DAUNOrubicin (Liposomal)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Injectable, Intravenous [preservative free]:

DaunoXome: 2 mg/mL (25 mL [DSC]) [pyrogen free]

Pharmacology

Mechanism of Action

Liposomal preparation of daunorubicin; 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 (over time). 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.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: ~5 to 8 L

Metabolism

Daunorubicinol (major active metabolite) is detected at low levels in plasma

Excretion

Primarily feces; some urine

Half-Life Elimination

Distribution: 4.4 hours

Use: Labeled Indications

Kaposi sarcoma: First-line treatment of advanced HIV-associated Kaposi sarcoma

Limitation of use: Daunorubicin (liposomal) is not recommended in HIV-related Kaposi sarcoma which is less than advanced.

Contraindications

Hypersensitivity to daunorubicin (liposomal) or any component of the formulation

Documentation of allergenic cross-reactivity for drugs in this class is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosage and Administration

Dosing: Adult

Note: DaunoXome has been discontinued in the US for more than 1 year.

Note: DAUNOrubicin (liposomal) is different from the conventional DAUNOrubicin formulation; do NOT substitute (indications and doses are different).

Kaposi sarcoma: IV: 40 mg/m² once every 2 weeks; continue until disease progression.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

ANC <750/mm³: Withhold treatment.

Infusion reactions (back pain, flushing, chest tightness): Temporarily interrupt infusion; may resume at a slower rate.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

The only fluid that may be mixed with daunorubicin (liposomal) is D5W. Dilute with an equivalent volume of D5W to a 1:1 solution (to a concentration of 1 mg daunorubicin liposomal/mL). Must not be mixed with saline, bacteriostatic agents (such as benzyl alcohol), or any other solution. Do not mix with other medications.

Administration

IV: Infuse over 1 hour; do not mix with other drugs. Do NOT administer with an in-line filter. Avoid extravasation.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Diluted daunorubicin liposomal for infusion in D5W may be refrigerated at 2°C to 8°C (36°F to 46°F) for a maximum of 6 hours (if not used immediately).

Drug Interactions

Ado-Trastuzumab Emtansine: May enhance the cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with ado-trastuzumab emtansine should avoid anthracycline-based therapy for up to 7 months after stopping ado-trastuzumab emtansine. Monitor closely for cardiac dysfunction in patients receiving this combination. Consider therapy modification

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bevacizumab: May enhance the cardiotoxic effect of Anthracyclines. Avoid combination

Cardiac Glycosides: May diminish the cardiotoxic effect of Anthracyclines. Anthracyclines 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. Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Cyclophosphamide: May enhance the cardiotoxic effect of Anthracyclines. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Fam-Trastuzumab Deruxtecan: May enhance the cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with fam-trastuzumab deruxtecan should avoid anthracycline-based therapy for up to 7 months after stopping fam-trastuzumab deruxtecan. Monitor closely for cardiac dysfunction in patients receiving this combination. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

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. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lumacaftor and Ivacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor and Ivacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 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.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 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.). Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Taxane Derivatives: May enhance the adverse/toxic effect of Anthracyclines. Taxane Derivatives may increase the serum concentration of Anthracyclines. Taxane Derivatives may also increase the formation of toxic anthracycline metabolites in heart tissue. Consider therapy modification

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with trastuzumab should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab. Monitor closely for cardiac dysfunction in patients receiving anthracyclines with trastuzumab. Consider therapy modification

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). 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. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

Frequency not always defined.

Cardiovascular: Edema (11%), chest pain (10%), angina pectoris (≤5%), atrial fibrillation (≤5%), cardiac arrest (≤5%), cardiac tamponade (≤5%), hypertension (≤5%), myocardial infarction (≤5%), palpitations (≤5%), pericardial effusion (≤5%), pulmonary hypertension (≤5%), sinus tachycardia (≤5%), supraventricular tachycardia (≤5%), syncope (≤5%), tachycardia (≤5%), ventricular premature contractions (≤5%), decreased left ventricular ejection fraction (3%; reduction of 20% to 25%), cardiomyopathy (cumulative, dose-related; total dose above 300 mg/m²)

Central nervous system: Fatigue (49%), headache (25%), rigors (19%), neuropathy (13%), depression (10%), malaise (10%), dizziness (8%), insomnia (6%), abnormality in thinking (≤5%), amnesia (≤5%), anxiety (≤5%), ataxia (≤5%), confusion (≤5%), drowsiness (≤5%), emotional lability (≤5%), hallucination (≤5%), hypertonia (≤5%), meningitis (≤5%), seizure (≤5%)

