the optimal doses, schedules, and duration of consolidation chemotherapy remain to be established.154 Maintenance therapy for AML generally is not recommended.154

Acute Lymphocytic Leukemia

Daunorubicin hydrochloride is used as a component of combination chemotherapeutic regimens for the induction of remissions of childhood or adult acute lymphocytic (lymphoblastic) leukemia (ALL).126,127,128,129,130,131,132 Combination therapy with an asparaginase preparation, a corticosteroid (dexamethasone or prednisone), and vincristine is used as an induction regimen for non-high-risk childhood ALL.128 (For additional information on the asparaginase component of ALL regimens, see Asparaginase [Erwinia chrysanthemi] 10:00.) The use of intensive induction regimens with 4 or more drugs, including an anthracycline (e.g., daunorubicin), an asparaginase preparation, a corticosteroid (e.g., prednisone), and vincristine, with or without cyclophosphamide, may improve the rate of event-free survival but is associated with greater toxicity.128 An induction regimen containing 4 or more drugs does not appear to be necessary to achieve favorable outcomes in patients at low or standard risk of treatment failure provided adequate intensification therapy is provided following achievement of remission.128,216 Therefore, some clinicians reserve such regimens for patients with high-risk childhood ALL.128 However, other clinicians have elected to use a 4- or 5-drug induction regimen for all patients with childhood ALL regardless of presenting features.128 Induction regimens for adult ALL typically include an anthracycline, prednisone, and vincristine; some regimens also add other drugs, such as an asparaginase preparation or cyclophosphamide.129

Various drugs have been used for combination chemotherapy of childhood and adult ALL,126,127,128,129,130,131,132 and comparative efficacy of these regimens is continually being evaluated.128,129,130,131,132 Other regimens are preferred in certain subsets of patients with ALL (e.g., B-cell ALL, T-cell ALL, Philadelphia chromosome-positive ALL);129,131 specialized references and experts should be consulted for additional information.

Chronic Myelogenous Leukemia

Daunorubicin hydrochloride is used with other antineoplastic agents in the treatment of the accelerated or blastic phase of chronic myelogenous leukemia†.127

AIDS-related Kaposi's Sarcoma

Daunorubicin citrate encapsulated in liposomes is used as first-line therapy for advanced AIDS-related Kaposi's sarcoma.127,133,189 The encapsulated drug is not recommended for patients with early stages of the disease.133 Administration of daunorubicin citrate encapsulated in liposomes (see Chemistry and Stability: Chemistry) allows the drug-containing liposomes to remain circulating in plasma for prolonged periods and reduces extravasation of the drug164,169 while substantially increasing concentrations of daunorubicin in the lesions of Kaposi's sarcoma compared with administration of comparable doses of conventional (nonencapsulated) daunorubicin hydrochloride injections (see Pharmacokinetics: Distribution).133,169 Liposomal anthracycline (daunorubicin or doxorubicin) is the first-line therapy of choice for advanced AIDS-related Kaposi's sarcoma.127,189 (See Uses: AIDS-related Kaposi's Sarcoma in Doxorubicin 10:00 for overview and further discussion of therapy.) The comparative efficacy of daunorubicin citrate encapsulated in liposomes relative to liposomal doxorubicin has not been established,133,134,135,136 but liposomal daunorubicin appears to be better tolerated than and comparably effective to combination chemotherapy (e.g., conventional doxorubicin, bleomycin, and vincristine) for the management of advanced AIDS-related Kaposi's sarcoma.135,189

Results of an open-label, randomized, multicenter, controlled clinical study in patients with advanced AIDS-related Kaposi's sarcoma (e.g., those with extensive mucocutaneous disease, lymphedema, symptomatic visceral disease) who had not received prior systemic chemotherapy, response rates (using the National Institute of Allergy and Infectious Diseases [NIAID] AIDS Clinical Trials Group [ACTG] criteria for response) and quality-of-life scores were similar in patients receiving daunorubicin citrate liposomal injection (40 mg/m² every 2 weeks) to those receiving combination chemotherapy every 2 weeks with conventional antineoplastic agents (e.g., conventional doxorubicin 10 mg/m², bleomycin 15 units, vincristine 1 mg).133,135 In this study, response rates of about 23-25 or 28-30%, respectively, reportedly were observed in patients receiving daunorubicin citrate liposomal injection or combination chemotherapy with conventional antineoplastic agents while median duration of response was 110-175 or 113-168 days in patients receiving daunorubicin citrate liposomal injection or combination chemotherapy with conventional antineoplastic agents, respectively.133,135 Median time to progression of the disease was 92-115 or 99-105 days, respectively, in patients receiving daunorubicin citrate liposomal injection or combination chemotherapy with conventional antineoplastic agents while median survival was 342-369 or 291-342 days in patients receiving daunorubicin citrate liposomal injection or combination chemotherapy with conventional antineoplastic agents, respectively.133,135 It should be considered, however, that no treatment has been shown conclusively to alter the natural history of AIDS-related Kaposi's sarcoma.177,188,189,190,191,195,209 Daunorubicin citrate liposomal injection also has been used as second-line treatment of advanced AIDS-related Kaposi's sarcoma that has progressed or relapsed with anthracycline or other systemic chemotherapy;134,203,204,205,206 responses have been reported in some patients, including partial responses in a limited number of patients who previously have received conventional (nonencapsulated) doxorubicin134,203 and in at least one patient who previously has received liposomal doxorubicin.204 However, limited evidence suggests that cross-resistance between liposomal daunorubicin and prior anthracycline therapy may occur.203

Toxicity, including cardiotoxicity and myelosuppression, has occurred in patients receiving liposomal daunorubicin;133 therefore, the usual precautions of conventional (nonencapsulated) anthracycline therapy should be observed when the liposomal formulation of daunorubicin is used.133,164

Other Uses

Daunorubicin possesses activity against a wide range of grafted or spontaneous animal tumors;125 however, in contrast to doxorubicin, daunorubicin hydrochloride has not been extensively studied in the treatment of solid tumors in humans.

Reconstitution and Administration

Daunorubicin hydrochloride is administered IV into a rapidly flowing IV infusion.125 The drug is extremely irritating to tissues and, therefore, should not be given IM or subcutaneously.125 Care should be taken to avoid extravasation of the drug. (See Cautions: Local Effects.)

