Daunorubicin Hydrochloride – Uses, Dosage, Side Effects, Interaction

Daunorubicin Hydrochloride is the hydrochloride salt of an anthracycline antineoplastic antibiotic with therapeutic effects similar to those of doxorubicin. Daunorubicin exhibits cytotoxic activity through topoisomerase-mediated interaction with DNA, thereby inhibiting DNA replication and repair and RNA and protein synthesis.

Mechanism of Action

Daunorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action: Daunorubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes.

Daunorubicin is an antineoplastic antibiotic. Daunorubicin has antimitotic and cytotoxic activity. Daunorubicin forms a complex with DNA by intercalation between base pairs. By stabilizing the complex between DNA and topoisomerase II, daunorubicin inhibits the activity of this enzyme, resulting in single-strand and double-strand breaks in DNA. Daunorubicin also may inhibit polymerase activity, affect regulation of gene expression, and be involved in free radical damage to DNA. Although daunorubicin is maximally cytotoxic in the S phase, the drug is not cycle-phase specific. Daunorubicin also has antibacterial and immunosuppressive properties.

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Anthracyclines are an important reagent in many chemotherapy regimes for treating a wide range of tumors. One of the primary mechanisms of anthracycline action involves DNA damage caused by inhibition of topoisomerase II. Enzymatic detoxification of anthracycline is a major critical factor that determines anthracycline resistance. Natural product, daunorubicin a toxic analogue of anthracycline is reduced to less toxic daunorubicinol by the AKR1B10, enzyme, which is overexpressed in most cases of smoking associate squamous cell carcinoma (SCC) and adenocarcinoma. In addition, AKR1B10 was discovered as an enzyme overexpressed in human liver, cervical and endometrial cancer cases in samples from uterine cancer patients. Also, the expression of AKR1B10 was associated with tumor recurrence after surgery and keratinization of squamous cell carcinoma in cervical cancer and estimated to have the potential as a tumor intervention target colorectal cancer cells (HCT-8) and diagnostic marker for non-small-cell lung cancer. This article presents the mechanism of daunorubicin action and a method to improve the effectiveness of daunorubicin by modulating the activity of AKR1B10.

Daunorubicin is an anthracycline antibiotic and antineoplastic agent. It acts by inhibiting cellular reproduction through interference with DNA replication although it may contribute to the induction of cell death by increasing oxidative stress through the generation of reactive oxygen species and free radicals. As an antineoplastic agent, daunorubicin carries significant toxicities including cytopenias, hepatotoxicity, and extravasation reactions. Like other anthracyclines, daunorubicin also exhibits cardiotoxicity in proportion with the cumulative dose received over time.

Indications

  • For remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults and for remission induction in acute lymphocytic leukemia of children and adults. Daunorubicin is indicated in combination with [cytarabine] for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older.
  • Daunorubicin is an anthracycline antibiotic that has antineoplastic activity and is used in the therapy of acute leukemia and AIDS-related Kaposi sarcoma.
  • Cerubidine in combination with other approved anticancer drugs is indicated for remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults and for remission induction in acute lymphocytic leukemia of children and adults.
  • In addition to its major use in treating AML, daunorubicin is also used to treat neuroblastoma. Daunorubicin has been used with other chemotherapy agents to treat the blastic phase of chronic myelogenous leukemia.
  • DaunoXome is indicated as a first line cytotoxic therapy for advanced HIV-associated Kaposi’s sarcoma. DaunoXome is not recommended in patients with less than advanced HIV-related Kaposi’s sarcoma.
  • Daunorubicin is indicated in combination with cytarabine for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older.
  • Acute Lymphoblastic Leukemia (ALL)
  • Acute Myeloid Leukemia With Myelodysplasia-Related Changes
  • Ewing’s Sarcoma
  • Lymphoma, Diffuse
  • Myeloblastic Leukemia
  • Myeloid Leukemia, Chronic, Chronic Phase
  • Non-Hodgkin’s Lymphoma (NHL)
  • Therapy-Related Acute Myeloid Leukemia
  • Wilms’ tumor

Use in Cancer

Daunorubicin hydrochloride is approved to be used with other drugs as remission induction therapy to treat:

It is also being studied in the treatment of other types of cancer.