Dermatologic: Diaphoresis (14%), alopecia (8%), pruritus (7%), folliculitis (≤5%), seborrhea (≤5%), xeroderma (≤5%)

Endocrine & metabolic: Dehydration (≤5%), hot flash (≤5%), increased thirst (≤5%)

Gastrointestinal: Nausea (54%), diarrhea (38%), abdominal pain (23%), anorexia (23%), vomiting (23%), stomatitis (10%), constipation (7%), tenesmus (5%), dental caries (≤5%), dysgeusia (≤5%), dysphagia (≤5%), gastritis (≤5%), gastrointestinal hemorrhage (≤5%), gingival hemorrhage (≤5%), hemorrhoids (≤5%), hiccups (≤5%), increased appetite (≤5%), melena (≤5%), xerostomia (≤5%)

Genitourinary: Dysuria (≤5%), nocturia (≤5%)

Hematologic & oncologic: Neutropenia (<1,000 cells/mm³: 36%; grade 4: 15%), lymphadenopathy (≤5%), splenomegaly (≤5%), bone marrow depression (especially granulocytes; platelets and erythrocytes less effected), severe granulocytopenia (may be associated with fever and result in infection)

Hepatic: Hepatomegaly (≤5%)

Hypersensitivity: Hypersensitivity reaction (24%)

Infection: Opportunistic infection (40%; median time to first infection/illness: 214 days)

Local: Inflammation at injection site (≤5%)

Neuromuscular & skeletal: Back pain (16%), arthralgia (7%), myalgia (7%), abnormal gait (≤5%), hyperkinesia (≤5%), tremor (≤5%)

Ophthalmic: Visual disturbance (5%), conjunctivitis (≤5%), eye pain (≤5%)

Otic: Deafness (≤5%), otalgia (≤5%), tinnitus (≤5%)

Renal: Polyuria (≤5%)

Respiratory: Cough (28%), dyspnea (26%), rhinitis (12%), sinusitis (8%), flu-like symptoms (5%), hemoptysis (≤5%), increased bronchial secretions (≤5%), pulmonary infiltrates (≤5%)

Miscellaneous: Fever (47%), infusion-related reaction (14%; includes back pain, flushing, chest tightness)

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: May cause bone marrow suppression, particularly neutropenia (may be severe). Monitor blood counts. Monitor closely for infections (including opportunistic infections).
• Extravasation: Avoid extravasation. Although not reported with daunorubicin (liposomal), daunorubicin (conventional) is associated with local tissue necrosis if extravasated.
• Infusion reactions: [US Boxed Warning]: The lipid component is associated with infusion-related reactions (back pain, flushing, chest tightness) usually within the first 5 minutes of infusion, and subsides with interruption of the infusion, and generally does not recur if the infusion is resumed at a lower rate. Monitor for infusion reactions; interrupt infusion if reaction occurs, and resume at reduced infusion rate.
• Myocardial toxicity: [US Boxed Warning]: Due to the potential for cardiac toxicity and heart failure, monitor cardiac function regularly, especially in patients with previous therapy with anthracyclines, thoracic radiation, or who have preexisting cardiac disease. Cardiomyopathy is usually associated with a decrease left in ventricular ejection fraction (LVEF). Although the risk increases with cumulative dose, irreversible cardiotoxicity may occur with anthracycline treatment at any dose level. Patients who have received prior anthracycline therapy (DOXOrubicin >300 mg/m² or equivalent), with preexisting heart disease, hypertension, concurrent administration of other antineoplastic agents, prior or concurrent chest irradiation, and advanced age are at increased risk. Evaluate LVEF prior to treatment and periodically during treatment (at cumulative doses of daunorubicin liposomal 320 mg/m² and every 160 mg/m² thereafter or every 160 mg/m² in patients at higher risk).

Disease-related concerns:

• Hepatic impairment: [US Boxed Warning]: Reduce dosage in patients with hepatic impairment.
• Renal impairment: Use with caution in patients with renal impairment; may require dosage reduction.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

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 preexisting 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

Pregnancy

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience flu-like symptoms, urine discoloration, abdominal pain, lack of appetite, hair loss, headache, cough, back pain, mouth irritation, lip irritation, or runny nose. Have patient report immediately to prescriber signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), signs of infection, chest pain, passing out, burning or numbness feeling, severe nausea, vomiting, excessive weight loss, severe diarrhea, bruising, bleeding, loss of strength and energy, vision changes, depression, or injection site pain or irritation (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.