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.
Only available with prescription
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.

部份中文司比定[CERUBIDINE]处方资料[仅供参考]
药品英文名
Daunorubicin
药品别名
红保霉素、红比霉素、红卫霉素、司比定、柔毛霉素、正定霉素、Cerubidine、Daunoblastina、Daunomycin、Daunorubicinum、DNR、DRB
药物剂型
注射剂(粉)：10mg，20mg。
药理作用
本药为第一代蒽环类抗生素，为周期非特异性抗癌药。其作用机制酷似阿霉素，可嵌入DNA，进而抑制RNA和DNA的合成，对RNA的影响尤为明显。但柔红霉素的抗瘤谱远较阿霉素窄，对实体瘤疗效也远不如阿霉素和表柔比星。
药动学
本药不能透过血-脑脊液屏障。给药大约40～50min后即在肝内代谢成具有抗癌活性的柔红霉素醇(daunorubicinol)，并与本药原形一起分布至全身，以肾脏、脾脏、肝和心脏浓度较高。柔红霉素半衰期α相为45min，β相为18.5h，柔红霉素醇半衰期为26.7h，其他代谢物约为50～55h，因此，本药的血药浓度持续时间较长。经尿排泄约25%为具有抗癌活性的代谢物，经肝排泄达40%。
适应证
1.主要用于治疗各种类型的急性白血病(包括急性粒细胞白血病、急性淋巴细胞白血病和急性单核细胞白血病、急性粒-单核细胞白血病及急性红白血病)、慢性粒细胞性白血病、恶性淋巴瘤。
2.也可用于治疗神经母细胞瘤、尤文瘤(Ewing)和肾母细胞癌等。
禁忌证
1.对柔红霉素、阿霉素或表柔比星过敏者，可能对本药存在交叉过敏。
2.周围血象中白细胞低于3.5×109/L或血小板低于50×109/L者。
3.发热或伴明显感染者。
4.恶病质者。
5.水、电解质或酸碱平衡紊乱者。
6.胃肠道梗阻者。
7.肝肾功能、心肺功能不全者。
8.既往用过足量阿霉素或表柔比星者。
9.哺乳期妇女、孕妇(尤其在妊娠头3个月内)。
注意事项
1.药物对儿童的影响：本药的心肌毒性在幼儿比在青年中明显，故儿童用药剂量酌减，2岁以下幼儿慎用。
2.药物对老人的影响：本药的心肌毒性在老年人比在中青年明显，老年人用药剂量应酌减，60岁以上老人慎用。
3.药物对妊娠的影响：由于本药能透过胎盘，并有致畸致突变作用，故孕妇不要使用，尤其在妊娠初期的3个月内。
4.用药前后及用药时应当检查或监测：用药前应测定心脏功能(包括心电图、超声心动图、血清酶学)，有条件时可监测左心室射血分数(LVEF)和PEP与LVEF之比。同时应密切监测血象，定期做肝、肾功能检查。
5.本药与阿霉素可能有交叉耐药性。
6.因对静脉有刺激，可致血栓性静脉炎，所以不宜滴注。本药仅能用作静脉注射，并避免药液外漏和接触皮肤。如注射局部有红肿、疼痛或药液外漏，应立即停止使用，并采取冷敷等措施。
7.急性白血病伴明显血小板减少者，仍可使用本药，部分病例反而可使出血停止、血小板数上升，但最好同时输注新鲜全血或血小板。
8.使用本药期间不能进行放射治疗，特别是胸部放疗。在停止放疗后至少3～4周才能使用本药。
9.用药期间要保证足够的尿量，可使用别嘌醇以预防高尿酸血症，对痛风患者可酌情增加别嘌醇等药的剂量。