If daunorubicin contacts the skin or mucosa, the area should be washed promptly and thoroughly with soap and water.125

Daunorubicin hydrochloride powder for injection is reconstituted by adding 4 mL of sterile water for injection to the vial labeled as containing 20 mg of daunorubicin.125 The vial should be gently agitated until the contents are completely dissolved.125 The resultant solution contains 5 mg of daunorubicin per mL.125 The manufacturer recommends that the desired dose of the reconstituted solution be withdrawn into a syringe containing 10-15 mL of 0.9% sodium chloride injection and then injected over 2-3 minutes into the tubing or sidearm of a freely flowing IV infusion of 0.9% sodium chloride or 5% dextrose injection.125 Small veins, swollen or edematous extremities, and areas overlying joints and tendons should be avoided as injection sites. The IV injection site and surrounding area should be observed for infiltration and vein irritation during administration of the drug. Patients should be instructed to immediately report any stinging or burning; if either occurs, the infusion should be stopped and restarted at another site, preferably in a different extremity. Following injection of daunorubicin, some clinicians recommend flushing the vein with the running IV infusion for 2-5 minutes and/or injecting 5-10 mL of IV solution into the sidearm to flush any remaining drug from the tubing. Daunorubicin hydrochloride has also been diluted in 100 mL of 0.9% sodium chloride or 5% dextrose injection and infused over 30-45 minutes.

Commercially available daunorubicin hydrochloride injection containing 5 mg/mL should be diluted prior to IV administration.215 The appropriate dose of the injection should be withdrawn into a syringe containing 10-15 mL of 0.9% sodium chloride injection and then injected into the tubing or sidearm of a rapidly flowing IV infusion of 5% dextrose or 0.9% sodium chloride injection.215 The injection should not be admixed with other drugs or heparin.215

Solutions of liposomal daunorubicin citrate injection should be diluted in 5% dextrose injection and infused slowly over 60 minutes.

Although tissue necrosis associated with extravasation of the liposomally encapsulated drug has not been reported to date, liposomal daunorubicin should be considered an irritant, and the usual precautions to avoid extravasation of the drug should be followed.133 When extravasation of liposomal daunorubicin citrate occurs, application of ice packs over the site of extravasation and local infiltration of dexamethasone or hydrocortisone may help alleviate the local reaction.165,206

Commercially available liposomal daunorubicin citrate injection for IV infusion containing 2 mg of the drug per mL must be diluted prior to administration.133 The appropriate dose of liposomal daunorubicin citrate should be withdrawn from the vial with a sterile syringe and transferred unto a small-volume PVC container containing an equivalent volume of dextrose 5% injection to provide a solution containing 1 mg of the drug per mL;133 strict aseptic technique must be observed since the injection does not contain any preservative or bacteriostatic agent.133 The manufacturer states that diluents containing preservatives (e.g., benzyl alcohol) or other diluents should not be used and other drugs should not be mixed with the solution.133 Because liposomal daunorubicin citrate occurs as a liposomal dispersion of the drug, inline filters should not be used.133 The manufacturer recommends that diluted liposomal daunorubicin citrate solutions be used immediately; however, if not used immediately, the manufacturer states that diluted solutions of liposomal daunorubicin are stable for up to 6 hours when refrigerated at 2-8°C.133

Parenteral daunorubicin hydrochloride solutions should be inspected visually for particulate matter prior to administration whenever solution and container permit.125 Because liposomal daunorubicin citrate occurs as a liposomal dispersion, the injection is not clear but rather is translucent and red; the injection should not be used if precipitation or foreign matter is evident or if the injection appears opaque.133

Daunorubicin as a single-entity preparation is not interchangeable with the fixed liposomal combination of daunorubicin and cytarabine (daunorubicin/cytarabine liposomal; Vyxeos^®).217 To avoid dosing errors, clinicians should confirm the correct drug name, formulation, and dose prior to preparation and administration.217

Dosage

Dosage of daunorubicin hydrochloride is expressed in terms of daunorubicin. Dosage of daunorubicin must be based on the clinical and hematologic response and tolerance of the patient and whether or not other chemotherapy or radiation therapy has been or is also being used in order to obtain optimum therapeutic results with minimum adverse effects. Clinicians should consult published protocols for the dosage of daunorubicin and other chemotherapeutic agents and the method and sequence of administration.

Conventional Daunorubicin Hydrochloride

Acute Myeloid Leukemia

In combination chemotherapy for remission induction in acute myeloid leukemia, the usual dosage of daunorubicin for adults younger than 60 years of age is 45 mg/m² (30 mg/m² for adults 60 years of age and older) administered daily on 3 successive days of the first course of induction therapy, and daily on 2 successive days of subsequent courses.125 Up to 3 courses of induction therapy may be required for optimal response.125

Acute Lymphocytic Leukemia

In combination chemotherapy for remission induction in acute lymphocytic leukemia in adults, the usual dose of daunorubicin is 45 mg/m² administered daily on the first 3 days of a course of induction therapy.125,126

In combination chemotherapy for remission induction in acute lymphocytic leukemia in children, the usual dose of daunorubicin is 25 mg/m² administered on the first day of each week.125 A complete remission generally will be obtained within 4 courses of therapy; if a partial remission is obtained following 4 courses of therapy, 1 or 2 additional courses of therapy may be administered in an effort to achieve a complete remission.125

In children younger than 2 years of age or with a body surface area of less than 0.5 m², the manufacturer states that daunorubicin dosage should be calculated on the basis of body weight (1 mg/kg) rather than body surface area.125

Consolidation and Cumulative Dosage

Appropriate consolidation therapy may be initiated after induction of a complete remission.

Total daunorubicin dosage should not exceed 550 mg/m² in adults because of the risk of cumulative cardiotoxicity.125 Cardiotoxicity may occur more frequently and at lower cumulative dosages of daunorubicin in children than in adults.125 In both adults and children, the total daunorubicin dosage administered should take into account previous or concomitant therapy with other potentially cardiotoxic agents or with related drugs such as doxorubicin.125 (See Cautions: Cardiac Effects and Precautions and Contraindications.) In adults who received irradiation of the cardiac region, congestive heart failure may occur at a lower cumulative dosage, and total daunorubicin dosage in these patients should be limited to 400 mg/m².125

Liposomal Daunorubicin Citrate

Kaposi's Sarcoma

The usual adult dosage of liposomal daunorubicin citrate for the first-line treatment of advanced AIDS-related Kaposi's sarcoma is 40 mg/m² administered as a 60-minute IV infusion once every 2 weeks.133 Blood cell counts should be performed prior to each dose of liposomal daunorubicin citrate.133 If absolute granulocyte count is less than 750/ mm³, therapy with the drug should be withheld until the counts exceed this level.133 Treatment should be continued until there is evidence of progressive disease (e.g., based on best response achieved, new visceral sites of involvement or progression of visceral disease, development of 10 or more new cutaneous lesions or a 25% increase in the number of lesions compared with baseline, a change in the character of 25% or more of all previously counted flat lesions to raised lesions, increased surface area of the indicator lesions) or until other complications of HIV disease preclude continuation of therapy.133

