Daunorubicin (Systemic)


VA CLASSIFICATION
Primary: AN200

Commonly used brand name(s): Cerubidine.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Leukemia, acute lymphocytic (treatment) or
Leukemia, acute nonlymphocytic (treatment)—Daunorubicin is indicated, in combination with other antineoplastics, for treatment of acute lymphocytic leukemia {01} {03} and acute nonlymphocytic leukemia (acute myelocytic leukemia {03}, acute monocytic leukemia1 , erythroleukemia1 ) {01}.

[Neuroblastoma (treatment)]1—Daunorubicin is used for treatment of solid tumors of childhood, such as neuroblastoma {06}.

[Lymphomas, non-Hodgkin's (treatment)]—Daunorubicin is used for treatment of non-Hodgkin's lymphomas such as lymphosarcoma and reticulum cell sarcomas {03}.

[Ewing's sarcoma (treatment)]—Daunorubicin is used for treatment of Ewing's sarcoma {03}.

[Wilms' tumor (treatment)]—Daunorubicin is used for treatment of Wilms' tumor {03}.

[Leukemia, chronic myelocytic (treatment)]—Daunorubicin is used for treatment of chronic myelocytic (myelogenous) leukemia {03}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    563.99

pKa—
    10.3

Mechanism of action/Effect:

Daunorubicin is an anthracycline glycoside; it is classified as an antibiotic but is not used as an antimicrobial agent. Daunorubicin is most active in the S phase of cell division, but is not cycle phase–specific. Its exact mechanism of antineoplastic action is unknown but may involve binding to DNA by intercalation between base pairs and inhibition of DNA and RNA synthesis by template disordering and steric obstruction.


Other actions/effects:

Also has immunosuppressant effects {01}.

Distribution:

Rapidly distributed throughout the body, especially to the kidneys, spleen, liver, and heart, as unchanged medication and metabolites. It does not cross the blood-brain barrier {01}.

Biotransformation:

Rapidly (within 1 hour) in the liver to produce an active metabolite, daunorubicinol {01}. Further metabolism—Hepatic {01}.

Half-life:


Distribution:

45 minutes.



Elimination:

Daunorubicin: 18.5 hours {01}.

Metabolites: 55 hours.

Daunorubicinol: 26.7 hours {01}.


Elimination:
    In the urine, 25% in an active form; an estimated 40% is eliminated by biliary excretion {01}.


Precautions to Consider

Carcinogenicity/Mutagenicity

Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use.

Daunorubicin subcutaneous injection causes fibrosarcomas at the injection site in mice; however, it did not cause a carcinogenic effect within 22 months of observation after oral or intraperitoneal administration in mice {01}. Daunorubicin is potentially carcinogenic in humans.

Pregnancy/Reproduction
Fertility—
Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking antineoplastic therapy, especially with the alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents.

Daunorubicin causes testicular atrophy in male dogs.

Pregnancy—
Adequate and well-controlled studies have not been done in humans {01}.

First trimester: It is usually recommended that use of antineoplastics, especially combination chemotherapy, be avoided whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered.

Other hazards to the fetus include adverse reactions seen in adults.

In general, use of a contraceptive is recommended during cytotoxic drug therapy.

Studies in rabbits found an increased incidence of fetal abnormalities (parieto-occipital cranioschisis, umbilical hernias, rachischisis) and abortions, and studies in mice showed decreases in fetal birth weight and postdelivery growth rate {01}.

FDA Pregnancy Category D {01}.

Breast-feeding

Although very little information is available regarding distribution of antineoplastic agents into breast milk, breast-feeding is not recommended while daunorubicin is being administered because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity).

Pediatrics

Appropriate studies on the relationship of age to the effects of daunorubicin have not been performed in the pediatric population.


Geriatrics


Although appropriate studies on the relationship of age to the effects of daunorubicin have not been performed in the geriatric population, cardiotoxicity may be more frequent in the elderly. Caution should also used be in patients who have inadequate bone marrow reserves due to old age. In addition, elderly patients are more likely to have age-related renal function impairment, which may require reduction of dosage in patients receiving daunorubicin.