Contraindications

  • are allergic to daunorubicin or any ingredients of this medication
  • are breast-feeding
  • have already been treated with the maximum allowable lifetime dose of any anthracycline drug (daunorubicin, doxorubicin, epirubicin, idarubicin) or mitoxantrone
  • have heart failure
  • have low blood cell counts caused by previous cancer drug treatment or radiation therapy
  • are over the age of 75
  • a bacterial infection
  • opportunistic fungal infection
  • an infection due to a protozoa organism
  • decreased function of bone marrow
  • low levels of granulocytes, a type of white blood cell
  • low levels of a type of white blood cell called neutrophils
  • inflammation of the covering of the heart or pericardium
  • cardiomyopathy, a disease of the heart muscle
  • rapid ventricular heartbeat
  • abnormal heart rhythm
  • chronic heart failure
  • inflammation of the middle tissue heart muscle
  • liver problems
  • seizures
  • high amount of uric acid in the blood
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • kidney disease with likely reduction in kidney function
  • an increased risk of developing an uncommon viral infection called an opportunistic infection

Dosage

Strengths: 20 mg; 5 mg/mL; 50 mg

Acute Nonlymphocytic Leukemia

Remission Induction in Combination:
Under 60 years:

  • 45 mg/m2 IV once daily on days 1, 2, and 3 of the first course and on days 1 and 2 of subsequent courses AND cytosine arabinoside (ara-C) 100 mg/m2 IV once daily for 7 days for the first course and 5 days for subsequent courses
  • The attainment of a normal-appearing bone marrow may require up to 3 courses of induction.
  • The doses presented here are manufacturer suggested; consult local and institutional protocol for further guidance.
  • For remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) in adults

Acute Lymphocytic Leukemia

Remission Induction in Combination:

  • 45 mg/m2/day IV on days 1, 2, and 3 AND vincristine 2 mg IV on days 1, 8, and 15; prednisone 40 mg/m2/day orally on days 1 through 22, then tapered between days 22 to 29; L-asparaginase 500 IU/kg/day IV on days 22 through 32
  • The doses presented here are manufacturer suggested; consult local and institutional protocol for further guidance.

Acute Nonlymphocytic Leukemia

Remission Induction in Combination:
60 years and older:

  • 30 mg/m2 IV once daily on days 1, 2, and 3 of the first course and on days 1 and 2 of subsequent courses AND cytosine arabinoside (ara-C) 100 mg/m2 IV once daily for 7 days for the first course and 5 days for subsequent courses
  • Duration of therapy: The attainment of a normal-appearing bone marrow may require up to 3 courses of induction.
  • The doses presented here are manufacturer suggested; consult local and institutional protocol for further guidance.
  • This daunorubicin dose-reduction is based on a single study and may not be appropriate if optimal supportive care is availabl
  • For remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) in adults

Pediatric Dose

Acute Lymphocytic Leukemia

Remission Induction in Pediatric Acute Lymphocytic Leukemia:
In Combination:
LESS THAN 2 YEARS OR LESS THAN 0.5 M2:

  • 1 mg/kg IV on day 1 every week, vincristine 1.5 mg/m2 IV on day 1 every week, prednisone 40 mg/m2 orally daily; complete remission will usually be obtained within 4 courses of therapy; however, if after 4 courses the patient is in partial remission, an additional 1 or 2 courses may be given to obtain complete remission

GREATER THAN 2 YEARS OR GREATER THAN 0.5 M2:

  • 25 mg/m2 IV on day 1 every week, vincristine 1.5 mg/m2 IV on day 1 every week, prednisone 40 mg/m2 orally daily; complete remission will usually be obtained within 4 courses of therapy; however, if after 4 courses the patient is in partial remission, an additional 1 or 2 courses may be given to obtain complete remission
  • The doses presented here are manufacturer suggested; consult local and institutional protocol for further guidance.

Administration advice:

  • This drug is for IV use only and should not be administered by intramuscular or subcutaneous routes, as severe tissue necrosis will result.
  • This drug should be given into a rapidly flowing IV infusion of 0.9% sodium chloride or 5% dextrose injection.
  • The tubing should be connected to a butterfly needle, inserted preferably into a large vein. The dose and the size of the vein will determine the rate of administration, which should not be less than 3 to 5 minutes. Erythematous streaking and facial flushing are indications of too rapid administration.
  • A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration.