Dosage in Renal and Hepatic Impairment

Doses of conventional or liposomal daunorubicin should be reduced in patients with hepatic or renal impairment.125,133 The manufacturers recommend that patients with serum bilirubin concentrations of 1.2-3 mg/dL receive 75% of the usual dose and those with serum bilirubin concentrations exceeding 3 mg/dL receive 50% of the usual dose of daunorubicin.125,133 The manufacturers recommend that patients with serum creatinine concentrations exceeding 3 mg/dL receive 50% of the usual dose of daunorubicin.125,133

Hematologic Effects

Hematologic toxicity occurs in all patients receiving daunorubicin.125 Severe myelosuppression occurs when daunorubicin is used in therapeutic dosages; this may cause infection or hemorrhage.125 Myelosuppression is manifested primarily by leukopenia, which is usually severe, and thrombocytopenia; anemia may also occur.

The principal dose-limiting toxicity of liposomal daunorubicin in patients with AIDS-related Kaposi's sarcoma has been myelosuppression, mainly granulocytopenia, which may be severe and associated with fever, and may result in infection;133,164 liposomal daunorubicin has a lesser effect on platelets and erythroid cells.133 Neutropenia (neutrophil count of less than 1000/mm³) has been reported in 51% (15% having a neutrophil count of less than 500/mm³) of patients receiving the liposomal preparation.133,135,164 However, experience with liposomal daunorubicin has been principally in patients who had baseline myelosuppression secondary to their underlying human immunodeficiency virus (HIV) infection and/or numerous concomitant drug therapy.133,164 Opportunistic infections, probably associated with severe myelosuppression, have been reported in 40% of patients receiving liposomal daunorubicin.133,164 Filgrastim (a granulocyte colony-stimulating factor, G-CSF) has been used with some success in a limited number of AIDS patients who developed severe neutropenia during liposomal daunorubicin therapy.204 Hematologic status must be monitored carefully in patients receiving daunorubicin. (See Cautions: Precautions and Contraindications.) Following administration of conventional (nonencapsulated) daunorubicin hydrochloride, leukocyte and platelet nadirs usually occur within 10-14 days, and leukocyte and platelet counts generally return to normal levels during the third week.

Cardiac Effects

As with doxorubicin, 3 types of cardiotoxicity may occur in patients receiving daunorubicin: an acute, transient type; a chronic, subacute type, which is related to cumulative dose and has a later, more indolent onset; and a late-onset type that manifests years after anthracycline therapy and occurs mainly in patients exposed to the drugs as children.137,138,139

Acute anthracycline-induced cardiotoxicity is uncommon.137,138,139 It occurs immediately after a single dose or a single course of anthracycline therapy and may involve abnormal ECG findings including ST-T wave changes (e.g., T-wave flattening and ST-segment depression), prolongation of the QT interval, and arrhythmias (e.g., sinus tachycardia; ventricular, supraventricular, and junctional tachycardia).137,139 Conduction disturbances (including atrioventricular [AV] and bundle-branch block) have been reported rarely in acute anthracycline-induced cardiotoxicity; such disturbances usually are associated more with late-onset anthracycline-induced cardiotoxicity.137,139 Although acute cardiotoxicity generally is transient, rarely, pericarditis-myocarditis syndrome (e.g., pericardial effusion and/or decreased myocardial contractility) that is not dose-related, and possible cardiac failure, may occur.125,137,138,139,140

Chronic cardiotoxicity may occur as total dosage of conventional (nonencapsulated) daunorubicin approaches 400-550 mg/m².125,164 Time of onset of chronic cardiotoxicity may vary but usually is manifested within 1 year of anthracycline therapy.137 In one study, onset of congestive heart failure developed 0-231 days after discontinuance of anthracycline therapy.137,142 Chronic cardiotoxicity reflects a progressive injury and loss of cardiac myocyte, with increasing cumulative anthracycline doses resulting in thinning of ventricular walls and decreased systolic performance.139 Initially, there is functional compensation by the remaining myocytes allowing overall cardiac function to appear normal despite histologic damage, which can be demonstrated by endomyocardial biopsy.139 However, as cumulative doses of anthracycline increase, there is a decrease in systolic performance, as measured by a decrease in fractional shortening (FS) and left-ventricular ejection fraction (LVEF) with eventual progression to symptomatic congestive heart failure, if cardiac reserve is exhausted, and cardiorespiratory decompensation.139

Symptoms of the described rapidly progressing syndrome may include tachycardia, tachypnea, dilation of the heart, exercise intolerance, pulmonary and venous congestion, poor perfusion, and pleural effusion; these manifestations may respond to cardiac supportive therapy and may be self-limiting, or, alternatively, may be irreversible and unresponsive to therapy and fatal.139 Early diagnosis of daunorubicin-induced congestive heart failure and prompt initiation of treatment is essential for optimizing response to supportive therapy.125

Congestive heart failure occurs in approximately 1-2% of adults at a total conventional daunorubicin dosage of 550 mg/m², but the incidence increases after this cumulative dosage is exceeded. In adults who received radiation therapy that encompassed the heart, congestive heart failure may occur at a lower total dosage of conventional (nonencapsulated) daunorubicin (400 mg/m²).125 The incidence of daunorubicin-induced myocardial toxicity increases after a cumulative dosage of conventional (nonencapsulated) daunorubicin exceeding 400-550 mg/m² in adults, 300 mg/m² in children older than 2 years of age, or 10 mg/kg in children younger than 2 years of age.125 In both adults and children, the total dose of daunorubicin administered should take into account any previous or concomitant therapy with other anthracyclines, such as doxorubicin, or with other potentially cardiotoxic drugs.125

Infants and children appear to be more susceptible to anthracycline-induced cardiotoxicity than adults, in whom cardiotoxicity is more clearly dose related.125 Impaired left ventricular systolic performance, reduced contractility, and congestive heart failure, sometimes resulting in death, have occurred in pediatric patients months to years following discontinuance of therapy with anthracyclines such as daunorubicin.125 These conditions appear to be dose dependent and are more likely to occur in patients who receive radiation therapy of the thorax.125 Such patients should receive long-term periodic evaluation of cardiac function.125

