Daunorubicin or Daunomycin is a chemotherapeutic medicine used in the treatment of various blood cancers including acute lymphoblastic leukemia and acute myeloid leukemia.

Indications of Daunorubicin:

• Acute lymphocytic leukemia:

  • It is indicated for the treatment (remission induction) of acute lymphocytic leukemia (ALL) in children and adults concurrently with other chemotherapy.

• Acute myeloid leukemia:

  • It is effective for treatment (remission induction) of acute myeloid leukemia (AML) in adults concurrently with other chemotherapy.

Daunorubicin dose in adults:

Note:

• An increased risk of cardiomyopathy is seen with cumulative doses above 550 mg/m² in adults without risk factors for cardiotoxicity and above 400 mg/m² in adults receiving chest irradiation.
• Antiemetics are recommended to prevent nausea and vomiting due to the moderate emetic potential of daunorubicin.

Daunorubicin dose in the treatment of Acute lymphocytic leukemia:

• CALGB 8811 regimen:

  • 45 mg/m² (in patients <60 years of age) IV 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.

• CCG 1961:

  • Adults ≤21 years of age:
    • Induction: 25 mg/m² IV once weekly for 4 weeks in combination with vincristine, prednisone, and asparaginase.

• GRAALL-2003:

  • Adults ≤60 years of age:

    • Induction: 50 mg/m² IV on days 1, 2, and 3 and 30 mg/m on days 15 and 16 in combination with prednisone, vincristine, asparaginase, cyclophosphamide, and G-CSF support.
    • Late intensification: 30 mg/m IV on days 1, 2, and 3 in combination with prednisone, vincristine, asparaginase, cyclophosphamide, and G-CSF support.

• MRC UKALLXII/ECOG E2993:

  • Adults <60 years of age:

    • Induction (Phase I): 60 mg/m² IV on days 1, 8, 15, and 22 in combination with vincristine, asparaginase, and prednisone.

  • PETHEMA ALL-96:

    • Adults ≤30 years of age:

      • Induction: 30 mg/m IV on days 1, 8, 15, and 22 in combination with vincristine, prednisone, asparaginase, and cyclophosphamide.
      • Consolidation-2/Reinduction: 30 mg/m IV on days 1, 2, 8, and 9 in combination with vincristine, dexamethasone, asparaginase, and cyclophosphamide.

  • Protocol 8707:

    • Adults ≤60 years of age:

      • Induction and Consolidation 2A cycles: 60 mg/m² IV on days 1, 2, and 3 in combination with vincristine, prednisone, and asparaginase.
      • An additional 60 mg/m daunorubicin dose may be administered on day 15 of induction if bone marrow biopsy on day 14 shows residual disease.

  • Manufacturer's labeling:

    • 45 mg/m² IV on days 1, 2, and 3 in combination with vincristine, prednisone, and asparaginase.

Daunorubicin dose in the treatment of Acute myeloid leukemia: Induction:

• CCG 2891:

  • Adults <21 years of age:
    • 20 mg/m²/day  IV continuous infusion on days 0 to 4 and 10 to 14 in combination with dexamethasone, cytarabine, thioguanine, and etoposide.
  • Adults <60 years of age:
    • 90 mg/m² IV on days 1, 2, and 3 in combination with cytarabine.
    • If the 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.
  • Adults <60 years of age:
    • 60 mg/m² IV on days 1, 2, and 3 in combination with cytarabine and cladribine.
    • In the case of partial remission, the dose can be repeated.
  • Adults ≥60 years of age:
    • 45 or 90 mg/m² IV on days 1, 2, and 3 in combination with cytarabine.
    • An increased remission rate and overall survival in the subgroup of patients 60 to 65 years of age as compared to patients >65 years of age was seen with an escalated dose of 90 mg/m².

  • Manufacturer's labeling:

    • Adults <60 years of age:
      • Induction: 45 mg/m² IV 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: 30 mg/m² IV on days 1, 2, and 3 of the first course of induction therapy.
      • Subsequent courses: 30 mg/m on days 1 and 2 in combination with cytarabine.

Daunorubicin dose in the treatment of Acute promyelocytic leukemia (off-label dosing):

• Induction:

  • Adults: 50 mg/m² IV on days 3, 4, 5, and 6 in combination with ATRA and cytarabine or 60 mg/m² on days 1, 2, and 3 in combination with ATRA and cytarabine.

