Medication Guide App

Daunorubicin, Liposomal (Systemic)


VA CLASSIFICATION
Primary: AN200

Commonly used brand name(s): DaunoXome.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antineoplastic—

Indications

Accepted

Kaposi"s sarcoma (KS), acquired immunodeficiency syndrome (AIDS)–associated (treatment)—Liposomal daunorubicin is indicated as a first-line cytotoxic therapy for advanced AIDS-associated KS {01} {02} {03}. Liposomal daunorubicin is not recommended in patients with less than advanced AIDS-associated KS {01}.

Note: The treatment of AIDS-associated KS is dependent on the extent and severity of the KS and the patient"s clinical condition {03} {08}. For patients with minimal disease, local treatments such as excision, radiotherapy, or intralesional chemotherapy will be adequate {07} {08}. However, for those with severe cutaneous or systemic disease, systemic chemotherapy may be required {02} {03} {08}. Patients with severe debilitation due to their general condition are best served by optimal palliative care {07} {08}.


Note: The USP medical experts chose to not include treatment for acute lymphoblastic leukemia{09}{10}{11}{12}{13}, acute myelogenous leukemia{11}{12}{14}{15}{16}, or multiple myeloma{17}{18}{19}{20}, as indications for liposomal daunorubicin. Currently, liposomal daunorubicin is appropriate for use in the treatment of acute lymphoblastic leukemia, acute myelogenous leukemia, and multiple myeloma, only in a clinical trial setting.{09}{14}{17}



Pharmacology/Pharmacokinetics

Note: A human pharmacokinetics study has shown that the pharmacokinetics of liposomal daunorubicin are significantly different from those of conventional daunorubicin, which may account for both its reduced toxicity and its potentially enhanced activity {02}. However, the pharmacokinetics of liposomal daunorubicin have not been evaluated in women, in a variety of ethnic groups, or in patients with renal and hepatic insufficiency {01}.


Physicochemical characteristics:
Source—
    Daunorubicin is an anthracycline antibiotic originally obtained from Streptomyces peucetius {01}. Daunorubicin also may be isolated from Streptomyces coeruleorubidus {01}. Liposomal daunorubicin is an aqueous solution of the citrate salt of daunorubicin encapsulated within lipid vesicles (liposomes) composed of a lipid bilayer of highly purified distearoylphosphatidylcholine (DSPC) and cholesterol in a 2:1 molar ratio {01} {03} {04} {05} {06}.

Mechanism of action/Effect:

Liposomal daunorubicin is a liposomal preparation of daunorubicin formulated to maximize the selectivity of daunorubicin for solid tumors in situ {01} {05} {06}. While in the circulation, the liposomal formulation helps to protect the entrapped daunorubicin from chemical and enzymatic degradation, minimizes protein binding, and generally decreases uptake by normal (nonreticuloendothelial system) tissues {01}. Once within the tumor environment, daunorubicin is released over time, enabling it to exert its antineoplastic activity {01}.

The specific mechanism by which liposomal daunorubicin is able to deliver daunorubicin to solid tumors in situ is not known {01} {03} {04}. However, it is believed to be a function of increased permeability of the tumor neovasculature to some particles in the size range of liposomal daunorubicin {01}.

In animal studies, liposomal daunorubicin has demonstrated improved activity against solid tumors compared with that of conventional daunorubicin {04}.

Distribution:

Limited to vascular fluid {01}.

Volume of distribution (Vol D)—Steady-state: 6.4 liters following intravenous administration of 40 mg per square meter of body surface area (mg/m 2), over 30 to 60 minutes {01}.

In animal studies, liposomal daunorubicin appeared to cross the blood-brain barrier and to accumulate selectively in solid tumor tissues to a greater extent than occurs with nonencapsulated daunorubicin {01}.

Biotransformation:

Daunorubicinol, the major active metabolite of daunorubicin, was detected at low concentrations in the plasma following intravenous administration of liposomal daunorubicin {01}.

Half-life:

Distribution—4.41 hours following intravenous administration of a 40 mg/m 2 dose over 30 to 60 minutes {01}.

Elimination:
    Plasma clearance—17 mL per minute following intravenous administration of a 40 mg/m 2 dose over 30 to 60 minutes {01}.


Precautions to Consider

Cross-sensitivity and/or related problems

Liposomal daunorubicin is not recommended in patients hypersensitive to daunorubicin or the liposomal components {01}.