Late-onset anthracycline-induced cardiotoxicity, which may include late-onset ventricular dysfunction, heart failure, conduction disturbances, and arrhythmias (e.g., nonsustained ventricular tachycardia), which may be life-threatening, occurs several years or even decades after discontinuance of anthracycline therapy, and it may develop after a prolonged asymptomatic interval.137,138,141,143,144,145,146,147 In one study in patients with solid tumors or leukemia, those who were followed for 4 to less than 10 or 10-20 years after discontinuance of anthracycline therapy had an 18 or 38% incidence, respectively, of abnormal FS in echocardiograms.137,141 It has been suggested that myocyte damage and ventricular dysfunction progress after the initial myocardial insult and may lead to late-onset cardiac decompensation.137,139,141 Some clinicians state that late-onset cardiotoxicity can manifest clinically in response to stressful situations (e.g., surgery, pregnancy), exercise (e.g., weight lifting), and acute viral infection.137,139,141

Cardiotoxicity also has been reported in patients receiving daunorubicin encapsulated in liposomes.133 Congestive heart failure was reported in a patient with AIDS-related Kaposi's sarcoma at a cumulative dose of 340 mg/m².133 Among 8 patients with AIDS-related Kaposi's sarcoma, decreases in LVEF occurred at a median cumulative dose of 320 mg/m² (range, 200-2100 mg/m²).133 Congestive heart failure has been reported at a cumulative dose as low as 200 mg/m² in patients with other malignancies receiving liposomal daunorubicin at doses exceeding the recommended dose of 40 mg/m² in clinical studies; decreases in LVEF occurred in 7 patients.133 The incidence of cardiotoxicity in patients receiving liposomal daunorubicin has not been established.133 Other serious adverse cardiac effects reported in patients receiving liposomal daunorubicin in clinical trials for AIDS-related Kaposi's sarcoma or other malignancies include pericardial effusion, pericardial tamponade, ventricular extrasystoles, cardiac arrest, sinus tachycardia, atrial fibrillation, pulmonary hypertension, myocardial infarction, supraventricular tachycardia, and angina pectoris.133 Further study and experience are needed to determine the relative risk of anthracycline-induced cardiotoxicity associated with liposomal versus conventional preparations.209

Hot flushes, hypertension, palpitation, syncope, and tachycardia have been reported in 5% of patients or less receiving liposomal daunorubicin.133 Edema and chest pain have been reported in patients receiving liposomal daunorubicin.133

For additional information on the cardiotoxicity of anthracyclines, see Cautions: Cardiac Effects in Doxorubicin Hydrochloride 10:00.

Infusion-related Effects

Back pain accompanied by flushing and chest tightness has been reported in about 14% of patients receiving liposomal daunorubicin in a phase III trial; these symptoms generally occur during the first 5 minutes of drug infusion, usually resolve if the infusion is stopped, and typically do not recur when the infusion is resumed at a slower rate.133 Similar manifestations also have been reported with other liposomal preparations and appear to be related to the lipid component of liposomal daunorubicin.133

GI Effects

Mucositis or stomatitis may occur as early as 3-7 days after administration of daunorubicin.125 Stomatitis usually begins as a burning sensation with erythema of the oral mucosa leading to ulceration in 2-3 days. Esophagitis may occur in some patients. Acute nausea and vomiting, usually mild, occur in patients receiving daunorubicin.125 Nausea and vomiting may occur soon after administration of the drug and last for 24-48 hours. Antiemetics may be of some help in preventing or treating nausea and vomiting.125 Diarrhea,125 abdominal pain,125 anorexia, and constipation have occasionally been reported.

Increased appetite, dysphagia, GI hemorrhage, gastritis, gingival bleeding, hemorrhoids, melena, dry mouth, taste perversion, thirst, hiccups, or tooth caries have been reported in 5% of patients or less receiving liposomal daunorubicin. 133 Constipation and tenesmus have been reported in patients receiving liposomal daunorubicin.133

Nervous System Effects

Neuropathy was reported in 13% of patients and amnesia, anxiety, ataxia, confusion, emotional lability, hallucination, abnormal thinking, hyperkinesia, hypertonia, tremor, somnolence, or seizures have been reported in 5% of patients or less receiving liposomal daunorubicin.133,164 Fatigue, headache, increased sweating, rigors, depression, malaise, dizziness, and insomnia have been reported in patients receiving liposomal daunorubicin.133

Dermatologic and Sensitivity Reactions

Reversible alopecia occurs in most patients receiving conventional (nonencapsulated) daunorubicin.125 Complete alopecia involving the scalp, axillary, and pubic hair almost always occurs with daunorubicin therapy, and patients should be advised of this effect. Growth of hair usually resumes 5 or more weeks after daunorubicin is discontinued. Limited data indicate that mild or moderate alopecia occurred in 6 or 2%, respectively, of patients with AIDS-related Kaposi's sarcoma receiving liposomal daunorubicin.133,164

Transverse pigmentation of fingernails and toenails has occurred in a patient receiving the drug. Rarely occurring adverse dermatologic effects include rash, contact dermatitis, and urticaria.125 Daunorubicin may also reactivate skin lesions produced by previous radiation therapy in some patients. Anaphylactoid reaction has been reported rarely in patients receiving daunorubicin.125 Folliculitis, seborrhea, or dry skin has been reported in 5% of patients or less receiving liposomal daunorubicin; allergic reactions and pruritus occurred in patients receiving the drug.133

Local Effects

Extravasation of daunorubicin can produce severe local tissue necrosis, severe cellulitis, thrombophlebitis, or painful induration.125 Extravasation is usually accompanied by an immediate burning sensation at the site. Slow, progressive necrosis of skin can develop, leading to deep, painful ulceration which can require multiple surgical debridements and skin grafting. Although injection site inflammation rarely has been reported in patients receiving liposomal daunorubicin citrate, tissue necrosis associated with extravasation of the liposomally encapsulated drug has not been reported to date;133 however, liposomal daunorubicin also should be considered an irritant, and the usual precautions to avoid extravasation of the drug should be followed.133 If extravasation occurs, as much infiltrated drug as possible should be aspirated. Although no specific treatments are of proven value in preventing or reducing tissue damage, the local reaction may be minimized by promptly infiltrating the area with hydrocortisone sodium succinate injection (50-100 mg of hydrocortisone) and/or sodium bicarbonate (5 mL of 8.4% injection) and applying cold compresses.165,206 Extensive necrosis of the hand, without evidence of infiltration or cellulitis at the infusion site, occurred in one patient following infusion of conventional (nonencapsulated) daunorubicin distal to an arteriovenous fistula.

