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DAUNOrubicin (Conventional)

Medically reviewed by Drugs.com. Last updated on Jul 20, 2020.

Pronunciation

(daw noe ROO bi sin con VEN sha nal)

Index Terms

  • Cerubidine
  • Conventional Daunomycin
  • Daunomycin
  • DAUNOrubicin Hydrochloride
  • Rubidomycin Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous, as hydrochloride:

Generic: 20 mg/4 mL (4 mL)

Solution, Intravenous, as hydrochloride [preservative free]:

Generic: 20 mg/4 mL (4 mL)

Pharmacologic Category

  • Antineoplastic Agent, Anthracycline
  • Antineoplastic Agent, Topoisomerase II Inhibitor

Pharmacology

Daunorubicin inhibits DNA and RNA synthesis by intercalation between DNA base pairs and by steric obstruction. Daunomycin 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.

Distribution

Distributes widely into tissues, particularly the liver, kidneys, lung, spleen, and heart; does not distribute into the CNS

Metabolism

Primarily hepatic to daunorubicinol (active), then to inactive aglycones, conjugated sulfates, and glucuronides

Excretion

Feces (40%); urine (~25% as unchanged drug and metabolites)

Half-Life Elimination

Initial: 45 minutes; Terminal: 18.5 hours; Daunorubicinol plasma half-life: ~27 hours

Use: Labeled Indications

Acute lymphocytic leukemia: Treatment (remission induction) of acute lymphocytic leukemia (ALL) in children and adults (in combination with other chemotherapy)

Acute myeloid leukemia: Treatment (remission induction) of acute myeloid leukemia (AML) in adults (in combination with other chemotherapy)

Contraindications

Hypersensitivity to daunorubicin or any component of the formulation

Canadian labeling: Patients who exhibit myocardial lesions or those ≥75 years of age

Dosing: Adult

Note: Cumulative doses above 550 mg/m2 in adults without risk factors for cardiotoxicity and above 400 mg/m2 in adults receiving chest irradiation are associated with an increased risk of cardiomyopathy. Daunorubicin is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016).

Acute lymphocytic leukemia (off-label dosing unless otherwise specified):

CALGB 8811 regimen: IV: 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 of induction (Course I; 4 week cycle), in combination with cyclophosphamide, prednisone, vincristine, and asparaginase (Larson 1995)

CCG 1961: Adults ≤21 years of age: IV: Induction: 25 mg/m2 once weekly for 4 weeks (in combination with vincristine, prednisone, and asparaginase) (Nachman 2009)

GRAALL-2003: Adults ≤60 years of age: IV:

Induction: 50 mg/m2 on days 1, 2, and 3 and 30 mg/m2 on days 15 and 16 (in combination with prednisone, vincristine, asparaginase, cyclophosphamide, and G-CSF support) (Huguet 2009)

Late intensification: 30 mg/m2 on days 1, 2, and 3 (in combination with prednisone, vincristine, asparaginase, cyclophosphamide, and G-CSF support) (Huguet 2009)

MRC UKALLXII/ECOG E2993: Adults <60 years of age: IV: Induction (Phase I): 60 mg/m2 on days 1, 8, 15, and 22 (in combination with vincristine, asparaginase, and prednisone) (Rowe 2005)

PETHEMA ALL-96: Adults ≤30 years of age: IV:

Induction: 30 mg/m2 on days 1, 8, 15, and 22 (in combination with vincristine, prednisone, asparaginase, and cyclophosphamide) (Ribera 2008)

Consolidation-2/Reinduction: 30 mg/m2 on days 1, 2, 8, and 9 (in combination with vincristine, dexamethasone, asparaginase, and cyclophosphamide) (Ribera 2008)

Protocol 8707: Adults ≤60 years of age: IV: Induction and Consolidation 2A cycles: 60 mg/m2 on days 1, 2, and 3 (in combination with vincristine, prednisone, and asparaginase). An additional 60 mg/m2 daunorubicin dose may be administered on day 15 of induction if bone marrow biopsy on day 14 shows residual disease (Linker 2002).

Manufacturer's labeling: IV: 45 mg/m2 on days 1, 2, and 3 (in combination with vincristine, prednisone, and asparaginase)

Acute myeloid leukemia (off-label dosing unless otherwise specified): Induction:

CCG 2891: Adults <21 years of age: IV: 20 mg/m2/day continuous infusion on days 0 to 4 and 10 to 14 (in combination with dexamethasone, cytarabine, thioguanine, and etoposide) (Woods 1996)

Adults <60 years of age: IV: 90 mg/m2 on days 1, 2, and 3 (in combination with cytarabine). If residual disease was observed on day 12 to day 14 bone marrow biopsy, 45 mg/m2 for 3 days was administered (in combination with cytarabine) (Fernandez 2009).