Carcinogenicity

Studies to evaluate the carcinogenic potential of liposomal daunorubicin have not been performed. However, the active ingredient, daunorubicin, was found to increase the incidence of mammary tumors in rats following a single dose of 12.5 mg per kg of body weight (mg/kg) (approximately two times the recommended human dose on a mg per square meter of body surface area [mg/m 2] basis) {01}.

Mutagenicity

Studies to evaluate the mutagenic potential of liposomal daunorubicin have not been performed. However, the active ingredient, daunorubicin, was mutagenic in in vitro tests (Ames test and V79 hamster cell assay) and clastogenic in in vitro (CCRF-CEM human lymphoblasts) and in vivo (SCE assay in mouse bone marrow) test systems {01}.

Pregnancy/Reproduction
Fertility—
Studies to evaluate the effects of liposomal daunorubicin on fertility have not been performed; however, the active ingredient, daunorubicin, caused testicular atrophy and total aplasia of spermatocytes in the seminiferous tubules in male dogs administered 0.25 mg/kg per day (approximately eight times the recommended human dose on a mg/m 2 basis) {01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}. Furthermore, the pharmacokinetics of liposomal daunorubicin have not been evaluated in women {01}.

In general, use of a contraceptive method is recommended during cytotoxic drug therapy {01}.

Liposomal daunorubicin caused severe maternal toxicity and embryolethality in rats administered doses of 2 mg/kg per day (one third of the maximum recommended human dose) on days 6 through 15 of gestation. Studies in rats administered doses of 0.3 mg/kg per day (one twentieth of the maximum recommended human dose) on days 6 through 15 of gestation showed that liposomal daunorubicin caused embryotoxicity (increased embryofetal deaths, reduced numbers of litters, and reduced litter size) and caused fetal malformations (anophthalmia, microphthalmia, incomplete ossification) {01}.

FDA Pregnancy Category D {01}.

Breast-feeding

It is not known whether liposomal daunorubicin is distributed into breast milk. However, breast-feeding is not recommended while liposomal daunorubicin is being administered because of the potential risk of adverse reactions in the infant.

Pediatrics

No information is available on the relationship of age to the effects of liposomal daunorubicin in pediatric patients. Safety and efficacy have not been established {01}.


Geriatrics


No information is available on the relationship of age to the effects of liposomal daunorubicin in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving liposomal daunorubicin. Safety and efficacy have not been established {01}.


Dental

The leukopenic and thrombocytopenic effects of liposomal daunorubicin may result in an increased incidence of certain microbial infections of the mouth, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Allopurinol or
Colchicine or
» Probenecid or
» Sulfinpyrazone    (liposomal daunorubicin may raise the concentration of blood uric acid; dosage adjustment of antigout agents may be necessary to control hyperuricemia and gout; allopurinol may be preferred to prevent or reverse liposomal daunorubicin–induced hyperuricemia because of risk of uric acid nephropathy with uricosuric antigout agents)


» Daunorubicin, prior use of or
» Doxorubicin, prior use of or
» Other anthracycline antineoplastics, prior use of    (use of liposomal daunorubicin in a patient who previously has received anthracenedione antineoplastic agents, daunorubicin, doxorubicin, or other anthracycline antineoplastics increases the risk for cardiotoxicity; dosage adjustment is necessary {02})

    (prior anthracycline use is also significantly associated with short survival {02})


Blood dyscrasia–causing medications (see Appendix II )    (leukopenic and/or thrombocytopenic effects of liposomal daunorubicin may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of liposomal daunorubicin, if necessary, should be based on blood counts {03})


» Bone marrow depressants, other (see Appendix II ) or
Radiation therapy    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)


Cyclophosphamide or
Radiation therapy to mediastinal area    (concurrent use may result in increased cardiotoxicity; it is recommended that the total dose of liposomal daunorubicin not exceed 400 mg/m 2)


Hepatotoxic medications, other (see Appendix II )    (concurrent use may increase the risk of toxicity; for example, high-dose methotrexate may impair liver function and increase toxicity of subsequently administered liposomal daunorubicin)


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by liposomal daunorubicin therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by liposomal daunorubicin therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the liposomal daunorubicin therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy. In addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
» Cardiac function tests    (left ventricular ejection fraction may be decreased, possibly indicating cardiotoxicity {01})


