Cerubidine (Daunorubicin)

CERUBIDINE®

Rh´ne-Poulenc Rorer

Daunorubicin

Antimitotic – Antibiotic

Action And Clinical Pharmacology: Daunorubicin inhibits the synthesis of nucleic acids; its effect on desoxyribonucleic acid is particularly rapid and marked. Ribonucleic acid is more gradually affected.

It appears that the action of the drug is the result of the formation of a complex with desoxyribonucleic acid in the cell nucleus; this blocks the site of action of the polymerases and gives daunorubicin a cytostatic activity.

Daunorubicin displays an immunosuppressive action.

Daunorubicin has no effect on respiration or cellular glycolysis up to elevated concentrations which would inhibit cell growth.

It exerts an antiviral effect on the herpes and on the vaccine viruses of the desoxyribonucleic acid group, but not on the polio or influenza virus of the ribonucleic acid group.

Daunorubicin is inactive when administered orally.

Teratogenicity: No teratogenic effects have been observed in the chicken embryo, even at embryotoxic doses. In the mouse, prolonged treatment at a dose of 1.15 mg/kg s.c. daily did not interfere with gestation or produce any teratogenic effects.

In rabbits, doses of 90 µg/kg and 250 µg/kg i.v. induced 66% and 100% abortions respectively; in some fetuses, abnormalities which could not be attributed to the drug, were observed.

Indications And Clinical Uses: The initial treatment of myeloblastic and acute lymphoblastic leukemias. Daunorubicin can also induce a remission in patients suffering from chronic myeloid leukemia, reticulosarcoma, Ewing or Wilms’ tumors and lymphosarcoma.

Precautions: Daunorubicin induces medullary aplasia and leukopenia. It is therefore imperative that patients be protected against infection during the period of aplasia.

At the start of therapy, the increase in uric acid in the blood due to leukocyte degradation can be controlled by administering allopurinol and liquids to stimulate urine excretion. Caution must be exercised in patients with renal insufficiency.

Daunorubicin can cause tissue necrosis, thus great care must be taken to inject the product directly into the vein.

When daunorubicin is employed in association with other anticancer agents, the dosage of each should be reduced so as to minimize the total toxic effect.

Some instances of cardiotoxicity may be observed when a cumulative dose of 25 mg/kg has been reached; in general, this dose must not be exceeded except in certain desperate cases where 30 mg/kg can be administered. Likewise, because of possible cardiotoxicity, the drug must not be administered to patients who exhibit myocardial lesions or to those above 75 years of age.

Before initiating treatment with daunorubicin, physical examination, appropriate x-rays and ECG should be performed and repeated at regular intervals thereafter, particularly when the cumulative dose has reached 15 mg/kg.

Daunorubicin should be employed only as a treatment to induce a remission, and not as maintenance therapy.

Adverse Reactions: At the start of treatment, the patient may experience anorexia, nausea and vomiting. These are transient effects and generally do not require an interruption of treatment. Antiemetics may help relieve vomiting.

Abdominal pain, constipation or diarrhea, alopecia, rash, petechiae or purpura may be observed during therapy.

Some cases of thrombocytopenia and anemia have been reported during the first or second week of treatment. These phenomena are transient and corrective measures such as blood or platelet transfusions are rarely required.

During the aplastic phase, cases of localized infection have occurred, particularly in the buccal cavity and pharynx. Septicemia not responsive to antibiotics has also been reported.

Some cases of cardiopathy attended by rhythm abnormalities, electrical modifications and indications of cardiac insufficiency have been observed in patients receiving a cumulative dose exceeding 30 mg/kg.

In young patients, the urine occasionally acquires a red tint. This coloration is due to the presence of daunorubicin and its metabolites and has no clinical significance.

During treatment with combinations of daunorubicin with other antileukemic agents, there have been occurrences of myalgia and neuropathy. These symptoms, already associated with the use of other agents, have not been directly attributed to daunorubicin.

Dosage And Administration: Daunorubicin is reserved mainly for the initial therapy of acute leukemia and other forms of malignant tumors which are sensitive to the drug.

It is administered by the i.v. route only. After dilution in 4 mL of sterile water for injection, daunorubicin is injected into the tubing of a running infusion of 100 or 250 mL of isotonic solution. The infusion is performed rapidly to avoid local stasis.

Freshly prepared solution may be kept for a period of 24 hours at room temperature or 48 hours in a refrigerator.

Initial treatment: A) Daunorubicin Alone: Acute Lymphoblastic Leukemia: Daunorubicin is instituted at a daily dose of 1 mg/kg (30 mg/m over a period of from 3 to 6 days. If, after this first administration, the number of white cells is less than 1 500, maintenance therapy is begun. However, if a partial remission is obtained, but the number of leukocytes is greater than 1 500, treatment should be repeated 1 or more times, as necessary, based on the hematological response. As soon as the remission is obtained, maintenance treatment can be started. The total dose during the initial treatment should not, as a rule, exceed 20 mg/kg.

Acute Myeloblastic, Granulocytic and Promyelocytic Leukemias: A daily dose of 2 mg/kg (60 mg/m is administered for a period of from 3 to 6 days, plus 1 or 2 supplementary injections which are given a few days after a remission is obtained if the blasts have not completely disappeared from the peripheral blood or marrow. The total dose varies from 3 to 22.5 mg/kg (90 to 600 mg/m. During the initial therapy, blood should be examined every day and marrow 2 or 3 times a week.

B) Combination Therapy: When daunorubicin is given in association with other antileukemic medication, it must be given every 2 or 3 days to avoid complete marrow aplasia; the treatment extends for a period of 2 to 4 weeks. Hemograms should be conducted before each injection and if they manifest a severe perturbation of the blood count, the medication should be stopped.

The dosage is from 1 mg/kg per injection every 2 or 3 days up to a total of 12 mg/kg. If only an incomplete remission is obtained after this treatment, daunorubicin can be continued up to the maximum dose of 20 mg/kg which must not be exceeded during any one treatment period. As soon as a complete remission is obtained the drug is withdrawn and maintenance treatment instituted.

Maintenance Treatment: Any standard chemotherapeutic agent may be employed during maintenance therapy. If the marrow is not completely ablastic in the course of 4 weeks, a weekly injection of 1 mg/kg daunorubicin may be given.

Cumulative Doses: As a rule the total cumulative dose should not exceed 25 mg/kg, e.g., approximately 500 mg/mfor a child of 10 kg; 600 mg/mfor a child of 20 kg; 750 mg/mfor a child of 30 kg and 900 mg/mfor an adult of 60 kg. In patients who have become resistant to all therapy and for whom a final effort is required to induce a remission, the total cumulative dose can be extended to 30 mg/kg.

Chronic Myeloid Leukemia: Injections of 1 to 2 mg/kg may be administered every day or every other day up to a total dose of 6 to 12 mg/kg.

Availability And Storage: Each vial contains: daunorubicin 20 mg. Nonmedicinal ingredients: D-mannitol. Boxes of 1.

CERUBIDINE® Rh´ne-Poulenc Rorer Daunorubicin Antimitotic – Antibiotic

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