Metabolic Effects

As a result of extensive purine catabolism accompanying rapid destruction of leukemic cells, hyperuricemia may occur in patients receiving daunorubicin; serum uric acid concentrations should be monitored, and appropriate therapy should be initiated as necessary.125 To minimize or prevent hyperuricemia, allopurinol typically is started prior to the initiation of antileukemic therapy.125

Other Adverse Effects

Transient fever and chills occur rarely after administration of daunorubicin, but the drug has been associated with one case of fulminant hyperpyrexia. Transient elevations in serum bilirubin, AST (SGOT), and alkaline phosphatase concentrations and hepatomegaly have occurred in patients receiving daunorubicin.

Dehydration, lymphadenopathy, abnormal gait, hemoptysis, pulmonary infiltration, increased sputum, conjunctivitis, ocular pain, loss of hearing, earache, tinnitus, dysuria, nocturia, and polyuria have been reported in 5% of patients or less receiving liposomal daunorubicin.133 Cough, dyspnea, rhinitis, sinusitis, flu-like symptoms, arthralgia, myalgia, and abnormal vision also have been reported in patients receiving liposomal daunorubicin.133

Precautions and Contraindications

The usual precautions and contraindications of daunorubicin apply to both the conventional and liposomally encapsulated formulations.

Daunorubicin is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity. Conventional (nonencapsulated) daunorubicin should be administered only by clinicians experienced in using chemotherapeutic agents for leukemia in facilities with adequate laboratory and supportive resources for monitoring and treating drug toxicity.125 The clinician and staff must be prepared to rapidly respond to and comprehensively treat severe hemorrhagic conditions and/or overwhelming infections in patients receiving daunorubicin.125 Liposomal daunorubicin must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents.133

Myelosuppression

Daunorubicin therapy should not be initiated in patients with preexisting drug-induced bone marrow suppression unless the potential benefit from such treatment outweighs the risk.125

The manufacturers state that appropriate measures must be taken to control systemic infections before beginning daunorubicin therapy;125 however, in some patients with acute leukemia, treatment of the underlying malignancy in addition to other therapy (e.g., anti-infective) may be necessary before systemic infections can be controlled.

One of the main dose-limiting toxicities of daunorubicin is myelosuppression.125,133 (See Cautions: Hematologic Effects.) Patients who receive myelosuppressive drugs experience an increased frequency of infections as well as hemorrhagic complications. Because these complications are potentially fatal, the patient should be instructed to notify the clinician if fever, sore throat, or unusual bleeding or bruising occurs.

The patient's hematologic status must be carefully monitored. Leukocyte, platelet, and erythrocyte counts should be determined prior to and at frequent intervals during daunorubicin therapy. Evaluation of bone marrow function is necessary to guide treatment, and sufficient time should elapse between courses of daunorubicin therapy to allow for bone marrow recovery. Treatment of severe hematologic toxicity may consist of supportive therapy, antibiotics for complicating infections, and blood product transfusions.

Cardiotoxicity

Because of the increased risk of cardiotoxicity, daunorubicin should not be used in patients who have already received the recommended maximum cumulative dose of doxorubicin or daunorubicin.125 (See Drug Interactions: Cardiotoxic Drugs.)

Preexisting cardiac disease or previous therapy with doxorubicin or other anthracyclines increases the risk of daunorubicin-induced cardiotoxicity, and the risk-benefit ratio should be considered carefully before initiating daunorubicin therapy in patients with these risk factors.125

Cardiotoxicity is a dose-limiting adverse effect associated with the use of daunorubicin.125,133 (See Cautions: Cardiac Effects.)

Previous therapy with anthracyclines (doxorubicin exceeding 300 mg/m² or equivalent) may predispose a patient to an increased risk of cardiotoxicity with liposomal daunorubicin and this must be carefully considered before beginning therapy with the drug.133 Infants and children are at greater risk of daunorubicin-induced cardiotoxicity.125 (See Pediatric Precautions.)

The manufacturer recommends that cardiac function be monitored carefully in patients receiving liposomal doxorubicin because of the risk of cardiac toxicity and congestive heart failure.133 Cardiac monitoring is necessary for all patients receiving liposomal daunorubicin and is particularly important in patients with preexisting cardiac disease, prior therapy with anthracyclines, or prior radiation therapy encompassing the heart.133

Because cardiotoxicity may occur months to years following discontinuance of daunorubicin therapy, long-term periodic evaluation of cardiac function should be performed.125 There is no completely reliable method for predicting which patients will develop congestive heart failure with daunorubicin. Endomyocardial biopsy, ejection fractions determined from echocardiograms or first-pass radionuclide angiography, systolic time intervals derived from phonocardiograms, and ECGs have been used serially to monitor the cardiac effects of the drug and may help identify patients at greatest risk of developing congestive heart failure. However, in most patients, routine serial ECG determinations or noninvasive studies of left ventricular function are not of proven value to predict the development of congestive heart failure.

The manufacturers of conventional (nonencapsulated) doxorubicin recommend that an ECG and/or determination of ejection fraction be performed before each course of daunorubicin therapy; if a decrease of 30% or greater in limb lead QRS voltage in the ECG or a decrease in the systolic ejection fraction from pretreatment baseline occurs, the benefit of therapy must be weighed against the risk of cardiac damage.125 The manufacturer of liposomal daunorubicin recommends that cardiac function be evaluated (e.g., history of previous cardiac disease, physical examination) before each course of liposomal daunorubicin therapy; in addition, determination of left ventricular ejection fraction (LVEF) should be performed at a total cumulative dose of 320 mg/m² and at every 160-mg/m² increment thereafter.133 The manufacturer states that regular cardiac monitoring is advised, particularly in patients who have received prior anthracycline therapy, who have preexisting cardiac disease, or who have had prior radiation therapy encompassing the heart; because these patients may be at greater risk for cardiotoxicity associated with daunorubicin therapy, monitoring of LVEF should be performed before the initiation of therapy, at a total cumulative dose of 160 mg/m², and at every 160-mg/m² increment thereafter.133

Hepatic and Renal Impairment

Hepatic or renal impairment may enhance the toxicity of usual doses of daunorubicin.125 The patient's hepatic and renal function should be evaluated prior to administration of daunorubicin, and the dosage of the drug should be reduced in patients with hepatic or renal impairment.125,133 (See Dosage in Renal and Hepatic Impairment in Dosage and Administration.)

Other Precautions and Contraindications

To minimize or prevent hyperuricemia, allopurinol typically is started prior to the initiation of antileukemic therapy and serum uric acid concentrations should be monitored.125

Conventional (nonencapsulated) daunorubicin may transiently impart a red color to the urine, and patients should be advised to expect this during therapy.125

Use of conventional (nonencapsulated) daunorubicin is contraindicated in patients with known hypersensitivity to the drug.125

Interruption of therapy and slowing of the infusion rate may be required in patients experiencing adverse infusion-related effects during liposomal daunorubicin therapy.133 (See Cautions: Infusion-related Effects.)