• Consolidation:

  • Adults: 50 mg/m² IV 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 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.

Daunorubicin dose in children:

Note:

• The dose, frequency, number of doses, and start date may vary by protocol and treatment phase; refer to individual protocols.
• Antiemetics are recommended to prevent nausea and vomiting due to the moderate emetic potential of daunorubicin.
• Dosing presented as both mg/m² and mg/kg;
• Use extra precaution and verify dosing units.
• Increased risk of cardiotoxicity can be seen in 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.

Daunorubicin dose in Acute lymphocytic leukemia (ALL):

• Manufacturer's labeling: Remission induction:

  • Infants and Children <2 years or BSA <0.5 m²:

    • 1 mg/kg/dose IV 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:

    • 25 mg/m IV 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:

    • Induction: 25 mg/m IV once weekly for 4 weeks in combination with vincristine, prednisone, and asparaginase.

  • GRAALL-2003:

  • Adolescents ≥15 years:

    • Induction:
      • 50 mg/m² IV on days 1, 2, and 3 and 30 mg/m on days 15 and 16 in combination with prednisone, vincristine, asparaginase, cyclophosphamide, and G-CSF support.
    • Late intensification:
      • 30 mg/m² IV on days 1, 2, and 3 in combination with prednisone, vincristine, asparaginase, cyclophosphamide, and G-CSF support.

  • MRC UKALLXII/ECOG E2993: Adolescents ≥15 years:

    • Induction (Phase I):
      • 60 mg/m² IV on days 1, 8, 15, and 22 in combination with vincristine, asparaginase, and prednisone.

  • PETHEMA ALL-96:

  • Adolescents ≥15 years:

    • Induction:
      • 30 mg/m² IV on days 1, 8, 15, and 22 in combination with vincristine, prednisone, asparaginase, and cyclophosphamide.
    • Consolidation-2/Reinduction:
      • 30 mg/m² IV on days 1, 2, 8, and 9 in combination with vincristine, dexamethasone, asparaginase, and cyclophosphamide.

Daunorubicin dose in the treatment of acute myelogenous leukemia (AML):

• Induction:

  • MRC AML 10/12: Infants and Children ≤16 years:

    • 50 mg/m IV on days 1, 3, and 5 for 2 cycles in combination with cytarabine and etoposide.

  • CCG 2891:

    • Infants and Children <3 years:

      • 0.67 mg/kg/day IV continuous infusion on days 0 to 4 and 10 to 14 in combination with dexamethasone, cytarabine, thioguanine, and etoposide.

    • Children ≥3 years and Adolescents:

      • 20 mg/m²/day IV continuous infusion on days 0 to 4 and 10 to 14 in combination with dexamethasone, cytarabine, thioguanine, and etoposide.

Pregnancy Risk Factor D

• Animal reproduction studies have revealed adverse outcomes.
• Daunorubicin has the ability to cross the placenta.
• Conception should be avoided in females of reproductive age.

Daunorubicin use during breastfeeding:

• Daunorubicin secretion in breast milk is not known.
• Due to the potential for serious adverse reactions in the breastfed infant, a decision be made whether to discontinue breastfeeding or to discontinue the drug depends on the importance of treatment to the mother as per manufacturer.

Daunorubicin Dose adjustment in renal disease:

• The manufacturer's labeling recommends the following adjustment:
• Serum Creatinine >3 mg/dl:
  • 50% dose reduction is needed.

Daunorubicin Dose adjustment in liver disease:

• The manufacturer's labeling recommends the following adjustments:

  • Serum bilirubin 1.2 to 3 mg/dl:
    • 25% dose reduction is required.
  • Serum bilirubin >3 mg/dl:
    • 50% dose reduction is required.

• The following adjustments have also been recommended:

  • Serum bilirubin 1.2 to 3 mg/dl:
    • 25% dose reduction is required.
  • Serum bilirubin 3.1 to 5 mg/dl: 
    • 50% dose reduction is required.
  • Serum bilirubin >5 mg/dl:
    • Use should be avoided.

