|
This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or
standards of non-Merck sources.
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(daw noe ROO bi sin SI trate lip po SOE mal)
Generic Available (U.S.)
No
Index Terms
U.S. Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
First-line treatment of advanced HIV-associated Kaposi's sarcoma (KS)
Pregnancy Risk Factor
D
Pregnancy Considerations
Teratogenic effects and embryotoxicity were noted in animal studies. There are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should avoid becoming pregnant while receiving treatment.
Lactation
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to daunorubicin citrate (liposomal), daunorubicin, or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Bone marrow suppression: See “Concerns related to adverse effects” below.
• Experienced physician: See “Other warnings/precautions” below.
• Hepatic impairment: See “Disease-related concerns” below.
• Infusion-related reactions: See “Concerns related to adverse effects” below.
• Myocardial toxicity: See “Concerns related to adverse effects” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Bone marrow suppression: [U.S. Boxed Warning]: May cause bone marrow suppression, particularly neutropenia; monitor closely for infections.
• Infusion-related reactions: [U.S. Boxed Warning]: The lipid component is associated with infusion-related reactions (back pain, flushing, chest tightness) usually within the first 5 minutes of infusion; monitor, interrupt infusion, and resume at reduced infusion rate.
• Myocardial toxicity: [U.S. Boxed Warning]: Monitor cardiac function regularly; especially in patients with previous therapy with high cumulative doses of anthracyclines, cyclophosphamide, or thoracic radiation, or who have pre-existing cardiac disease. Although the risk increases with cumulative dose, irreversible cardiotoxicity may occur with anthracycline treatment at any dose level. Patients with pre-existing heart disease, hypertension, concurrent administration of other antineoplastic agents, prior or concurrent chest irradiation, and advanced age are at increased risk. Evaluate left ventricular ejection fraction (LVEF) prior to treatment and periodically during treatment.
Disease-related concerns:
• Hepatic impairment: [U.S. Boxed Warning]: Use with caution in patients with hepatic impairment; dosage reduction is recommended.
• Renal impairment: Use with caution in patients with renal impairment; may require dosage reduction.
Special populations:
• Elderly: Use with caution in the elderly; safety and efficacy have not been established.
• Pediatrics: Safety and efficacy have not been established in children.
Other warnings/precautions:
• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.
Adverse Reactions
>10%:
Cardiovascular: Edema (11%)
Central nervous system: Fatigue (49%), fever (47%), headache (25%), neutropenic fever (17%)
Gastrointestinal: Nausea (54%), diarrhea (38%), abdominal pain (23%), anorexia (23%), vomiting (23%)
Hematologic: Myelosuppression (onset: 7 days; nadir: 14 days; recovery 21 days), neutropenia (up to 55%; grade 4: 15%), anemia (up to 55%; grade 4: 2%), thrombocytopenia (up to 12%; grade 4: 1%)
Neuromuscular & skeletal: Rigors (19%), back pain (16%), neuropathy (13%)
Respiratory: Cough (28%), dyspnea (26%), rhinitis (12%)
Miscellaneous: Opportunistic infections (40%), allergic reactions (24%), diaphoresis (14%), infusion-related reactions (14%; includes back pain, flushing, chest tightness)
1% to 10%:
Cardiovascular: Chest pain (10%), hypertension (≤5%), palpitation (≤5%), syncope (≤5%), tachycardia (≤5%), LVEF decreased (3%), CHF/cardiomyopathy
Central nervous system: Depression (10%), malaise (10%), dizziness (8%), insomnia (6%), abnormal thinking (≤5%), amnesia (≤5%), anxiety (≤5%), ataxia (≤5%), confusion (≤5%), emotional lability (≤5%), hallucination (≤5%), meningitis (≤5%), seizure (≤5%), somnolence (≤5%)