Hematocrit or
Hemoglobin or
» Leukocyte counts or
Platelet counts    (may be decreased {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Previous hypersensitivity reaction to liposomal daunorubicin or its components{01}
Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression
» Cardiac disease, pre-existing    (may increase risk of cardiotoxicity; monitoring of cardiac function is recommended {01})


» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


» Granulocytopenia, severe{01}    (treatment should be withheld if the absolute granulocyte count is lower than 750 cells per cubic millimeter {01})


» Hepatic function impairment    (excretion may be delayed; reduction in dosage is recommended; three fourths of the normal dose is recommended in patients with serum bilirubin concentrations of 1.2 to 3 mg per deciliter; one half of the normal dose is recommended in patients with serum bilirubin concentrations of greater than 3 mg per deciliter {01})


» Renal function impairment    (excretion may be delayed; reduction in dosage is recommended; one half of the normal dose is recommended in patients with serum creatinine concentrations greater than 3 mg per deciliter {01})


» Sensitivity to daunorubicin or to the liposomal components{01}
» Tumor cell infiltration of the bone marrow
» Caution should be used also in patients with inadequate bone marrow reserves due to previous cytotoxic drug or radiation therapy

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Alanine aminotransferase (ALT [SGPT]) values, serum and
Aspartate aminotransferase (AST [SGOT]) values, serum and
Bilirubin concentrations, serum and
Lactate dehydrogenase (LDH) values, serum    (recommended prior to initiation of therapy and at periodic intervals during therapy; frequently varies according to clinical state, agent, dose, and other agents being used concurrently)


» Cardiac function    (recommended prior to initiation of therapy and at periodic intervals during therapy)


» Hematocrit or hemoglobin and
» Leukocyte count, total and, if appropriate, differential and
» Platelet count    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequently varies according to clinical state, agent, dose, and other agents being used concurrently {01})


» Left ventricular ejection fraction    (determination recommended at total cumulative doses of 320 mg/m 2, 480 mg/m 2, and every 240 mg/m 2 thereafter {01})


» Observation for evidence of intercurrent or opportunistic infections


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Dyspnea {01}{03}(shortness of breath; troubled breathing)—less frequently, may be severe or associated with pulmonary infiltrations
    
neuropathy {01}{03}(weakness or numbness in arms or legs)
    
neutropenia {01}{03}(cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; sore throat)

Note: Clinical studies have demonstrated that neutropenia is the predominant hematologic toxicity following treatment with liposomal daunorubicin {03}. In one study, 36% of patients experienced grade 3 neutropenia (< 1000 cells/mm 2), while 15% of patients experienced grade 4 neutropenia (< 500 cells/mm 2) {03}. Futhermore, patients receiving this medication may experience a higher frequency of opportunistic infections and neutropenic fevers {03}. Acquired immunodeficiency syndrome (AIDS) patients are susceptible to a variety of opportunistic infections, and chemotherapy-associated bone marrow suppression may enhance this risk {03}. It is possible that liposomal daunorubicin may interfere with monocyte-macrophage function, and thus increase susceptibility to opportunistic infections {03}.


Incidence less frequent
    
Anemia {02}{03}(unusual tiredness or weakness)
    
cardiotoxicity {01}{03}(irregular heartbeat; shortness of breath; swelling of the feet and lower legs)
    
chest pain{01}
    
edema {01}(swelling of abdomen, face, fingers, hands, feet, or lower legs; weight gain)
    
gastrointestinal hemorrhage {01}(black, tarry stools; bloody stools; bloody vomit)
    
hemoptysis {01}(coughing up blood)
    
hypertension{01}{03} —usually asymptomatic
    
renal effects, including dysuria {01}(painful or difficult urination), nocturia {01}(unusual nighttime urination), or polyuria (producing large amounts of pale, dilute urine){01}
    
stomatitis {01}(sores in mouth and on lips)
    
syncope {01}(fainting)
    
tachycardia {01}{03}(fast heartbeat)
    
thrombocytopenia {02}(black, tarry stools; unusual bleeding or bruising; blood in urine or stools; pinpoint red spots on skin)

Note: Cardiac function should be monitored regularly in patients receiving liposomal daunorubicin because of the potential risk for cardiotoxicity and congestive heart failure {01}. Cardiac monitoring is advised especially in those patients who have received prior anthracycline therapy or who have pre-existing cardiac disease {01}. Cardiotoxicity can occur with cumulative doses of greater than 300 mg per square meter of body surface area {01}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal pain{01}{03}
    
allergic reaction{01} (chills; fever; skin rash or itching)—severe reactions occur less frequently
    
diarrhea{01}{03}
    
headache{01}{03}
    
infusion-related reaction {01}{03}(back pain; chest tightness; flushing)—usually mild to moderate in severity
    
nausea and vomiting{01}{03} —severe reactions occur less frequently
    
rigors {01}{03}(feeling unusually cold; shivering)

Note: An infusion-related reaction may occur during the first 5 minutes of the infusion and may be related to the liposomal component of liposomal daunorubicin {01}.


