英文药名：Cerubidin（Daunorubicin HCl Powder Infus）

中文药名：盐酸柔红霉素粉末

生产厂家：赛诺菲-安万特爱尔兰有限公司
药品介绍：
成份
盐酸柔红霉素 Daunorubicin HCl
适应症
急性粒细胞性白血病，急性淋巴细胞性白血病。也可用于神经母细胞瘤和横纹肌瘤。
用量
500 ug - 3 mg/kg/日，静注，共3-5次，连续或隔日给药，停药1周后重复，总剂量不宜超过20 mg/kg。全积累量应不超过400-500 mg/m2。2岁以下幼儿不能超过200-250 mg/m2。
禁忌
严重心脏病人，严重感染或骨髓抑制病人，妊娠初期及哺乳期妇女禁用。
注意事项
用药期间应严密监测血象，肝功能及心电图变化。在静滴时应防止药物漏出血管外，以免引起组织损害和坏死。用药期间及停用本品后3-6月内禁用病毒疫苗接种。
不良反应
骨髓抑制，脱发及胃肠道反应，口腔炎。
药物相互作用
勿与肝素混用。

Cerubidin 20mg Powder for Concentrate for Solution for Infus
1. NAME OF THE MEDICINAL PRODUCT
Cerubidin 20mg Powder for Concentrate for Solution for Infusion.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Daunorubicin Hydrochloride equivalent to daunorubicin 20mg.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Powder for Concentrate for solution for infusion.
A microcrystalline, orange-red, sterile powder
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
As an antimitotic and cytotoxic for the induction of remissions in acute lymphocytic and myelogenous leukaemias.
Daunorubicin, as part of combination regimen, is indicated for the treatment of acute lymphocytic leukemia and acute myeloid leukemia in children.
4.2 Posology and method of administration
For intravenous administration only.
The solution is given via the tubing of a freely running intravenous infusion, over a 20 minute period. This technique minimises the risk of thrombosis or perivenous extravasation which can lead to severe cellulitis and vesication.
Adults:
40 - 60mg/m2 on alternate days for a course of up to three infusions.
Acute Myelogenous Leukaemia:
45mg/m2/day is the recommended dose.
Acute Lymphocytic Leukaemia:
45mg/m2/day is the recommended dose.
Pediatric patients:
Cerubidin dosage for children (over 2 years) is usually calculated based on the body surface area and adjusted to meet individual requirements of each patient, on the basis of clinical response and the patient's haematological status. Courses may be repeated after 3 to 6 weeks.
Current specialized protocols and guidelines should be consulted for appropriate treatment regimen.
For children over 2 years the maximum cumulative dose is 300 mg/m2
For children under 2 years of age (or below 0.5 m2 body surface area), the maximum cumulative dose is 10 mg/kg
Elderly
Use with care in patients with inadequate bone marrow reserves. A dosage reduction of up to 50% is recommended.
The dosage should be reduced in patients with impaired hepatic or renal function. A 25% reduction is recommended in patients with serum bilirubin concentrations of 1.2-3mg/100ml and a 50% reduction in cases with serum bilirubin or creatinine concentrations above 3 mg/100ml.
The number of infusions required varies widely from patient to patient and must be determined in each case according to response and tolerance.
Cerubidin/Daunorubicin is extremely irritating to tissues and may only be administered intravenously after dilution. Cerubidin/Daunorubicin should be administrated through a large vein and the infusion should be kept free flowing. When second or subsequent infusions are given, the doses and time intervals on the effect on the previous doses and must be the subject of careful deliberation, examination of the peripheral blood and, under some circumstances, of the bone marrow
The effect of Cerubidin/Daunorubicin on the disease process and on normal blood precursors cannot be exactly predicted for any particular case. The difference between the incomplete treatment, a satisfactory remission and overdosage with possible irreversible aplasia of the bone marrow depends on the correct choice of dosage, time intervals and total number of doses.
4.3 Contraindications
Use in the management of non-malignant disease.
Use in the presence of acute infections.
Use in patients with marked marrow depression unless considered essential by the physician/oncologist.
Use in patients in the presence of oropharyngeal ulceration.
Use in patients recently exposed to, or with existing chicken pox or herpes zoster.
Use via intramuscular or subcutaneous routes.
4.4 Special warnings and precautions for use
Daunorubicin should only be administered under the direction of a specialist having the facilities for regular monitoring of clinical, biochemical and haematological effects during and after administration.
Daunorubicin has been shown to be carcinogenic in animals. The possibility of a similar effect should be borne in mind when designing the long-term management of the patient.
Extreme caution should be exercised when using the product in patients with cardiac disorders or in the elderly. Cardiotoxicity if it occurs is likely to be heralded by either a persistent tachycardia, shortness of breath, swelling of feet and lower limbs or by minor changes in the electrocardiogram and for this reason an electrocardiographic examination should be made at regular intervals during the treatment. Cardiotoxicity usually appears within 1 to 6 months after initiation of the therapy. It may develop suddenly and not be detected by routine ECG. It may be irreversible and fatal but responds to treatment if detected early.