Dermatologic: Alopecia (8%), pruritus (7%), dry skin (≤5%), folliculitis (≤5%), seborrhea (≤5%)
Endocrine & metabolic: Dehydration (≤5%), hot flashes (≤5%)
Gastrointestinal: Stomatitis (10%), constipation (7%), tenesmus (5%), appetite increased (≤5%), dental caries (≤5%), dysphagia (≤5%), gastrointestinal hemorrhage (≤5%), gastritis (≤5%), gingival bleeding (≤5%), hemorrhoids (≤5%), melena (≤5%), splenomegaly (≤5%), taste perversion (≤5%), xerostomia (≤5%)
Genitourinary: Dysuria (≤5%), nocturia (≤5%), polyuria (≤5%)
Hepatic: Hepatomegaly (≤5%)
Local: Injection site inflammation (≤5%)
Neuromuscular & skeletal: Arthralgia (7%), myalgia (7%), gait abnormal (≤5%), hyperkinesia (≤5%), hypertonia (≤5%), tremor (≤5%)
Ocular: Abnormal vision (5%) conjunctivitis (≤5%), eye pain (≤5%)
Otic: Deafness (≤5%), earache (≤5%), tinnitus (≤5%)
Respiratory: Sinusitis (8%), hemoptysis (≤5%), pulmonary infiltrate (≤5%), sputum increased (≤5%)
Miscellaneous: Flu-like syndrome (5%), hiccups (≤5%), lymphadenopathy (≤5%), thirst (≤5%)
Postmarketing and/or case reports: Angina, atrial fibrillation, cardiac arrest, MI, pericardial effusion, pericardial tamponade, pulmonary hypertension, supraventricular tachycardia, ventricular extrasystoles
Metabolism/Transport Effects
Substrate of P-glycoprotein
Drug Interactions
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
Bevacizumab: May enhance the cardiotoxic effect of Antineoplastic Agents (Anthracycline). Risk C: Monitor therapy
Cardiac Glycosides: May diminish the cardiotoxic effect of Antineoplastic Agents (Anthracycline). Antineoplastic Agents (Anthracycline) may decrease the serum concentration of Cardiac Glycosides. The effects of liposomal formulations may be unique from those of the free drug, as liposomal formulation have unique drug disposition and toxicity profiles, and liposomes themselves may alter digoxin absorption/distribution. Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Taxane Derivatives: May enhance the adverse/toxic effect of Antineoplastic Agents (Anthracycline). Taxane Derivatives may increase the serum concentration of Antineoplastic Agents (Anthracycline). Taxane Derivatives may also increase the formation of toxic anthracycline metabolites in heart tissue. Risk D: Consider therapy modification
Trastuzumab: May enhance the cardiotoxic effect of Antineoplastic Agents (Anthracycline). Risk D: Consider therapy modification
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Storage
Store intact vials of solution under refrigeration at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Diluted daunorubicin liposomal for infusion may be refrigerated at 2°C to 8°C (36°F to 46°F) for a maximum of 6 hours. Do not use with in-line filters.
Reconstitution
Only fluid which may be mixed with DaunoXome® is D5W. Dilute to a 1:1 solution (1 mg daunorubicin liposomal/mL D5W). Must not be mixed with saline, bacteriostatic agents (such as benzyl alcohol), or any other solution.
Compatibility
Stable in D5W. Incompatible with normal saline, sodium bicarbonate and fluorouracil, heparin, dexamethasone.
Mechanism of Action
Liposomes have been shown to penetrate solid tumors more effectively, possibly because of their small size and longer circulation time. Once in tissues, daunorubicin is released. Daunorubicin inhibits DNA and RNA synthesis by intercalation between DNA base pairs and by steric obstruction; and intercalates at points of local uncoiling of the double helix. Although the exact mechanism is unclear, it appears that direct binding to DNA (intercalation) and inhibition of DNA repair (topoisomerase II inhibition) result in blockade of DNA and RNA synthesis and fragmentation of DNA.