Incidence less frequent
    
Arthralgia or myalgia {01}(pain in joints or muscles)
    
conjunctivitis {01}(dry, irritated, itching, or red eyes)
    
constipation{01}
    
dizziness{01}
    
dry mouth{01}
    
dysphagia{01} (difficulty swallowing)
    
eye pain{01}
    
folliculitis {01}(painful, red, hot, or irritated hair follicles)
    
gingival bleeding {01}(bleeding gums)
    
hemorrhoids {01}(bleeding after defecation; uncomfortable swelling around anus)
    
injection site inflammation {01}(red, hot, or irritated skin at site of injection; pain at site of injection; swelling or lump under skin at site of injection)—if extravasation occurs
    
insomnia {01}(sleeplessness)
    
somnolence {01}(extreme feeling of sleepiness)
    
tenesmus {01}(frequent urge to defecate)
    
tinnitus {01}(ringing sound in ears)
    
tooth caries {01}(tooth pain)
    
tremor {01}(uncontrollable movement of body)


Note: Local tissue necrosis has not been observed when extravasation occurs {01}.



Those not indicating need for medical attention
Incidence less frequent
    
Alopecia {01}{03}(loss of hair)

Note: Alopecia, a frequent side effect associated with anthracycline therapy, is usually mild to moderate in severity following liposomal daunorubicin therapy {03}. In one study, alopecia occurred in only 8% of patients treated with liposomal daunorubicin {03}.






Overdose
For specific information on the agents used in the management of liposomal doxorubicin overdose, see:    • Filgrastim and/or
   • Sargramostim in Colony Stimulating Factors (Systemic) monograph.


For more information on the management of overdose, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Mucositis (sores in mouth and on lips)
    
neutropenia {01}{03}(cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; sore throat)— usually asymptomatic
    
thrombocytopenia {01}{03}(black, tarry stools; blood in urine or stools; pinpoint red spots on skin; unusual bleeding or bruising)—usually asymptomatic


Treatment of overdose
Treatment of leukopenia includes antibiotic therapy and administration of colony stimulating factors (filgrastim [rG-CSF] or sargramostim [rGM-CSF]) {01}.

Treatment of thrombocytopenia includes hospitalization of the patient and platelet transfusions {01}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Daunorubicin, Liposomal (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to daunorubicin or the liposomal component {01}

Pregnancy—Use is not recommended because of embryotoxic and maternotoxic potential; advisability of using contraception {01}





Breast-feeding—Use is not recommended because of the potential for serious adverse effects in nursing infants
Other medications, especially daunorubicin, doxorubicin, live virus vaccines, other anthracycline antineoplastics, other bone marrow depressants, previous cytotoxic drug or radiation therapy, probenecid or sulfinpyrazone {01}
Other medical problems, especially bone marrow depression; cardiac disease, pre-existing; chickenpox; granulocytopenia, severe; hepatic function impairment; herpes zoster; renal function impairment; or tumor cell infiltration of bone marrow {01}

Proper use of this medication
Caution in taking combination therapy; taking each medication at the right time

Importance of ample fluid intake and subsequent increase in urine output to aid in excretion of uric acid

Frequency of nausea and vomiting; importance of continuing medication despite stomach upset

» Proper dosing{01}

Precautions while using this medication
» Importance of close monitoring by the physician {01}

» Avoiding immunizations unless approved by the physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding persons who have taken oral poliovirus vaccine, or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur
» Possibility of local tissue injury and scarring if infiltration of intravenous solution occurs; telling doctor or nurse right away about redness, pain, or swelling at injection site


Side/adverse effects
May cause adverse effects such as blood problems, loss of hair, heart problems, and cancer

Signs of potential side effects, especially dyspnea; neuropathy; neutropenia; anemia; cardiotoxicity; chest pain; edema; gastrointestinal hemorrhage; hemoptysis; hypertension; renal effects, including dysuria, nocturia, or polyuria; stomatitis; syncope; tachycardia; and thrombocytopenia {01}

Physician or nurse can help in dealing with side effects

Reddish urine for 1 to 2 days after administration may be alarming to patient although medically insignificant

Possibility of hair loss; normal hair growth should resume after treatment has ended


General Dosing Information
Patients receiving liposomal daunorubicin should be under supervision of a physician experienced in cancer chemotherapy {01}.