Adults <60 years of age: IV: 60 mg/m2 on days 1, 2, and 3 (in combination with cytarabine and cladribine); may repeat if partial remission occurs (Holowiecki 2012).

Adults ≥60 years of age: IV: 45 or 90 mg/m2 on days 1, 2, and 3 (in combination with cytarabine); the escalated 90 mg/m2 dose was associated with increased remission rates and overall survival in the subgroup of patients 60 to 65 years of age as compared to patients >65 years of age (Lowenberg 2009)

Manufacturer's labeling:

Adults <60 years of age: Induction: IV: 45 mg/m2 on days 1, 2, and 3 of the first course of induction therapy; subsequent courses: 45 mg/m2 on days 1 and 2 (in combination with cytarabine)

Adults ≥60 years of age: Induction: IV: 30 mg/m2 on days 1, 2, and 3 of the first course of induction therapy; subsequent courses: 30 mg/m2 on days 1 and 2 (in combination with cytarabine)

Acute promyelocytic leukemia (off-label dosing):

Induction: Adults: IV: 50 mg/m2 on days 3, 4, 5, and 6 (in combination with ATRA and cytarabine) (Powell 2010) or 60 mg/m2 on days 1, 2, and 3 (in combination with ATRA and cytarabine) (Ades 2008)

Consolidation: Adults: IV: 50 mg/m2 on days 1, 2, and 3 for 2 cycles (in combination with ATRA; arsenic trioxide was administered for 2 cycles prior to daunorubicin and ATRA) (Powell 2010) or 60 mg/m2 on days 1, 2, and 3 during cycle 1 of consolidation (in combination with cytarabine), followed by 45 mg/m2 on days 1, 2, and 3 during cycle 2 of consolidation (in combination with cytarabine) (Ades 2008)

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Dose, frequency, number of doses, and start date may vary by protocol and treatment phase; refer to individual protocols. Daunorubicin is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2011; Roila 2010). Dosing presented as both mg/m2 and mg/kg; use extra precaution and verify dosing units. Cumulative doses above 10 mg/kg in infants and children <2 years of age or above 300 mg/m2 in children and adolescents >2 years of age are associated with an increased risk of cardiotoxicity.

Acute lymphocytic leukemia (ALL):

Manufacturer's labeling: Remission induction:

Infants and Children <2 years or BSA <0.5 m2: IV: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone)

Children and Adolescents ≥2 years and BSA ≥0.5 m2: IV: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone)

Alternate dosing:

CCG 1961: Children and Adolescents: IV: Induction: 25 mg/m2 once weekly for 4 weeks (in combination with vincristine, prednisone, and asparaginase) (Nachman 2009; Siebel 2008)

GRAALL-2003 (Huguet 2009): Adolescents ≥15 years: IV:

Induction: 50 mg/m2 on days 1, 2, and 3 and 30 mg/m2 on days 15 and 16 (in combination with prednisone, vincristine, asparaginase, cyclophosphamide, and G-CSF support)

Late intensification: 30 mg/m2 on days 1, 2, and 3 (in combination with prednisone, vincristine, asparaginase, cyclophosphamide, and G-CSF support)

MRC UKALLXII/ECOG E2993: Adolescents ≥15 years: IV: Induction (Phase I): 60 mg/m2 on days 1, 8, 15, and 22 (in combination with vincristine, asparaginase, and prednisone) (Rowe 2005)

PETHEMA ALL-96 (Ribera 2008): Adolescents ≥15 years: IV:

Induction: 30 mg/m2 on days 1, 8, 15, and 22 (in combination with vincristine, prednisone, asparaginase, and cyclophosphamide)

Consolidation-2/Reinduction: 30 mg/m2 on days 1, 2, 8, and 9 (in combination with vincristine, dexamethasone, asparaginase, and cyclophosphamide)

Acute myelogenous leukemia (AML):

Induction:

MRC AML 10/12: Infants and Children ≤16 years: IV: 50 mg/m2 on days 1, 3, and 5 for 2 cycles (in combination with cytarabine and etoposide) (Gibson 2005)

CCG 2891 (Woods 1996):

Infants and Children <3 years: IV: 0.67 mg/kg/day continuous infusion on days 0 to 4 and 10 to 14 (in combination with dexamethasone, cytarabine, thioguanine, and etoposide)

Children ≥3 years and Adolescents: IV: 20 mg/m2/day continuous infusion on days 0 to 4 and 10 to 14 (in combination with dexamethasone, cytarabine, thioguanine, and etoposide)

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Reconstitution

Dilute vials of powder for injection [Canadian product] with 4 mL SWFI for a final concentration of 5 mg/mL. May further dilute solution or reconstituted daunorubicin solution in D5W or NS for infusion.