The risk of congestive heart failure increases significantly when the total cumulative dosage exceeds 600 mg/m2 body surface area in adults, 300 mg/m2 in children over 2 years or 10mg/kg bodyweight in children under 2 years. Cardiotoxicity may be more frequent in children and the elderly. The dosage should be modified if previous or concomitant cardiotoxic drug therapy is used.
Daunorubicin should be used with care in patients at risk of hyperuricaemia (e.g. in the presence of gout, urate and renal calculi), tumor cell infiltration of the bone marrow and in patients with inadequate bone marrow reserves due to previous cytotoxic drug or radiation therapy. The cumulative dose of daunorubicin should be limited to 400mg/m2 when radiation therapy to the mediastinum has been previously administered. The dose of daunorubicin should not be repeated in the presence of bone marrow depression or buccal ulceration.
Rapid destruction of a large number of leukaemia cells may cause a rise in the blood uric acid or urea and so it is a wise precaution to check these concentrations three or four times a week during the first week of treatment. Fluids should be administered and allopurinol used in severe cases to prevent the development of hyperuricaemia.
Care should be taken to avoid extravasation during intravenous administration. All steps should be taking to avoid tissuing and bandages should not be used. Facial flushing or erythematous streaking along the vein indicates too rapid infusion. If tissue necrosis is suspected, the infusion should be stopped immediately and resumed in another vein. Where extravasation has occurred, an attempt should be made to aspirate the fluid back through the needle. The affected area may be injected with hydrocortisone. Sodium bicarbonate (5 ml of 8.4%) may also be injected in the hope that through pH changes the drug will hydrolyse. The opinion of a plastic surgeon should be sought as skin grafting may be required.
Application of ice packs may help decrease local discomfort and also prevent extension. Liberal application of corticosteroid cream and dressing the area with sterile gauze should then be carried out.
Each patient should be given a clinical and bacteriological examination to determine whether infection is present; any infection should be adequately eliminated before treatment with Daunorubicin which might depress the bone marrow to the point where anti-infective agents would no longer be effective. If facilities are available, patients should be treated in a germ-free environment or, where it is not possible, reverse barrier nursing and aseptic precautions should be employed. Anti-infective therapy should be employed in the presence of suspected or confirmed infection and during a phase of aplasia. It should be continued for some time after the marrow has regenerated. Care should also be used in patients at risk of infection.
Personnel handling this product should wear protective clothing and be trained in good handling techniques.
4.5 Interaction with other medicinal products and other forms of interaction
None known.
4.6 Pregnancy and lactation
Daunorubicin has been shown to be teratogenic. The product should not be used in pregnancy unless considered absolutely essential by the physician. Daunorubicin should not be administered to mothers who are breast-feeding infants.
4.7 Effects on ability to drive and use machines
Not applicable.
4.8 Undesirable effects
Side effects include those common to all anti-neoplastic agents: gastrointestinal disturbances, headache, allergic reactions, fever, weakness, alopecia, stomatitis.
Local Adverse reactions:
Two kinds of local adverse reactions are reported:
• Extravasation with risk of tissue necrosis: the infusion must be stopped, a maximum of infiltrated product aspirated and a cold dressing applied. A corticosteroid may possibly be injected or dimethyl sulfoxide applied topically. Daily surveillance is required. Indwelling i.v catheters and Portacath devices reduce the risk of extravasation.
• Recall of skin reaction due to prior radiotherapy, consisting of pain and erthyema which may last several days.
Cardiotoxicity:
Acute toxicity:
• Onset within 48 hours
• ECG modification may occur: arrhythmias, in particular prolonged QT interval usually with no clinical signs. In the event of arrhythmia, treatment can be continued but any associated electrolyte imbalance (hypokalemia, hyponatremia, etc.) must be corrected.
• Early onset of acute myopericarditis is rare.
Chronic toxicity:
• Cardiomyopathy which may progress to congestive heart failure; this potentially fatal condition requires specialized care.
• Chronic toxicity is correlated to the total cumulative dose administered.
Prevention:
Cardiotoxicity may be prevented by:
• Clinical monitoring
• Regular monitoring of cardiac function by eva luating ventricular performance using echocardiography or radionuclide scanning. These tests should be performed before the first administration and repeated regularly. Treatment should be discontinued if any significant change occurs.
• Some cardioprotective drugs can limit risks of toxicity.
Bone marrow depression: in every patient bone marrow function will be depressed by treatment with daunorubicin and in a variable proportion of cases, severe aplasia will develop. Risk of sepsis, severe opportunistic infections may occur with bone marrow depression.
Leucopenia is usually more significant than thrombocytopenia. The nadir for leucopenia usually occurs between 10-14 days and recovery occurs gradually over the next 1-2 weeks. Bone marrow depression must be anticipated in every case by eliminating infection before the treatment, by isolating the patient from infection during the treatment and by means of supportive therapy. This includes the continuous administration of anti-infective agents, the administration of platelet-rich plasma or fresh whole blood transfusion and, under some circumstances, the transfusion of white cell concentrates.
Other less serious adverse reactions that have been reported (in order of reducing frequency) are: stomatitis, alopecia, phlebitis, fever, anaemia, nausea, vomiting, mucositis, diarrhoea and rash.
The urine may be temporarily coloured red after treatment.
4.9 Overdose
In the event of overdose, all the adverse reactions may be exacerbated. Blood and bone marrow counts should be performed regularly and cardiological, radiological, and ultrasound investigations carried out to define appropriate symptomatic treatment.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Cerubidin is an anthracycline glycoside antibiotic and is a potent antileukaemia agent. It also has immunosuppressant effects.
The exact mechanism of the antineoplastic action of daunorubicin is uncertain but may involve binding to DNA and RNA by intercalation between base pairs and inhibition of DNA and RNA synthesis by template disordering and steric obstruction. Daunorubicin is most active in the S phase of cell division but is not cycle phase-specific. Tumour cell cross-resistance has been observed between daunorubicin and doxorubicin.
No controlled paediatric studies have been conducted.
The literature mentions the use of daunorubicin in treatment regimens for Acute Myelogenous Leukaemia and Acute Lymphocytic Leukaemia, including paediatric age groups. However, due to the ongoing search for a balance in gain or maintenance of efficacy and a decrease in toxicity the use of daunorubicin in the treatment of paediatric ALL and AML is fluctuating in clinical practice, mainly depending on risk stratification and specific subgroups. Published studies suggest no differences in safety profile between pediatric patients and adults.
5.2 Pharmacokinetic properties

Daunorubicin is rapidly taken up by the tissues, especially by the kidneys, spleen, liver and heart. It does not cross the blood brain barrier. Subsequent release of the drug and its metabolites from the tissues is slow (T½ = 55 hours). Daunorubicin is rapidly metabolised in the liver. The major metabolite, daunorubicinol is also active. Daunorubicin is excreted slowly in the urine, mainly as metabolites with 25% excreted in the first 5 days. Biliary excretion also makes a significant (40%) contribution to elimination
5.3 Preclinical safety data
None.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
D-Mannitol.
6.2 Incompatibilities
This medicinal product should not be mixed with other medicinal products except those mentioned in section 6.6.
The reconstituted product is incompatible with heparin sodium injection and dexamethasone sodium phosphate injection.
6.3 Shelf life
3 years.
The product after first opening and reconstitution of the powder should be used within 24 hours (see 6.4 for storage details). Once the reconstituted solution has been diluted in the infusion medium, it should be used immediately.
6.4 Special precautions for storage
Do not store above 25ºC. Store in the original container. If prepared aseptically, the reconstituted solution may be stored for up to 24 hours in a refrigerator at 2 – 8ºC protected from light. The reconstituted solution further diluted in infusion medium should be used immediately'
6.5 Nature and contents of container
Uncoloured Type III (Ph.Eur.) neutral glass vial fitted with butyl rubber stopper and aluminium overseal.
The vials are available in packs of 1 or 10 vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
The contents of the vial should be reconstituted with water for injections Ph. Eur. 4ml to give a solution of concentration 5 mg per ml. The calculated dose of Cerubidin should be further diluted with normal saline to give a final concentration of 1 mg per ml. Once diluted the infusion should be given immediately. The solution should be infused over a 20 minute period into the tubing, or side arm, of a well placed, rapidly flowing i.v. infusion of normal saline (to minimise extravasation and possible tissue necrosis). Alternatively, cerubidin may be added to a mini bag of sodium chloride injection 0.9% w/v and this solution infused into the side arm of a rapidly flowing infusion of normal saline.
Special Protection Information
Cerubidin should only be handled by staff experienced with cytotoxic drugs. Reconstitution should be carried out in a designated area. Protective clothing (including gloves and eye protection) should be worn. Double gloving is recommended for dealing with major spillages. Waste should be disposed of carefully in suitable separate containers, clearly labelled as to their contents (it should be noted that the patient's body fluids and excreta will contain appreciable amounts of antineoplastic agents and they should be treated as hazardous waste). All staff exposed to cerubidin should be recorded and monitored. Pregnant staff should not handle cerubidin
Spill or Leaks Procedures
Daunorubicin infusion may be neutralised with sodium hypochlorite prior to disposal of unused drug or if vial is accidentally broken. The neutralised drug can be disposed of in the sink.
7. MARKETING AUTHORISATION HOLDER
sanofi-aventis Ireland Ltd.
Citywest Business Campus
Dublin 24.
8. MARKETING AUTHORISATION NUMBER(S)
PA 540/96/1
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
20th April 1995/20th April 2010
10. DATE OF REVISION OF THE TEXT
September 2011