In addition to the usual precautions and contraindications associated with daunorubicin therapy, use of liposomal daunorubicin citrate is contraindicated in patients who are hypersensitive to daunorubicin or to any component in the liposomal formulation.133

The pharmacokinetic properties, formulation, and dosage of daunorubicin as a single entity preparation differ from those of the fixed liposomal combination of daunorubicin and cytarabine (Vyxeos^®); these preparations are not interchangeable.217

Pediatric Precautions

Safety and efficacy of conventional (nonencapsulated) daunorubicin in children have not been specifically studied to date.125 The risk of cardiotoxicity should be weighed carefully before initiating daunorubicin therapy, particularly in infants and children.125 The manufacturers report that cardiotoxicity may occur more frequently and at lower cumulative doses of daunorubicin in children than in adults.125 (See Cautions: Cardiac Effects.)

Safety and efficacy of liposomal daunorubicin in children have not been established.133

Geriatric Precautions

The manufacturer states that safety and efficacy of liposomal daunorubicin citrate in geriatric patients have not been established.133

Safety and efficacy of conventional (nonencapsulated) daunorubicin in geriatric patients have not been specifically studied to date.125 The manufacturers report that cardiotoxicity may occur more frequently in geriatric patients than in younger patients receiving daunorubicin.125 Daunorubicin should be administered with caution in patients who have inadequate bone marrow reserves because of old age.125 In addition, because geriatric patients may have decreased renal function, reduction of daunorubicin dosage may be necessary.125

Mutagenicity and Carcinogenicity

Daunorubicin is potentially mutagenic and carcinogenic. Conventional (nonencapsulated) daunorubicin was mutagenic when tested in vitro with the Ames test and V79 hamster cell assay.125,133 In addition, conventional (nonencapsulated) daunorubicin was clastogenic in vitro in human lymphoblasts (CCRF-CEM) and in vivo mouse bone marrow (SCE) tests.125,133

Secondary leukemias have been reported in patients receiving topoisomerase II inhibitors in combination with other antineoplastic agents or radiation therapy.125 In male rats receiving conventional (nonencapsulated) daunorubicin 3 times weekly for 6 months at 1/70^th the recommended human dose based on body surface area, peritoneal sarcomas were found at 18 months.125 A high incidence of mammary tumors was seen in female rats 120 days after receiving a single 12.5-mg/kg IV dose (about twice the daily recommended human dose on a mg/m² basis) of conventional (nonencapsulated) daunorubicin.133 Mammary adenocarcinomas appeared at 1 year in rats receiving a single IV dose of conventional (nonencapsulated) daunorubicin (at about 1.6 times the recommended human dose based on body surface area).125 Fibrosarcomas have developed at the injection site following subcutaneous injection of the conventional (nonencapsulated) form of the drug in mice.125 When conventional (nonencapsulated) daunorubicin was administered intraperitoneally 3 times weekly in mice, no carcinogenic effect was observed after 18 months.125

Studies to determine the mutagenic and carcinogenic potential of liposomal daunorubicin have not been performed to date.133

Pregnancy, Fertility, and Lactation

Pregnancy

Conventional (nonencapsulated) daunorubicin can cause fetal toxicity when administered to pregnant women,125 but potential benefits from use of the drug may be acceptable in certain conditions despite possible risks to the fetus.125,213,214 An increased incidence of fetal abnormalities (parieto-occipital cranioschisis, umbilical hernias, or rachischisis) and abortions was observed in rabbits receiving conventional (nonencapsulated) daunorubicin at doses of 0.05 mg/kg daily (approximately 1/100^th of the highest recommended human dose based on body surface area).125 An increased incidence of esophageal, cardiovascular, and urogenital abnormalities as well as rib fusions were observed in rats receiving conventional (nonencapsulated) daunorubicin at doses of 4 mg/kg daily (approximately one-half the human dose based on body surface area).125 Decreased fetal birthweight and post-delivery growth rate were observed following administration of the drug to mice.125

Encapsulated daunorubicin citrate in liposomes also can cause fetal toxicity when administered to pregnant women.133 Reproduction studies in rats given liposomal daunorubicin dosages of 2 mg/kg daily (approximately (1/3) of the recommended human dosage on a mg/m² basis) revealed evidence of severe maternal toxicity and embryolethality, while dosages of 0.3 mg/kg daily (approximately 120^th of the recommended human dosage on a mg/m² basis) were associated with embryotoxicity (e.g., increased embryofetal deaths, reduction in the number of offspring per litter, decreased litter sizes) and fetal malformations (characterized by anophthalmia, microphthalmia, and incomplete ossification).133

There are no adequate and well-controlled studies using conventional or liposomal daunorubicin in pregnant women.125,133 Conventional or liposomal daunorubicin should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.213 If the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.125,133 Women of childbearing potential should be advised to avoid becoming pregnant while receiving the drug.125,133

Fertility

Following IV administration of daunorubicin in male dogs at a dosage of 0.25 mg/kg daily (about 8 times the human dose on a mg/m² basis), testicular atrophy and total aplasia of the spermatocyte series in the seminiferous tubules with complete aspermatogenesis were observed.125,133 The effects of liposomal daunorubicin on fertility have not been adequately studied.133

Lactation

It is not known whether daunorubicin is distributed into milk.125 Because of the potential for serious adverse reactions to daunorubicin in nursing infants, nursing should be discontinued during daunorubicin therapy.125

Liposomal daunorubicin citrate has been studied mainly in patients with Kaposi's sarcoma; such patients usually receive a variety of concomitant drugs (e.g., antiretroviral agents, antiviral agents, anti-infective agents).133 Although interactions of daunorubicin citrate liposomal injection with other drugs have not been reported, no formal drug interaction studies employing liposomal daunorubicin citrate have been performed to date.133

Cardiotoxic Drugs

The risk of cardiotoxicity is increased if daunorubicin is used in a patient who has received previous therapy with doxorubicin.125 Daunorubicin therapy should not be used in patients who have received the recommended maximum cumulative dose of doxorubicin or daunorubicin.125 Because potentiation of cardiotoxic effects may result, caution is advised when daunorubicin is used concurrently with other cardiotoxic drugs, such as cyclophosphamide.125

Myelosuppressive Drugs

Because potentiation of hematologic toxicity may result, caution is advised when daunorubicin is used concurrently with other myelosuppressive agents; reduction of daunorubicin dosage may be required.125

Hepatotoxic Drugs

Concurrent use of hepatotoxic therapy, such as high-dose methotrexate, may cause hepatic impairment and interfere with the metabolism of daunorubicin, resulting in increased risk of toxicity.125

Pharmacology

Daunorubicin is an antineoplastic antibiotic. Daunorubicin has antimitotic and cytotoxic activity.125 Daunorubicin forms a complex with DNA by intercalation between base pairs.125 By stabilizing the complex between DNA and topoisomerase II, daunorubicin inhibits the activity of this enzyme, resulting in single-strand and double-strand breaks in DNA.125 Daunorubicin also may inhibit polymerase activity, affect regulation of gene expression, and be involved in free radical damage to DNA.125 Although daunorubicin is maximally cytotoxic in the S phase, the drug is not cycle-phase specific. Daunorubicin also has antibacterial and immunosuppressive properties.