Common Side Effects of Daunorubicin:

• Cardiovascular:

  • Cardiac failure
  • ECG abnormality

• Dermatologic:

  • Alopecia (reversible)

• Gastrointestinal:

  • Nausea (mild)
  • Stomatitis
  • Vomiting (mild)

• Genitourinary:

  • Red urine discoloration

• Hematologic & oncologic:

  • Bone marrow depression

• Miscellaneous:

  • Radiation recall phenomenon

Rare Side Effects of Daunorubicin:

• Dermatologic:

  • Discoloration of sweat

• Endocrine & metabolic:

  • Hyperuricemia

• Gastrointestinal:

  • Abdominal pain
  • Diarrhea
  • Discoloration of saliva
  • Gastrointestinal ulcer

• Local:

  • Post-injection flare

• Ophthalmic:

  • Discoloration of tears

Contraindications to Daunorubicin:

• Hypersensitivity to daunorubicin and any component of the formulation

Canadian labeling

• Seniors over 75 years old
• Myocardial lesions in patients with heart disease

Warnings and precautions

• Suppression of bone marrow: [US Boxed Warning]

  • The effects of therapeutic doses on bone marrow can be severe enough that they may cause hemorhage or infections.
  • Patients with preexisting drug-induced bone loss (preexisting) should be cautious.
  • Before and during treatment, blood counts should be taken frequently.

• Extravasation: [US Boxed Warning]

  • Only IV administration of Daunorubicin is recommended.
  • It can cause severe tissue damage, including pain, ulceration and necrosis secondary extravasation.
  • To prevent extravasation, it is important to ensure proper needle and catheter placements before and during infusion.

• Gastrointestinal toxicities:

  • Due to its moderate emetic properties, antiemetics should be administered with daunorubicin.

• [US Boxed Warning] Cardiomyopathy

  • Treatment can cause myocardial toxicities or heart failure. This is often due to dose.
  • Cardiotoxicity is possible with doses exceeding 550 mg/m2 for adults and 400 mg/m2 for adults who have received chest radiation. Children aged >2 years old should receive 300 mg/m2 while children under 2 years old must receive 300 mg/m2. Children below 2 years of age should receive 10 mg/kg.
  • It is also higher in older age, children and infants, hypertension, preexisting cardiac disease, chest irradiation, combination treatment antineoplastic agents, and other health conditions.
  • When prescribing the cumulative dose, it is important to consider whether you have had any prior treatment with anthracyclines and anthracenediones or with concomitant treatment using other cardiotoxic agents.
  • Although the risk of irreversible cardiotoxicity increases with increasing cumulative doses, it can still occur at any dose.
  • It is important to monitor the ejection fraction at baseline, periodically with ECHO scans or MUGA scans, and regularly ECG.
  • The following are the ASCO guidelines that increase the risk of developing cardiac dysfunction:
    • High-dose anthracycline treatment (eg, epirubicin >=600mg/m2, doxorubicin>=250 mg/m2, epirubicin>=600 mg/m2)
    • High-dose radiotherapy (>=30 Gy), with the heart in treatment field
    • Lower-dose anthracycline (eg doxorubicin 250 mg/m2, epirubicin 600 mg/m2) when combined with lower-dose radiotherapy (30 Gy) with the heart in treatment field
    • Low-dose anthracycline (eg doxorubicin at 250 mg/m2, epirubicin at 600 mg/m2), or trastuzumab by itself AND any of these risk factors:
      • Multiple cardiovascular risk factors (>=2) include old age, obesity and smoking.
    • Lower-dose anthracycline treatment (eg, epirubicin 600m/m2 and doxorubicin) followed by trastuzumab as sequential therapy.
    • Anthracycline-induced cardiotoxicity can also be caused by >=60 years old at the time of treatment, and >=2 cardiovascular risk factor (smoking or diabetes) during or after treatment.
  • ASCO guidelines recommend that patients with cancer undergo a thorough assessment. This includes a history, physical examination, and screening for cardiovascular disease risk factors like hypertension, diabetes and dyslipidemia.
  • Before starting potentially cardiotoxic therapies, an echocardiogram is recommended. Modifiable risk factors such as smoking, diabetes, hypertension, and obesity should be managed before therapy can begin.
  • Cardio-protectants such as dexrazoxane or continuous infusions are recommended for high-dose anthracycline treatment.
  • Patients who present with symptoms or signs of cardiac dysfunction should have an echocardiogram.
  • If an echocardiogram is impossible, a cardiac MRI or MUGA scanning should be performed.
  • Referral to a cardiologist may be necessary if there are any abnormalities in your serum cardiac biomarkers.