Liposomal daunorubicin should be administered intravenously over a period of 60 minutes at a dose of 40 mg per square meter of body surface area (mg/m 2), with doses repeated every 2 weeks {01}. Blood counts should be performed prior to each dose and therapy should be withheld if the absolute granulocyte count is less than 750 cells/mm 3 {01}.

Treatment with liposomal daunorubicin should be continued until there is evidence of progressive disease, or until other intercurrent complications of human immunodeficiency virus (HIV) disease preclude continuation of therapy {01}.

Patients may experience an acute reaction following rapid infusion {01} {03}. The reaction usually consists of shortness of breath, facial flushing, back pain, fever, and chills {03}. This reaction is related to the rate of infusion; slowing the infusion rate may eliminate this problem {01}.

If the reaction persists after the infusion rate is decreased, the infusion should be discontinued {03}. After discontinuation of the infusion, intravenous administration of diphenhydramine and hydrocortisone and oxygen administration via facial mask usually helps full recovery with no sequelae {03}.

Dosage should be adjusted for patients with impaired renal function. A dose reduction of 50% is recommended if serum creatinine concentrations are > 3 mg per deciliter (mg/dL) {01}.

Dosage should be adjusted for patients with impaired hepatic function. A dose reduction of 25% is recommended if serum bilirubin concentrations are 1.2 to 3 mg/dL. A dose reduction of 50% is recommended if serum bilirubin concentrations are > 3 mg/dL {01}.

Safety considerations for handling this medication
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastic agents may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include:    • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.


Parenteral Dosage Forms

Note: The dosing and strengths of the dosage forms available are expressed in terms of liposomal daunorubicin base (not the citrate salt).


DAUNORUBICIN, LIPOSOMAL INJECTION

Usual adult dose
AIDS-associated Kaposi's sarcoma
Intravenous infusion (over sixty minutes), 40 mg (base) per square meter of body surface area, repeated every two weeks {01}.

Note: Dosage should be adjusted for patients with impaired renal function. A dose reduction of 50% is recommended if serum creatinine concentrations are > 3 mg per deciliter (mg/dL) {01}.
Dosage should be adjusted for patients with impaired hepatic function. A dose reduction of 25% is recommended if serum bilirubin concentrations are 1.2 to 3 mg/dL. A dose reduction of 50% is recommended if serum bilirubin concentrations are > 3 mg/dL {01}.



Usual pediatric dose
Safety and efficacy have not been established {01}.

Usual geriatric dose
Safety and efficacy have not been established {01}.

Size(s) usually available:
U.S.—


2 mg per mL (base) (25-mL, single-dose vial) (Rx) [DaunoXome]{01}

Canada—
Not commercially available.

Packaging and storage:
Store between 2 and 8 ºC (36 and 46 ºF). Do not freeze. Protect from light {01}.

Preparation of dosage form:
Liposomal daunorubicin should be diluted 1:1 with 5% dextrose injection before administration {01}. Each vial of liposomal daunorubicin contains daunorubicin citrate equivalent to 50 mg daunorubicin base at a concentration of 2 mg per mL {01}. The recommended concentration after dilution is 1 mg daunorubicin per mL {01}.

Note: Aseptic techniques should be strictly observed when handling liposomal daunorubicin, since no preservatives or bacteriostatic agents are present in liposomal daunorubicin or in the materials recommended for dilution {01}.


Stability:
Diluted liposomal daunorubicin is stable for 6 hours when stored between 2 and 8 ºC (36 and 46 ºF) {01}.

Incompatibilities:
Liposomal daunorubicin should be diluted only in 5% dextrose injection {01}. Liposomal daunorubicin should not be mixed with other medications, other diluents, or bacteriostatic agents {01}. Mixing liposomal daunorubicin with any other diluent may cause precipitation {01}.