Pharmacokinetics

Encapsulation of daunorubicin citrate in liposomes substantially alters the pharmacokinetics of the drug relative to conventional IV formulations (i.e., nonencapsulated drug) with resultant decreased distribution into the peripheral compartment, increased distribution into Kaposi's lesions, and decreased plasma clearance.133,135,164,165,166 The pharmacokinetics of the drug encapsulated in liposomes have not been evaluated separately by gender, ethnic group, or hepatic or renal impairment.133,164 In the Pharmacokinetics section, liposomal daunorubicin citrate was administered as the drug encapsulated in liposomes composed of a phospholipid bilayer of distearoylphosphatidylcholine (DSPC) and cholesterol.133,164

Absorption

Daunorubicin hydrochloride is extremely irritating to tissues and, therefore, must be administered IV. Following IV infusion of a single 40-mg/m² dose of liposomal daunorubicin citrate as a liposomal injection in patients with AIDS-related Kaposi's sarcoma, mean peak plasma daunorubicin (mostly bound to liposomes) concentrations are approximately 18 mcg/mL following a 30-60 minute infusion.133,164 Peak plasma concentrations of daunorubicin are higher following IV administration of liposomal daunorubicin citrate than those attained following IV administration of conventional (nonencapsulated) daunorubicin hydrochloride.164 In one study in patients with disseminated malignancies receiving a single 80-mg/m² IV dose of nonencapsulated daunorubicin, peak plasma concentrations of the drug were 0.4 mcg/mL while in patients with solid tumors (including those with Kaposi's sarcoma) who received a single 80-mg/m² IV dose of liposomal daunorubicin, peak plasma concentrations of daunorubicin were about 44 mcg/mL (about 100-fold greater than those receiving a comparable dose of the nonencapsulated drug);164 area under the plasma concentration-time curve (AUC) was about 36-fold greater than that observed with conventional daunorubicin hydrochloride.164 Following IV administration of liposomal daunorubicin, peak plasma concentrations and AUCs of daunorubicin generally increase linearly with increasing doses (at doses of 10-80 mcg/mL).164,167

Distribution

Daunorubicin administered as a conventional (nonencapsulated) injection is rapidly and widely distributed in tissues, with highest levels in the spleen, kidneys, liver, lungs, and heart.125 The drug is absorbed by cells and binds to cellular components, particularly nucleic acids.125 The volume of distribution of daunorubicin hydrochloride administered IV as a conventional (nonencapsulated) injection is about 1006-1055 L.133,164,167 Noncapsulated daunorubicin is approximately 63% bound to serum proteins, principally albumin; the protein binding of liposomally encapsulated drug is minimal.164

Encapsulation of daunorubicin in liposomes substantially slows the rate of distribution of the drug into the extravascular space.164 As a result, the liposomally encapsulated daunorubicin citrate does not distribute into plasma and tissues as widely as daunorubicin hydrochloride administered as the conventional injection; liposomal daunorubicin distributes mainly into intravascular fluid, whereas nonencapsulated daunorubicin distributes widely into extravascular fluids and tissues.133,164 Animal studies indicate that liposomally encapsulated daunorubicin citrate distributes from blood vessels into tumors, and once distributed into the tissue compartment, the drug is released.133,164 The exact mechanism of drug release from liposomal encapsulation is not known;133 however, it has been suggested that liposomes penetrate the tumor cells by endocytosis where the entrapped daunorubicin gradually is released directly within cells to exert its antineoplastic effects.133,164,167 Because of the gradual release and higher intracellular concentrations of liposomal daunorubicin when compared with the nonencapsulated drug, liposomally encapsulated daunorubicin is more cytotoxic over time than the conventional (nonencapsulated) drug.164,170 The volume of distribution of daunorubicin following IV administration of a single 40-mg/m² dose of the drug as a liposomal injection in patients with AIDS-related Kaposi's sarcoma is about 6.4 L.133,164,168

Daunorubicin citrate administered IV as an injection encapsulated in liposomes distributes into Kaposi's sarcoma lesions to a greater extent than into healthy skin.164,167 Following IV administration of a single 20- or 40-mg/m² dose of daunorubicin citrate as liposomal injections in patients with Kaposi's sarcoma, distribution of daunorubicin into Kaposi's sarcoma lesions was about 4- to 12-fold higher than that observed in healthy skin;167 24 hours after such administration, daunorubicin concentrations in Kaposi's sarcoma lesions were 1.07 or 1.06 mcg/g, respectively, while daunorubicin was not detected in healthy skin.167 In addition, animal studies indicate that accumulation of daunorubicin in solid tumors following IV administration of the liposomally encapsulated drug was tenfold greater than that following IV administration of comparable doses of a conventional (nonencapsulated) injection.133,169

There is no evidence that daunorubicin administered as a conventional injection crosses the blood-brain barrier.125

Although preclinical data suggest that liposomal daunorubicin crosses the blood-brain barrier in animals, it is not known whether liposomal daunorubicin crosses the blood-brain barrier in humans.133,164 It appears that daunorubicin crosses the placenta.125,133 It is not known if daunorubicin is distributed into milk.125

Elimination

Following rapid IV administration of conventional daunorubicin hydrochloride injection, total plasma concentrations of daunorubicin and its metabolites decline in a triphasic manner, and plasma concentrations of unchanged daunorubicin decline in a biphasic manner. The plasma half-life of nonencapsulated daunorubicin averages 45 minutes in the initial phase and 18.5 hours in the terminal phase.125 By 1 hour after administration of nonencapsulated daunorubicin, the predominant form of the drug in plasma is the active metabolite daunorubicinol, which has an average terminal plasma half-life of 26.7 hours.125,171