Administration

Daunorubicin is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016).

IV: For IV administration only. Do not administer IM or SubQ. Administer as slow IV push over 1 to 5 minutes into the tubing of a rapidly infusing IV solution of D5W or NS or may dilute further and infuse over 15 to 30 minutes.

Vesicant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Initiate antidote (dexrazoxane or dimethyl sulfate [DMSO]). Apply dry cold compresses for 20 minutes 4 times daily for 1 to 2 days (Perez Fidalgo 2012); withhold cooling beginning 15 minutes before dexrazoxane infusion; continue withholding cooling until 15 minutes after infusion is completed. Topical DMSO should not be administered in combination with dexrazoxane; may lessen dexrazoxane efficacy.

Dexrazoxane: 1,000 mg/m2 (maximum dose: 2,000 mg) IV (administer in a large vein remote from site of extravasation) over 1 to 2 hours days 1 and 2, then 500 mg/m2 (maximum dose: 1,000 mg) IV over 1 to 2 hours day 3; begin within 6 hours of extravasation. Day 2 and day 3 doses should be administered at approximately the same time (± 3 hours) as the dose on day 1 (Mouridsen 2007; Perez Fidalgo 2012). Note: Reduce dexrazoxane dose by 50% in patients with moderate to severe renal impairment (CrCl <40 mL/minute).

DMSO: Apply topically to a region covering twice the affected area every 8 hours for 7 days; begin within 10 minutes of extravasation; do not cover with a dressing (Perez Fidalgo 2012).

Storage

Solution: Store intact vials at 2°C to 8°C (36°F to 46°F). Protect from light. Retain in carton until time of use. Solution prepared for infusion in D5W or NS may be stored at 20°C to 25°C (68°F to 77°F) for up to 24 hours. Discard unused portion.

Lyophilized powder [Canadian product]: Store intact vials of powder at 15°C to 30°C (59°F to 86°F). Protect from light. Retain in carton until time of use. Reconstituted daunorubicin is stable for 24 hours at room temperature or 48 hours when refrigerated at 2°C to 8°C (36°F to 46°F). Protect reconstituted solution from light.

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. Management: Consider avoiding Echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. Consider therapy modification

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

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

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

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. Management: Avoid use of immunosuppressants (including systemic corticosteroids) prior to initiation of nivolumab. Use of immunosuppressants after administration of nivolumab (eg, for immune-related toxicity) is unlikely to affect nivolumab efficacy. Consider therapy modification

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

Ozanimod: Immunosuppressants may enhance the immunosuppressive effect of Ozanimod. 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

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

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Management: Consider avoiding concomitant use of roflumilast and immunosuppressants as recommended by the Canadian product monograph. Inhaled or short-term corticosteroids are unlikely to be problematic. 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. Management: Consider separating doxorubicin and paclitaxel administration by as much time as possible, using liposomal doxorubicin or epirubicin instead of doxorubicin, or using docetaxel instead of paclitaxel. Monitor closely for cardiovascular and other toxicities. 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. Management: Concomitant use of upadacitinib with potent immunosuppressants is not recommended. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs. 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 defined.

>10%:

Cardiovascular: Cardiac failure (dose-related, may be delayed for 7 to 8 years after treatment), ECG abnormality (transient, generally asymptomatic and self-limiting; includes atrial premature contractions, ST segment changes on ECG, supraventricular tachycardia, ventricular premature contractions)

Dermatologic: Alopecia (reversible)

Gastrointestinal: Nausea (mild), stomatitis, vomiting (mild)

Genitourinary: Red urine discoloration

Hematologic & oncologic: Bone marrow depression (onset: 7 days; nadir: 10 to 14 days; recovery: 21 to 28 days; primarily leukopenia; anemia, thrombocytopenia)

Miscellaneous: Radiation recall phenomenon

1% to 10%:

Dermatologic: Discoloration of sweat

Endocrine & metabolic: Hyperuricemia

Gastrointestinal: Abdominal pain, diarrhea, discoloration of saliva, gastrointestinal ulcer

Local: Post-injection flare

Ophthalmic: Discoloration of tears

<1%, postmarketing, and/or case reports: Anaphylactoid reaction, cardiac arrhythmia, cardiomyopathy, hepatitis, hypersensitivity reaction (systemic; includes angioedema, dysphagia, dyspnea, pruritus, urticaria), increased serum bilirubin, increased serum transaminases, infertility, injection site reaction (includes injection site cellulitis, local thrombophlebitis, pain at injection site), leukemia (secondary), myocardial infarction, myocarditis, nail bed changes (pigmentation), nail disease (banding), onycholysis, pericarditis, skin rash, sterility, typhlitis (neutropenic)

ALERT: U.S. Boxed Warning

Extravasation:

Daunorubicin must be given into a rapidly flowing intravenous infusion. It must never be given by the intramuscular or subcutaneous route. Severe local tissue necrosis will occur if there is extravasation during administration.

Experienced physician:

It is recommended that daunorubicin be administered only by physicians who are experienced in leukemia chemotherapy and in facilities with laboratory and supportive resources adequate to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity. The physician and institution must be capable of responding rapidly and completely to severe hemorrhagic conditions and/or overwhelming infection.

Bone marrow suppression:

Severe myelosuppression occurs when used in therapeutic doses; this may lead to infection or hemorrhage.

Cardiomyopathy:

Myocardial toxicity manifested in its most severe form by potentially fatal congestive heart failure may occur either during therapy or months to years after termination of therapy. The incidence of myocardial toxicity increases after a total cumulative dose exceeding 400 to 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.

Hepatic impairment:

Dosage should be reduced in patients with impaired hepatic function.

Renal impairment:

Dosage should be reduced in patients with impaired renal function.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: May cause severe bone marrow suppression when used at therapeutic doses; may lead to infection or hemorrhage. Use with caution in patients with drug-induced bone marrow suppression (preexisting), unless the therapy benefit outweighs the toxicity risk. Monitor blood counts at baseline and frequently during therapy.

• Extravasation: [US Boxed Warning]: Vesicant; if extravasation occurs, severe local tissue damage leading to ulceration and necrosis, and pain may occur. For IV administration only. NOT for IM or SubQ administration. Administer through a rapidly flowing IV line. Ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation.

• Gastrointestinal toxicity: Daunorubicin is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016).

• Cardiomyopathy: [US Boxed Warning]: May cause cumulative, dose-related myocardial toxicity; may lead to heart failure. May occur either during treatment or may be delayed (months to years after cessations of treatment). The incidence of myocardial toxicity increases as the total cumulative (lifetime) dosages approach 550 mg/m2 in adults, 400 mg/m2 in adults receiving chest radiation, 300 mg/m2 in children >2 years of age, or 10 mg/kg in children <2 years of age. Total cumulative dose should take into account prior treatment with other anthracyclines or anthracenediones, previous or concomitant treatment with other cardiotoxic agents or irradiation of chest. Although the risk increases with cumulative dose, irreversible cardiotoxicity may occur at any dose level. Patients with preexisting heart disease, hypertension, concurrent administration of other antineoplastic agents, prior or concurrent chest irradiation, advanced age; and infants and children are at increased risk. Monitor left ventricular (LV) function (baseline and periodic) with ECHO or MUGA scan; monitor ECG.

ASCO has developed guidelines for prevention and monitoring of cardiac dysfunction in adult survivors of cancer (ASCO [Armenian 2017]). According to the guidelines, the risk of cardiac dysfunction is increased with the following:

• High-dose anthracycline therapy (eg, doxorubicin ≥250 mg/m2, epirubicin ≥600 mg/m2)

• High-dose radiotherapy (≥30 Gy) with the heart in the treatment field

• Lower-dose anthracycline (eg, doxorubicin <250 mg/m2, epirubicin <600 mg/m2) in combination with lower-dose radiotherapy (<30 Gy) with the heart in the treatment field

• Lower-dose anthracycline (eg, doxorubicin <250 mg/m2, epirubicin <600 mg/m2) or trastuzumab alone AND any of the following risk factors: Multiple cardiovascular risk factors (≥2 risk factors), including smoking, hypertension, diabetes, dyslipidemia, and obesity (during or after completion of therapy), or older age (≥60 years of age) at cancer treatment, or compromised cardiac function (eg, borderline low LVEF [50% to 55%], history of MI, moderate or higher valvular heart disease) before or during treatment

• Treatment with lower-dose anthracycline (eg, doxorubicin <250 mg/m2, epirubicin <600 mg/m2) followed by trastuzumab (sequential therapy)

• Other risk factors for anthracycline-induced cardiotoxicity include ≥60 years of age at time of treatment and ≥2 cardiovascular risk factors (smoking, hypertension, diabetes, dyslipidemia, or obesity) during or after treatment.

The ASCO guidelines recommend a comprehensive assessment in patients with cancer that includes a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking. An echocardiogram should be obtained prior to initiating potentially cardiotoxic therapies. Modifiable risk factors (smoking, hypertension, diabetes, dyslipidemia, obesity) should be actively managed before initiating potentially cardiotoxic therapies. Consider cardioprotectants (eg, dexrazoxane) or continuous infusions in patients who are likely to receive high-dose anthracycline therapy. In patients who develop signs/symptoms of cardiac dysfunction during therapy, an echocardiogram is recommended for diagnostic workup; if echocardiogram is not available or feasible, a cardiac MRI (preferred) or MUGA scan may be utilized. Serum cardiac biomarkers are recommended, along with referral to a cardiologist if indicated.

• Secondary malignancy: Secondary leukemias may occur when used with combination chemotherapy or radiation therapy.

• Tumor lysis syndrome: May cause tumor lysis syndrome and hyperuricemia. Urinary alkalinization and prophylaxis with an antihyperuricemic agent may be necessary. Monitor electrolytes, renal function, and hydration status.

Disease-related concerns:

• Hepatic impairment: [US Boxed Warning]: Dosage reductions are recommended in patients with hepatic impairment; significant hepatic impairment may result in increased toxicities.

• Renal impairment: [US Boxed Warning]: Dosage reductions are recommended in patients with renal impairment; significant renal impairment may result in increased toxicities.

Special populations:

• Elderly: Cardiotoxicity may occur more frequently in elderly patients. Use with caution in patients with impaired renal function and/or poor marrow reserve due to advanced age; dosage adjustment may be necessary.

• Pediatric: Infants and children are at increased risk for developing delayed cardiotoxicity; long-term periodic cardiac function monitoring is recommended. A panel from the American Society of Pediatric Hematology/Oncology (ASPHO) and International Society of Pediatric Oncology (SIOP) recommends in favor of an anthracycline infusion duration of at least 1 hour in pediatric patients to reduce the potential for cardiotoxicity (ASPHO/SIOP [Loeffen 2018]). However, extravasation risks should also be minimized and the protocol infusion duration specified in a protocol should be followed, particularly if the patient is receiving dexrazoxane as a cardioprotectant.

• Radiation recipients: Use with caution in patients who have received radiation therapy; reduce dosage in patients who are receiving radiation therapy simultaneously.

Dosage form specific issues:

• Formulations (conventional vs liposomal): Use caution when selecting product for preparation and dispensing; indications, dosages, and adverse event profiles differ between conventional daunorubicin hydrochloride solution and daunorubicin liposomal.

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 platelet count, liver function test, ECG, left ventricular ejection function (echocardiography [ECHO] or multigated radionuclide angiography [MUGA] scan), renal function test, signs/symptoms of extravasation

Cardiovascular monitoring (ASCO [Armenian 2017]): Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking. Echocardiogram (prior to treatment). In patients who develop signs/symptoms of cardiac dysfunction during therapy, an echocardiogram is recommended for diagnostic workup; if echocardiogram is not available or feasible, a cardiac MRI (preferred) or MUGA scan may be utilized; obtain serum cardiac biomarkers.

Reproductive Considerations

Women of reproductive potential should avoid pregnancy.

Pregnancy Considerations

Daunorubicin crosses the placenta. Based on data from animal reproduction studies, in utero exposure to daunorubicin may cause fetal harm.

Patient Education

What is this drug used for?

• It is used to treat leukemia.

• It may be given to you for other reasons. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Urine discoloration

• Mouth irritation

• Mouth sores

• Hair loss

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Heart problems like 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

• Infection

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding

• Chest pain

• Passing out

• Severe abdominal pain

• Severe nausea

• Vomiting

• Excessive weight loss

• Severe diarrhea

• Severe loss of strength and energy

• Bone pain

• Severe injection site redness, burning, pain, swelling, or irritation

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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