Note: Liposomal daunorubicin is a red, translucent dispersion. In-line filters should not be used because liposomal daunorubicin is not a clear solution {01}.




Developed: 06/23/1998
Revised: 12/04/2001



References
  1. DaunoXome package insert (NeXstar—US), Rev 4/96, Rec 6/96.
  1. Gill PS, Espina BM, Muggia F, et al. Phase I/II clinical and pharmacokinetic evaluation of liposomal daunorubicin. J Clin Oncol 1995; 13(4): 996-1003.
  1. Gill PS, Wernz J, Scadden DT, et al. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi"s sarcoma. J Clin Oncol 1995; 13(4): 2353-64.
  1. Forssen EA, Malé-Brune R, Adler-Moore JP, et al. Fluorescence imaging studies for the disposition of daunorubicin liposomes (DaunoXome) within tumor tissue. Cancer Res 1996; 56: 2066-75.
  1. Forssen EA, Coulter DM, Proffitt RT. Selective in vivo localization of daunorubicin small unilamellar vesicles in solid tumors. Cancer Res 1992; 52: 3255-61.
  1. Forssen EA, Ross ME. DaunoXome treatment of solid tumors: preclinical and clinical investigations. J Liposome Res 1994; 4(1): 481-512.
  1. Coukell AJ, Spencer CM. Polyethylene glycol-liposomal doxorubicin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of AIDS-related Kaposi"s sarcoma. Drugs 1997; 53(3): 520-38.
  1. Harrison M, Tamlinson D, Stewart S. Liposomal-entrapped doxorubicin: an active agent in AIDS-related Kaposi"s sarcoma. J Clin Oncol 1995; 13(4): 914-20.
  1. Reviewers' consensus on the use of liposomal daunorubicin for the treatment of acute lymphoblastic leukemia, 7/19/00.
  1. Baruchel A, Auvrignon A, Perel Y, et al. Liposomal daunorubicin (DaunoXome®) for childhood acute lymphoblastic leukemia: a phase I-II study. Blood 1998; 92: 234a [Abst 956].
  1. Cortes J, Kantarjian H, O'Brien S, et al. High-dose liposomal daunorubicin (DNX) and Ara-C (HDAC) for refractory or relapsed acute leukemias: a dose searching study. Blood 1998; 92: 234a [Abst 957].
  1. Cripe L, Kneebone P, Roberts L, et al. A phase I trial of liposomal daunorubicin (DaunoXome®) administered with high-dose cytarabine (HiDAC) to patients (pts) with relapsed acute leukemia (AL). Blood 1998; 92: 233a [Abst 955].
  1. Koller C, Cortes J, O'Brien S, et al. A pilot study of dose-intensive anthracyclines for acute lymphoblastic leukemia (ALL) using liposomal daunorubicin (LD) with hyperfractionated cyclophosphamide (CTX), vincristine (VCR), and prednisone (PDN) (HYPERCVXD). Proc Am Soc Clin Oncol 1998; 17: 28a [Abst 110].
  1. Reviewers' consensus on the use of liposomal daunorubicin for the treatment of acute myelogenous leukemia, 7/19/00.
  1. Cortes J, O'Brien S, Estey E, et al. Phase I study of liposomal daunorubicin in patients with acute leukemia. Investigational New Drugs 1999; 17: 81-87.
  1. Massumoto C, Graziani S. Liposomal daunorubicin (LD) associated with cyclophosphamide for relapsed hematologic malignancies pre-peripheral blood stem cell transplantation (PBSCT). Blood 1998; 92: 324b [Abst 4396].
  1. Reviewers' consensus on the use of liposomal daunorubicin for the treatment of multiple myeloma, 7/19/00.
  1. Powles R, Sirohi B, Kulkarni S, et al. Acute lymphoblastic leukemia-type intensive chemotherapy to eliminate minimal residual disease after high-dose melphalan and autologous transplantation in multiple myeloma- a phase I/II feasibility and tolerance study of 17 patients. Bone Marrow Transplant 2000; 25(9): 949-56.
  1. Pratt G, Wiles ME, Rawstron AC, et al. Liposomal daunorubicin: in vitro and in vivo efficacy in multiple myeloma. Hematol Oncol 1998; 16: 47-55.
  1. Mohrbacher A, Gregory S, Justice G, L, et al. Liposomal daunorubicin is effective therapy for multiple myeloma . Proc Am Soc Clin Oncol 1998; 17: 110a [Abst 448].
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