Plasma concentrations of liposomally encapsulated daunorubicin citrate appear to decline principally in a monoexponential fashion, although biexponential elimination from plasma has been described occasionally in some patients.133,164,165,167 In a few patients receiving 60-mg/m² IV doses of daunorubicin liposomal injection, evidence of saturable clearance mechanisms has been reported.164,165,167 Following IV administration of a single 40-mg/m² dose as liposomal daunorubicin injection in patients with AIDS-related Kaposi's sarcoma, the apparent elimination half-life of daunorubicin averaged 4.4 hours, which is shorter than that of conventional daunorubicin and probably represents a distribution half-life.133,164

Daunorubicin hydrochloride is extensively metabolized in the liver and other tissues, mainly by cytoplasmic aldo-keto reductases, producing daunorubicinol, the major metabolite which has antineoplastic activity.125,164 Approximately 40% of the drug in the plasma is present as daunorubicinol within 30 minutes and 60% in 4 hours after a dose of nonencapsulated daunorubicin.125 Daunorubicinol has been detected only in low concentrations in the plasma following IV administration of daunorubicin citrate liposomal injection.133,164,167,168 In patients with AIDS-associated Kaposi's sarcoma receiving IV administration of liposomal daunorubicin doses of 40 mg/m², the AUC of daunorubicinol represented only 2% of the total daunorubicin AUC.164,168 Additional metabolism by reductive cleavage of the glycosidic bond produces aglycones, which have little or no cytotoxic activity and are demethylated and conjugated with sulfate and glucuronide by microsomal enzymes.

Daunorubicin and its metabolites are excreted in urine and bile.125 Following administration of nonencapsulated daunorubicin, urinary excretion of the drug and its metabolites is reported to be 14-23% of the dose, with most urinary excretion of the drug occurring within 3 days. After the first 24 hours, the drug is excreted in urine mainly as daunorubicinol. An estimated 40% of a dose is eliminated by biliary excretion.125 In one study in patients with disseminated solid malignancies who received a single 80-mg/m² IV dose of nonencapsulated daunorubicin, plasma clearance of the drug was about 236 mL/minute.133,164 Plasma clearance of daunorubicin encapsulated in liposomes appears to be substantially slower.133,164,168 In adults with AIDS-related Kaposi's sarcoma, plasma clearance of liposomal daunorubicin following administration of a single 40-mg/m² IV dose averaged 17.3 mL/minute.133,164,168 This reduction in plasma clearance with the liposomal injection results in a substantial increase in the AUC compared with that of nonencapsulated drug.133,164

Chemistry and Stability

Chemistry

Daunorubicin is an anthracycline glycoside antibiotic produced by Streptomyces coeruleorubidus. The drug is structurally related to doxorubicin and epirubicin. Daunorubicin differs structurally from doxorubicin in that daunorubicin contains an acetyl group instead of a hydroxyacetyl group in the 8-position.164

As a conventional injection, daunorubicin is commercially available as the hydrochloride salt which occurs as a hygroscopic, reddish, lyophilized crystalline powder; the commercially available product also contains mannitol. Daunorubicin hydrochloride is soluble in water, slightly soluble in alcohol, and has a pK_a of 10.3. Following reconstitution of the commercially available powder for injection with sterile water for injection as directed, daunorubicin hydrochloride solutions have a pH of 4.5-6.5.125

A conventional injection also is commercially available as a deep red sterile solution with a pH of 3-4.215

As an injection, daunorubicin also is available in a liposomal formulation.133,164 In the liposomal injection, an aqueous solution of the citrate salt of daunorubicin is encapsulated in lipid vesicles (liposomes).133,164 Liposomes are spherical, microscopic vesicles composed of a phospholipid bilayer that is capable of encapsulating the drug.133,164 These liposomes contain distearoylphosphatidylcholine (DSPC) and cholesterol in the phospholipid bilayer in a 2:1 molar ratio and have a mean diameter of 45 nm (range: 35-65 nm).133,164 The total lipid-to-daunorubicin base weight ratio is 18.7:1 equivalent to a 10:5:1 molar composition of DSPC:cholesterol:daunorubicin.133,164

The physicochemical properties of liposomes (e.g., size, fluidity of the membrane, surface charge) depend on the lipid composition and method of preparation of the liposomes.164 The selection of appropriate lipid components and ratios ensures the formation of stable vesicles that retain the pharmacologically active drug in the presence of serum at body temperature and also controls the length of time these vesicles remain intact in systemic circulation.164 It has been suggested that liposomes can penetrate the altered and often compromised vasculature of tumors because of their small size (usually less than 100 nm in diameter; preferably 30-80 nm) and persistence in blood circulation.164 The ability to achieve sustained high plasma concentrations of the drug encapsulated in liposomes is related to the stability of such liposomes; the addition of cholesterol strengthens the bilayers of the liposomes, particularly in the presence of serum by controlling loss of DSPC to high-density lipoproteins.164 Animal studies indicate that the net neutral surface charge also may contribute to the stability of the liposomes in vivo; the leakage of daunorubicin from the liposomes appears to be less than 1% over 24 hours.164

Daunorubicin citrate liposomal injection is a sterile, pyrogen-free, translucent red liposomal dispersion and has a pH of 4.9-6.133 Daunorubicin citrate liposomal injection also contains sucrose for isotonicity, glycine as a stabilizing agent, and calcium chloride dihydrate.133

Stability

Daunorubicin hydrochloride powder for injection should be stored at 15-30°C, protected from light, and stored in the carton until time of use.125

Following reconstitution as directed, daunorubicin hydrochloride solutions are stable for 24 hours at room temperature or 48 hours when refrigerated at 2-8°C.125 The reconstituted solution should be protected from sunlight.125 Daunorubicin hydrochloride is unstable in solutions with a pH greater than 8; decomposition is indicated by a color change from red to blue-purple. A precipitate may form immediately if daunorubicin hydrochloride solution is mixed with heparin sodium injection or dexamethasone sodium phosphate injection. The manufacturer states that daunorubicin hydrochloride injection should not be mixed with other drugs or heparin.125

Commercially available daunorubicin hydrochloride injection should be protected from light in the carton until time of use and refrigerated at 2-8°C.215 Following further dilution in 0.9% sodium chloride injection, resultant solutions are stable for 24 hours at room temperatures of 15-30°C; these solutions contain no preservatives, and unused portions should be discarded after this period.215

Commercially available daunorubicin citrate liposomal injection should be refrigerated at 2-8°C and protected from light and freezing;133 the shelf-life of the injection is 24 weeks when stored as recommended.164 When diluted as directed with dextrose 5% injection, solutions of daunorubicin citrate liposomal injection are stable for up to 6 hours when refrigerated at 2-8°C.133

Additional Information

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