Pharmacodynamics/Kinetics
Distribution: Vd: 5-8 L
Metabolism: Similar to daunorubicin, but metabolite plasma levels are low
Half-life elimination: Distribution: 4.4 hours; Terminal: 3-5 hours
Excretion: Primarily feces; some urine
Clearance, plasma: 17.3 mL/minute
Dosage
Refer to individual protocols. I.V.:
Adults: HIV-associated KS: 40 mg/m2 every 2 weeks
Elderly: Use with caution.
Dosage adjustment for toxicity: Withhold treatment for ANC <750/mm3
Elderly: Use with caution.
Dosing adjustment in renal impairment: Serum creatinine >3 mg/dL: Administer 50% of normal dose
Dosing adjustment in hepatic impairment:
Bilirubin 1.2-3 mg/dL: Administer 75% of normal dose
Bilirubin >3 mg/dL: Administer 50% of normal dose
Dosage: Combination Regimens
Leukemia, acute lymphocytic: Hyper-CVAD (Leukemia, Acute Lymphocytic)
Administration: I.V.
Infuse over 1 hour; do not mix with other drugs. Avoid extravasation.
Administration: I.V. Detail
pH: 5-6
Monitoring Parameters
CBC with differential and platelets (prior to each dose), liver function tests, renal function tests; evaluate cardiac function (baseline left ventricular ejection fraction [LVEF] prior to treatment initiation; repeat LVEF at total cumulative doses of 320 mg/m2, and every 160 mg/m2 thereafter; patients with pre-existing cardiac disease, history of prior chest irradiation, or history of prior anthracycline treatment should have baseline LVEF and every 160 mg/m2 thereafter); signs and symptoms of infection or disease progression; monitor closely for infusion reactions
Patient Education
This medication can only be administered by infusion. You will be monitored closely. Report immediately any swelling, pain, burning, or redness at infusion site; chest pain or tightness; or difficulty breathing or swallowing. It is important that you maintain adequate nutrition between treatments and adequate hydration, unless instructed to restrict fluid intake. You will be more susceptible to infection. May cause nausea or vomiting, diarrhea, loss of hair (reversible), or red-pink urine (normal). Report immediately chest pain, palpitations, rapid heartbeat, swelling of extremities, or difficulty breathing. Report unresolved nausea, vomiting, or diarrhea; alterations in urinary pattern (increased or decreased); opportunistic infection (eg, fever, chills, unusual bruising or bleeding, fatigue, purulent vaginal discharge, unhealed mouth sores); CNS changes (depression, insomnia, abnormal thinking, confusion, seizures); abdominal pain or blood in stools; excessive fatigue; or yellowing of eyes or skin.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Stomatitis.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May produce myelosuppression; caution with clozapine and carbamazepine
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
Evaluate patient for use cautions prior to beginning therapy (eg, pre-existing bone marrow depressions, impaired hepatic or renal function, or cardiac disease). Infusion site should be closely monitored to avoid extravasation. Patient must be monitored closely during infusions for infusion-related reaction (back pain, flushing, chest tightness). If infusion reaction occurs, interrupt infusion and restart at reduced rate.
Oncology: Vesicant
May be an irritant
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [strength expressed as base, preservative free]:
DaunoXome®: 2 mg/mL (25 mL) [contains sucrose 2125 mg/25 mL]
References
Eckardt JR, Campbell E, Burris HA, et al, “A Phase II Trial of DaunoXome®, Liposome-Encapsulated Daunorubicin, in Patients With Metastatic Adenocarcinoma of the Colon,” Am J Clin Oncol, 1994, 17(6):498-501.
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.
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, 1996, 14(8):2353-64.
Guaglianone P, Chan K, Dela Flor-Weiss E, et al, “Phase I and Pharmacologic Study of Liposomal Daunorubicin (DaunoXome®),” Invest New Drugs, 1994, 12(2):103-10.
Schurmann D, Dormann A, Grunewald T, et al, “Successful Treatment of AIDS-Related Pulmonary Kaposi's Sarcoma With Liposomal Daunorubicin,” Eur Respir J, 1994, 7(4):824-5.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
| 