Dental

The bone marrow depressant effects of daunorubicin may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Daunorubicin also commonly causes stomatitis which may be associated with considerable discomfort.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Allopurinol or
Colchicine or
» Probenecid or
» Sulfinpyrazone    (daunorubicin may raise the concentration of blood uric acid; dosage adjustment of antigout agents may be necessary to control hyperuricemia and gout; allopurinol may be preferred to prevent or reverse daunorubicin-induced hyperuricemia because of risk of uric acid nephropathy with uricosuric antigout agents)


Blood dyscrasia–causing medications (see Appendix II )    (leukopenic and/or thrombocytopenic effects of daunorubicin may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of daunorubicin, if necessary, should be based on blood counts)


» Bone marrow depressants, other (see Appendix II ) or
Radiation therapy    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)


Cyclophosphamide or
Radiation therapy to mediastinal area    (concurrent use may result in increased cardiotoxicity; it is recommended that the total dose of daunorubicin not exceed 400 mg per square meter of body surface)


Doxorubicin    (use of daunorubicin in a patient who has previously received doxorubicin increases the risk of cardiotoxicity; dosage adjustment is necessary. Daunorubicin should not be used in patients who have previously received complete cumulative doses of doxorubicin or daunorubicin; in patients who have previously received less than a complete cumulative dose of doxorubicin, the total cumulative dose of doxorubicin plus daunorubicin should not exceed 550 mg per square meter of body surface {02})


Hepatotoxic medications, other (see Appendix II )    (concurrent use may increase the risk of toxicity; for example, high-dose methotrexate may impair liver function and increase toxicity of subsequently administered daunorubicin)


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by daunorubicin therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by daunorubicin therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the daunorubicin therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy. In addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alkaline phosphatase values, serum and
Aspartate aminotransferase (AST [SGOT]) values, serum and
Bilirubin concentrations, serum    (may be increased transiently)


Uric acid    (concentrations in blood and urine may be increased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression{01}
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


Gout, history of or
Urate renal stones, history of    (risk of hyperuricemia)


» Heart disease
» Hepatic function impairment    (reduction in dosage is recommended; three quarters of the normal dose is recommended in patients with serum bilirubin concentrations of 1.2 to 3 mg per 100 mL; one half of the normal dose is recommended in patients with serum bilirubin concentrations of greater than 3 mg per 100 mL {01})


» Infection{01}
Renal function impairment    (reduced elimination; dosage reduction is recommended; one half of the normal dose is recommended in patients with serum creatinine concentrations of greater than 3 mg per 100 mL {01})


Sensitivity to daunorubicin
» Tumor cell infiltration of the bone marrow
» Caution should be used also in patients with inadequate bone marrow reserves due to previous cytotoxic drug or radiation therapy.

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Alanine aminotransferase (ALT [SGPT]) values, serum and
Aspartate aminotransferase (AST [SGOT]) values, serum and
Bilirubin concentrations, serum and
Lactate dehydrogenase (LDH) values, serum    (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


» Chest x-ray and
» Echocardiography and
Electrocardiogram (ECG) studies{01} and
» Radionuclide angiography determination of ejection fraction{01}    (recommended prior to initiation of therapy and at periodic intervals during therapy)


» Hematocrit or hemoglobin and
» Leukocyte count, total and, if appropriate, differential and
» Platelet count    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


Uric acid concentrations, serum{01}    (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)




Side/Adverse Effects

Note: Many “side effects” of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Esophagitis or stomatitis (sores in mouth and on lips)
    
leukopenia or infection (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)—usually asymptomatic

Note: With esophagitis or stomatitis, sores in mouth and on lips occur 3 to 7 days after administration {01}.
Leukopenia occurs in all patients. The nadir of the leukocyte count occurs 10 to 14 days after a dose. Recovery usually occurs within 21 days after a dose.
In addition to the risk of infection, febrile drug reactions may also occur during or immediately after administration.


Incidence less frequent
    
Cardiotoxicity in the form of congestive heart failure (irregular heartbeat; shortness of breath; swelling of feet and lower legs)
    
cellulitis or tissue necrosis{01} (pain at injection site)—caused by extravasation
    
gastrointestinal ulceration (stomach pain)
    
hyperuricemia{01} or uric acid nephropathy (joint pain; lower back or side pain)
    
thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic

Note: Incidence of cardiotoxicity is more frequent in adults receiving a total cumulative dosage over 550 mg per square meter of body surface (450 mg per square meter of body surface in patients who have received previous chest irradiation), in the elderly, and in patients with a history of cardiac disease or mediastinal radiation.
Cardiotoxicity usually appears within 1 to 6 months after initiation of therapy. It may develop suddenly and may not be detected by routine ECG. It may be irreversible and fatal but responds to treatment if detected early.
Hyperuricemia or uric acid nephropathy occurs most commonly during initial treatment of patients with leukemia or lymphoma, as a result of rapid cell breakdown which leads to elevated serum uric acid concentrations.


Incidence rare
    
Allergic reaction (skin rash or itching)
    
cardiotoxicity in the form of pericarditis-myocarditis{01}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Nausea and vomiting

Note: Nausea and vomiting are usually mild and transient, occurring soon after administration and lasting 24 to 48 hours.


Incidence less frequent or rare
    
Darkening or redness of skin —if patient has received previous radiation therapy
    
diarrhea{01}



Those not indicating need for medical attention
Incidence more frequent
    
Loss of hair
    
reddish urine{01}

Note: Loss of hair occurs in most patients {01}. Growth usually resumes 5 or more weeks after therapy is completed.
Reddish urine usually clears within 48 hours.


Those indicating the need for medical attention if they occur after medication is discontinued
    
Cardiotoxicity (irregular heartbeat; shortness of breath; swelling of feet and lower legs)





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Daunorubicin (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to daunorubicin

Pregnancy—Use not recommended because of mutagenic, teratogenic, and carcinogenic potential; advisability of using a contraceptive; telling physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of risk of serious side effects





Use in the elderly—Increased risk of cardiotoxicity, bone marrow depression
Other medications, especially probenecid, sulfinpyrazone, other bone marrow depressants, or previous cytotoxic drug or radiation therapy
Other medical problems, especially chickenpox, herpes zoster, heart disease, hepatic function impairment, or infection

Proper use of this medication
Caution in taking combination therapy; taking each medication at the right time

Importance of ample fluid intake and subsequent increase in urine output to aid in excretion of uric acid

Frequency of nausea and vomiting; importance of continuing medication despite stomach upset

» Proper dosing

Precautions while using this medication
» Importance of close monitoring by the physician

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur
» Possibility of local tissue injury and scarring if infiltration of intravenous solution occurs; telling doctor or nurse right away about redness, pain, or swelling at injection site


Side/adverse effects
May cause adverse effects such as blood problems, loss of hair, heart problems, and cancer; importance of discussing possible effects with physician

Signs of potential side effects, especially esophagitis, stomatitis, leukopenia, infection, cardiotoxicity, cellulitis or tissue necrosis caused by extravasation, gastrointestinal ulceration, hyperuricemia, uric acid nephropathy, thrombocytopenia, and allergic reaction

Physician or nurse can help in dealing with side effects

Reddish urine may be alarming to patient although medically insignificant

Possibility of hair loss; normal hair growth should return after treatment has ended


General Dosing Information
Patients receiving daunorubicin should be under supervision of a physician experienced in cancer chemotherapy. It is recommended that the patient be hospitalized at least during initial treatment.

A variety of dosage schedules of daunorubicin, alone or in combination with other antitumor agents, are used. The prescriber may consult the medical literature as well as the manufacturer's literature in choosing a specific dosage.

Dosage must be adjusted to meet the individual requirements of each patient, on the basis of clinical response and appearance or severity of toxicity.

The desired dose of daunorubicin is withdrawn from the vial of reconstituted solution into a syringe containing 10 to 15 mL of 0.9% sodium chloride injection and then injected over 2 to 3 minutes into the tubing or side arm of a rapidly running intravenous infusion of 5% dextrose injection or 0.9% sodium chloride injection.

Care must be taken to avoid extravasation during intravenous administration. Facial flushing or erythematous streaking along the vein indicates overly rapid injection.

Administration by intravenous infusion is not recommended because of irritation to the vein and the risk of thrombophlebitis.

If extravasation of daunorubicin occurs during intravenous administration, as indicated by local burning or stinging, the injection and infusion should be stopped immediately and resumed, completing the dose, in another vein.

Because it will cause local tissue necrosis, daunorubicin must not be administered intramuscularly or subcutaneously.

Development of uric acid nephropathy in patients with leukemia or lymphoma may be prevented by adequate oral hydration and, in some cases, administration of allopurinol. Alkalinization of urine may be necessary if serum uric acid concentrations are elevated.

In general, it is recommended that a course of daunorubicin be administered no more frequently than every 21 days to allow the bone marrow to recover.

In acute leukemia, daunorubicin may be administered despite the presence of thrombocytopenia and bleeding; stoppage of bleeding and increase in platelet count have occurred during treatment in some cases and platelet transfusions are useful in others.

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of daunorubicin. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.

Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests.

Safety considerations of handling this medication
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastics may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include:    • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.


Combination chemotherapy
Daunorubicin may be used in combination with other agents in various regimens. As a result, incidence and/or severity of side effects may be altered and different dosages (usually reduced) may be used. For example, daunorubicin is part of the following chemotherapeutic combination:    —daunorubicin, vincristine, and prednisone.
For specific dosages and schedules, consult the literature. For information regarding each agent, consult the individual monographs.


Parenteral Dosage Forms

DAUNORUBICIN HYDROCHLORIDE FOR INJECTION USP

Note: The doses and strengths of the available dosage forms are expressed in terms of the daunorubicin base, not the hydrochloride salt.


Usual adult dose
Leukemia, acute lymphocytic
Intravenous, 45 mg (base) per square meter of body surface on days 1, 2, and 3 of a thirty-two–day course in combination with vincristine, prednisone, and asparaginase {01}.

Leukemia, acute nonlymphocytic
Intravenous, 45 mg (base) per square meter of body surface on days 1, 2, and 3 of the first course and days 1 and 2 of the second course, in combination with cytarabine {01}.


Usual adult prescribing limits
Up to a total lifetime dosage of 550 mg (base) per square meter of body surface, 450 mg per square meter of body surface in patients who have received previous chest irradiation (to reduce risk of cardiotoxicity).

Usual pediatric dose
Leukemia, acute lymphocytic
Intravenous, 25 mg (base) per square meter of body surface once a week, in combination with vincristine and prednisone.


Note: In children less than 2 years of age or below 0.5 square meter of body surface, dosage should be calculated on the basis of mg per kg of body weight rather than body surface area.


Usual geriatric dose


For patients 60 years of age and older:


Leukemia, acute nonlymphocytic—
Intravenous, 30 mg (base) per square meter of body surface on days 1, 2, and 3 of the first course and days 1 and 2 of the second course, in combination with cytarabine {01}.



Note: This dose is based on a single study and may not be appropriate if optimal supportive care is available {01}.


Size(s) usually available:
U.S.—


20 mg (base) (21.4 mg as HCl) (Rx) [Cerubidine (mannitol 100 mg)]

Canada—


20 mg (base) (21.4 mg as HCl) (Rx) [Cerubidine]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light.

Preparation of dosage form:
Daunorubicin for Injection USP is reconstituted for intravenous administration by adding 4 mL of sterile water for injection to the vial and shaking gently to dissolve, producing a solution containing 5 mg of daunorubicin (base) per mL.

Stability:
Reconstituted solutions of daunorubicin are stable for 24 hours at room temperature or 48 hours between 2 and 8 °C (36 and 46 °F) when protected from light.

Note: Any daunorubicin powder or solution that comes in contact with the skin or mucosa should be washed off thoroughly with soap and water.




Revised: 09/27/1997



References

Note: References used in the development and subsequent revisions of this monograph have not been incorporated into the database and therefore are not listed below.

  1. Cerubidine package insert (Wyeth-Ayerst—US), Rev 5/14/92.
  1. Reviewer comment, 3/1/87.
  1. Cerubidine product monograph (Rhone-Poulenc Rorer—Canada), Rev 5/91.
  1. DeVita VT, Hellman S, Rosenberg SA. Cancer principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers; 1997.
  1. Young RC, Ozols RF, Myers CE. The anthracycline antineoplastic drugs. NEJM 1981; 305: 139-53.
  1. Reviewers' responses to Hematologic-Oncologic Disease Advisory Panel Memo #9 of 1/30/97.
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