Side Effects

The Most Common

  • abdominal pain
  • constipation
  • darkening of soles, palms, or nails
  • nausea
  • vomiting
  • sores in the mouth and throat
  • diarrhea
  • stomach pain
  • hair loss
  • red urine
  • redness, pain, swelling, or burning at the site where the injection was given
  • rash
  • hives
  • itching
  • difficulty breathing or swallowing

More Common

  • diarrhea
  • hot flashes
  • nausea and vomiting
  • reddish-coloured urine (not blood) – this is normal, and lasts 1 to 2 days after each dose
  • difficulty breathing,
  • swelling of your face, lips, tongue, or throat,
  • chest pain,
  • shortness of breath,
  • sores in your mouth and throat,
  • easy bruising,
  • unusual bleeding (nose, mouth, vagina, or rectum),
  • nausea,
  • upper stomach pain,
  • itching,
  • loss of appetite,
  • dark urine,
  • clay-colored stools,
  • yellowing of the skin or eyes (jaundice), and
  • pain, burning, irritation, or skin changes where the injection was given

Rare

  • reduction in number of menstrual periods
  • temporary total loss of hair (returns after treatments end)
  • skin rash or itching
  • sores in mouth and on lips
  • black, tarry stools
  • blood in urine
  • cough or hoarseness with fever or chills
  • fever or chills
  • irregular heartbeat or palpitations in the chest
  • lower back or side pain with fever or chills
  • pain at injection site
  • painful or difficult urination with fever or chills
  • pinpoint red spots on skin
  • shortness of breath or swelling of the lips, tongue, or face
  • swelling of feet and lower legs
  • unusual bleeding or bruising

Interaction

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Pregnancy and Lactation

Pregnancy Category D

Pregnancy

There is a possibility of birth defect if either the man or woman is using daunorubicin at the time of conception, or if it is taken during pregnancy. Effective birth control should be practiced while using this medication. This medication may harm the baby if used during pregnancy. Tell your doctor immediately if you become pregnant while using this medication.

Lactation

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cerubidine (daunorubicin) , mothers should be advised to discontinue nursing during Cerubidine therapy.

How should this medicine be used?

Daunorubicin comes as a solution (liquid) or as a powder to be mixed with liquid to be injected intravenously (into a vein) by a doctor or nurse in a medical facility along with other chemotherapy medications. When daunorubicin is used to treat AML, it is usually injected once a day on certain days of your treatment period. When daunorubicin is used to treat ALL, it is usually injected once a week. The length of treatment depends on the types of drugs you are taking, how well your body responds to them, and the type of cancer you have. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

What special precautions should I follow?

Before receiving daunorubicin injection,

  • tell your doctor and pharmacist if you are allergic to daunorubicin, any other medications, or any of the ingredients in daunorubicin injection. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), methotrexate (Rheumatrex, Trexall), sirolimus (Rapamune), and tacrolimus (Prograf). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Other medications may also interact with daunorubicin, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
  • tell your doctor if you have or have ever had any medical condition.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. You should not become pregnant while you are receiving daunorubicin injection. If you become pregnant while receiving daunorubicin, call your doctor. Daunorubicin may harm the fetus.

References

  1. https://www.cancer.gov/about-cancer/treatment/drugs/daunorubicinhydrochloride
  2. https://pubchem.ncbi.nlm.nih.gov/compound/Daunorubicin
  3. https://pubchem.ncbi.nlm.nih.gov/compound/Daunorubicin-hydrochloride
  4. https://www.drugs.com/mtm/daunorubicin.html
  5. https://www.ncbi.nlm.nih.gov/books/NBK559073/
  6. https://www.webmd.com/drugs/2/drug-5021/daunorubicin-intravenous/details/list-contraindications
  7. https://rxharun.com/daunorubicin-uses-dosage-side-effects-interactions/#gsc.tab=0
  8. https://en.wikipedia.org/wiki/Daunorubicin
  9. https://medlineplus.gov/druginfo/meds/a682289.html
  10. https://go.drugbank.com/drugs/DB00694
  11. CAMEO Chemical Reactivity Classification
  12. ChemIDplus Chemical Information Classification
  13. CompTox Chemicals Dashboard Chemical Lists
  14. NCI Thesaurus Tree
  15. Lipid Classification
  16. IARC Classification
  17. LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
  18. LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    NORMAN Suspect List Exchange Classification
  19. PubChem
  20. Antibiotics, Antineoplastic
    Topoisomerase II Inhibitors
  21. Anatomical Therapeutic Chemical (ATC) classification
    Target-based classification of drugs
  22. NCBI