10.在用药期间和周围血象白细胞减少时不能进行牙科手术(包括拔牙)，尤其是伴有血小板减少时。
11.因本药骨髓抑制较严重，故不宜用药过久。如出现口腔溃疡(此反应多在骨髓毒性之前出现)，应立即停药。
12.曾用过大剂量环磷酰胺者，本药的每次用量和总累积剂量均应相应减少。
13.为避免严重心脏损害，本药总累积量不应超过450～550mg/m2。
14.临用前将所需用量加入5～10ml氯化钠注射剂中，振荡溶解后，再加入氯化钠注射剂配制成浓度为2～5mg/ml。
15.本药可组成以下联合化疗方案：CODP(环磷酰长春新大麦、柔红霉素和泼尼松)、DOAP(柔红霉素、长春新大麦、阿糖胞苷和泼尼松)、DAMP(柔红霉素、阿糖胞苷、巯嘌呤或硫鸟嘌呤和泼尼松)等。联合化疗时剂量决而不行至单用时常规剂量的2/3。
16.用药后48h内尿色可呈红色。
不良反应
1.胃肠道：较常见的为恶心、呕吐、口腔炎和食管炎，一般在给药3～7天后可出现口唇溃疡。偶可出现胃痛，腹泻或全胃肠炎，但其发生率较阿霉素低。
2.骨髓抑制：较严重。白细胞减少几乎不可避免，大多在首次用药后10～14天降至最低点，在3周内逐渐恢复。血小板减少较罕见，且大多不严重。
3.心血管：主要为心肌毒性，儿童年龄越小发生心肌病的机会越大，心电图变化多呈一时性和可逆性。滴注快时可出现心律失常。也可出现充血性心力衰竭，心衰的发生与使用本药累积量有关系，常在总累积量达400～500mg/m2时发生；2岁以上儿童总累积量在200～300mg/m2以上可发生；2岁以下总累积量10mg/kg时即可发生。60岁以上老人或原有心肌病变者，或既往接受过胸部放射治疗者可能发生猝死，而此时常规心电图尚无明显改变。本药还可使肝脏中心静脉及肝小叶静脉闭塞而导致黄疸、腹水、肝大及肝性脑病。
4.泌尿生殖系统：可致高尿酸血症和肾脏损害。本药在动物中可引起迟发的生殖功能减退和障碍，如可致雄狗睾丸萎缩。
5.皮肤毛发：脱发虽常见，但大多可在疗程结束后5～6周再生。过敏性皮炎、瘙痒较少见。
6.局部：静脉注射本药漏出血管外可导致局部疼痛、组织坏死、蜂窝织炎。
7.本药在人体中有潜在致畸、致突变和致癌作用。
8.其他：尚有药物热，但罕见。
用法用量
1.成人：
(1)静脉注射：每次30～40mg/m2，缓慢静脉注射，每3～4周连用23天。总累积剂量应控制在400～500mg/m2内。
(2)肾功有不全时剂量：本药用量应予酌减。
(3)肝功能不全时剂量：血清胆红素在12～30mg/L时，每次用常规剂量的3/4；血清胆红素大于30mg/L时只能用常规剂量的一半。
2.老年人剂量：老年人剂量酌减。
3.儿童：静脉注射20mg/m2，每周1次。2岁以下幼儿及体表面积小于0.5m2者，剂量为每次0.5～1mg/kg，连用2-3次或每周1次，用3～4周。2岁以下幼儿总累积量不能超过200～250mg/m2。
药物相应作用
1.与氧烯洛尔合用可加重心脏毒性。
2.对心脏或肝脏有毒性的药物不能与本药同用。
3.和大多数抗癌药一样，使用本药期间，接种活疫苗将增加活疫苗所致感染的危险，故用药期间不能接种活疫苗。化疗停止至少3个月才能接种活疫苗。
专家点评
本品主要用于治疗急性白血病，与Ara-C合用治疗急性粒细胞性白血病缓解期超过60%，与泼尼松、长春新碱合用治疗急性淋巴细胞白血病可提高缓解率。单用该药缓解率高而缓解期短。