• Secondary malignancy

  • Secondary leukemia can be caused by combination chemotherapy and radiation therapy.

• Tumor lysis syndrome

  • Prophylaxis with antihyperuricemic agents and urinary alkalization may be required in order to prevent hyperuricemia and tumor lysis syndrome.
  • Regularly check your hydration status, electrolytes and RFTs.

• Hepatic impairment: [US-Boxed Warning]

  • A liver derangement could lead to severe toxicities. Therefore, dose reduction is necessary.

• Renal impairment: [US-Boxed Warning]

  • Dose reduction is required because renal impairment can increase the risk for toxicity.

Daunorubicin: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• CBC with differential and platelet counts,
• Liver function tests,
• Renal function tests
• Signs and symptoms of extravasation
• ECG,
• Left ventricular ejection function (echocardiography [ECHO] or multigated radionuclide angiography [MUGA] scan)

Cardiovascular monitoring (ASCO):

• A detailed history and physical examination, screening for cardiovascular disease risk factors such as smoking, obesity, hypertension, diabetes, dyslipidemia should be done before starting therapy.
• An echocardiogram should be done before starting therapy.
• An echocardiogram should be done in patients presenting with signs/symptoms of cardiac dysfunction during therapy.
• A cardiac MRI or MUGA scan in addition to serum cardiac biomarkers should be done if an echocardiogram is not feasible.

How to administer Daunorubicin?

• Antiemetics are used to prevent nausea and vomiting due to the moderate emetic properties of daunorubicin.
• Daunorubicin should not be administered intravenously as a slow IV push for up to 1 to 5 minutes in the tubing of D5W/NS IV solution. It may also dilute further and infuse for 15 to 30 minutes.
• To avoid extravasation, it is important to ensure proper needle and catheter placement before and during infusion.

Extravasation management

• In case of extravasation, the infusion should be stopped immediately.
• Extravasated solution should only be aspirated gently without flushing. The needle/cannula should then be removed.
• It is important to elevate the extremity and give antidote (dexrazoxane [DMSO])
• For a period of 1 to 2 days, dry cold compresses should only be used for 20 minutes four times per day. Withholding cooling for 15 minutes prior to dexrazoxane injections is recommended.
• Keep the infusion going for at least 15 minutes.
• Topical DMSO should never be used in conjunction with dexrazoxane. It may reduce dexrazoxane's efficacy.

Dexrazoxane

• 1000 mg/m2 (maximum dosage: 2,000 mg) IV (administered in a large vein distant from the site of extravasation) for 1 to 2 hour days 1 and 2. Then 500 mg/m2 IV (maximum dosage: 1,000 mg) IV for 1 to 2 hour days 3 should be administered within 6 hours.
• Day 2 and day 3 should be taken at the same time (+-3 hours) as day 1.

Notification:

• Patients with severe or moderately impaired renal function (CrCl 40ml/min) will need to be given dexrazoxane at 50%.

DMSO:

• It is recommended to apply topical creams to the area twice as large for one week, starting within 10 minutes after extravasation.
• It is not a good idea to dress up.

Mechanism of action of Daunorubicin:

• Daunorubicin is known to cause intercalation of DNA base pairs, and steric obstruction at points where the double helix is being uncoilled locally.
• This causes DNA and RNA synthesis to be inhibited.
• While the exact mechanism of blockage of DNA and RNA production and fragmentation is unknown, it is thought that intercalation and topoisomerase II inhibition are responsible.

Distribution:

• Distributes widely into tissues, particularly the liver, kidneys, lungs, spleen, and heart.
• It does not distribute into the CNS.

Metabolism:

• Primarily occurs in the liver to the active form - daunorubicinol, then to inactive aglycones, conjugated sulfates, and glucuronides.

Half-life elimination:

• Initial: 45 minutes.
• Terminal: 18.5 hours
• Daunorubicinol plasma half-life: 27 hours

Excretion:

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

International Brands of Daunorubicin:

• Cerubidine
• Cerubidin
• Cerubidine
• Danocin
• Daunobin
• Daunoblastin
• Daunoblastina
• Daunocin
• Daunoplus
• Daunorrubicina
• Daunorubicin Injection
• Daunorubicina
• Daunotec
• DaunoXome
• Donobin
• Maxidauno
• Rubicin
• Rubilem

Daunorubicin Brand Names in Pakistan: