PHYSICAL AND CHEMICAL DESCRIPTION

Daunorubicin (R.P. 13 057) is an antibiotic produced by Streptomyces coeruleorubidis. It is the hydrochloride of 4-methoxy 6, 9, 11-trihydroxy 7, 8, 9, 10-tetrahydro (2, 3, 6-tridesoxy 3-amino L-lyxo-1-hexopyranosyl) 7-oxy-9-acetyl 5, 12-naphthacenequinone.

The hydrochloride is an orange-red microcrystalline powder. It is soluble in water, methanol and aqueous alcohol solutions. It is practically insoluble in chloroform, ether and benzene.

PROPERTIES

Daunorubicin inhibits the synthesis of nucleic acids, both by binding desoxyribonucleic acid and by inhibiting the reproduction of desoxyribonucleic acid and the synthesis of ribonucleic acid in the cell nucleus. As a result there is an interruption of cell division.

INDICATIONS

CERUBIDINE^® is indicated in the initial treatment of myeloblastic and acute lymphoblastic leukemias. It can also induce a remission in patients suffering from chronic myeloid leukemia, reticulosarcoma, Ewing or Wilms tumors and lymphosarcoma.

PRECAUTIONS


CERUBIDINE^® 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.

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

When CERUBIDINE^® is employed in association with other anti-cancer agents, the dosage of each should be reduced so as to minimize the total toxic effect.

Some instances of cardio-toxicity 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 cardio-toxicity, the drug must not be administered to patients who exhibit myocardial lesions or to those above 75 years of age.

Before initiating treatment with CERUBIDINE^®, physical examination, appropriate X-rays and E.C.G. should be performed and repeated at regular intervals thereafter, particularly when the cumulative dose has reached 15 mg/kg.

It is also recommended that CERUBIDINE^® be employed only as a treatment to induce a remission, and not as maintenance therapy.

SIDE EFFECTS

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 CERUBIDINE^® and its metabolites and has no clinical significance.

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

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 immuno-suppressive action as demonstrated by the inhibition of the production of heterohemagglutinins, by the prolongation of tolerance of skin grafts in mice and by the marked reduction of systemic lesions and arthritis provoked by Freund's complete adjuvant in the rat. Nevertheless, at non-toxic doses (1.25 mg/kg I.P.), daunorubicin does not decrease the number of immunologically active splenic cells in the mouse.
Daunorubicin has no effect on respiration or cellular glycolysis up to elevated concentrations which would inhibit cell growth.

In vitro, up to a concentration of 2.3 mcg/mL, daunorubicin partially inhibits KB cells cultivated in stationary tubes and exerts a total inhibition at a concentration of 4.6 mcg/mL.

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.

In vivo, in the mouse, chicken and rabbit, daunorubicin provides a variable anti-tumor activity on grafted tumors and on tumors which appear either spontaneously or as a result of a virus.

In the mouse, it exerts a potent effect (I.V,, I.P.) on grafted mammary adenomas, a moderate effect on pulmonary papillary adenomas, but only a slight effect on solid Ehrlich adenocarcinoma at a dose of 3 mg/kg S.C. for 6 days. By the I.P. route, daunorubicin is effective against ascitic tumors and by the S.C. route, against solid sarcomas when treatment is instituted immediately after the graft.

The drug possesses a significant inhibitory action on the Shope fibroma when administered by the S.C. route in the rabbit.

In the reticulosarcoma of mice, daunorubicin, administered by the I.P. route, reduces the weight of the spleen by 55% and prolongs the life of the animal by 25%. Administered I.P., daunorubicin is also extremely effective in lymphoblastic leukemia and demonstrates a good effect on C 1498 myeloid leukemia. It is also very active by the I.P. route in L 1210 leukemia and Rauscher leukemia.

In the anesthetized dog, a dose of 5 mg/kg I.V. of daunorubicin does not produce any significant changes in arterial pressure and no effects were observed on the ECG or pulse. However, the same dose in the dog under pentobarbital anesthesia with atropine, produces an immediate and sustained (4 to 20 hours)
reduction (10%) of cardiac rhythm, but without appreciably affecting the contracting force of the right ventricle, the blood pressure, or respiratory rate and amplitude. The drug exerts no clear effect on the sympathetic and parasympathetic systems.

Daunorubicin is inactive when administered orally.

TERATOGENICITY STUDIES

No teratological 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 0.09 mg/kg and 0.25 mg/kg I.V. induced 66% and 100% abortions respectively; in some fetuses, abnormalities which could not be attributed to the drug, were observed.

Acute toxicity - The acute toxicity of daunorubicin is approximately 20 mg/kg in the mouse, 6 mg/kg in the guinea pig, 4 mg/kg in the dog and between 12.5 and 25 mg/kg in the rat. The animals usually died from the third post-drug day. No particular toxic symptoms were observed, except that the animals languished in a state of profound torpor.

Chronic toxicity - Daily injections of 0,25, 0.50 and 1 mg/kg I.V. for 3 months in the rabbit did not produce mortality. The appearance and behaviour of the animals remained normal. At the 1 mg/kg dose, anemia, benign leukopenia and a slight slowing in weight gain were observed, but these effects disappeared spontaneously by the sixth week. At higher doses (2 mg/kg), the animals died between the 4th and 10th day.

In the dog, a daily dose of 0.25 mg/kg for 3 months was well tolerated. No abnormalities were observed in the hemogram or bone marrow but there were testicular alterations with apparently irreversible total aspermatogenesis. At more elevated dosages (0.5 and 1 mg/kg), tolerance is rather poor with marked harmful effects on the blood.

DOSAGE AND ADMINISTRATION

CERUBIDINE^® 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 sterile water, CERUBIDINE^® is injected into the tubing of a running infusion of 100 or 250 mL 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) Cerubidine alone

Acute lymphoblastic leukemia - CERUBIDINE^® is instituted at a daily dose of 1 mg/kg (30 mg/m²) over a period of 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 one 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 granulocitic and promyelocytic leukemias - A daily dose of 2 mg/kg (60 mg/m ) is administered for a period of 3 to 6 days. plus one or two 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 - 600 mg/m²). During the initial therapy, blood should be examined every day and marrow 2 or 3 times a week.

B) Combination therapy

When CERUBIDINE^® 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. It is recommended that hemograms 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, CERUBIDINE^® 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 therapy

Any standard chemotherapeutic agents 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 CERUBIDINE® may be given.

Cumulative doses

As a rule the total cumulative dose should not exceed 25 mg/kg, e.g., approximately 500 mg/m² for a child of 10 kg; 600 mg/m for a child of 20 kg; 750 mg/m² for a child of 30 kg and 900 mg/m² for 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.

SUPPLY

Vials of 20 mg daunorubicin.

REFERENCES

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Boiron M, Jacquillat, Cl, Neil M, Thomas, M, Bernard J. Traitement des leucemies aigues granulocytaires par la rubidomycine. Fath-Biol 1967; 1W(19-20): S2l-924.

Bornstein RS, Theologides A, Kennedy BJ. Daunorubicin in acute myelogenous leukemia in adults. JAMA 1969; 207(7): February 17.

Di Marco A, Massino L. La daunomicina. Minerva Medica 1968; 59(69): August 29.

Dreyfus B, Sultan C, Boiron M, Jacquillat C, Weil M, Rochang H.Sur le traitement d'attaque par la rubidomycine de 19 cas de leucemie aigüe myeloblastique. Presse Med 1968; 76(2; January 13): 55-57.

Hardisty RM, Norman FM. Preliminary experience with rubidomycin in the treatment of acute lymphoblastic leukemia resistant to other antimetabolites. Path-Biol 1967; 15(19-20): 941-942.

Holland JF. Daunomycin treatment in acute leukemia. Path-Biol 1967; 15(19-20): 929-932.

Julou L. Ducrot R, Fournel J, Ganter P, Maral R, Poulaire P, Koenig F, Myon J, Pascal S, Pasquet J. Un nouvel antibiotique doué d'activité antitumorale: la rubidomycine (13 057 R.P.) - III - Etude toxicologique et pharmacologique. Arzneimittel-Forschung 1967; 17: 948-954.

Kourilsky FM, Dupuy JM, Fradelizi D, Jacquillat CI, Bernard J. Abolition des reactions d'hypersensibilité retardée et gravité des aplasies induites par la rubidomycine. Path-Biol 1967; 15(19-20): 959.

Kreiter H, Begemann H, Rabtetter J. Bilan du traitement de leucemies aigues myeloblastiques par la daunomycine et la cytosine arabinoside. Medizinische Klinik 1968; 51: 2058-2066.

Macrez CI, Marneffe-Lebrequier H, Ripault J, Clauvel JP, Jacquillat CI, Weil M. Accidents cardiaques observes au cours des traitements par la rubidomycine. Path-Biol 1967; 15(19-20): 949-953.

Mathe O, Schwarzenberg L, Schneider M, Schlumberger JR, Hayat M, Amiel JL, Cattan A, Jasmin C. Acute lymphoblastic leukemia treated with a combination of prednisone, vincristine and rubidomycin. The Lancet 1967; August 19: 380-382.

Tan C, Tasaka H, Yu KP, Murphy L, Karnofsky D. Daunomycin, an antitumor antibiotic. in the treatment of neoplastic disease. Cancer 1967; 20(March): 333-353.