Following the special precautions for storage (see below) the shelf life for the powder for solution for injection is 5 years. The expiration date is printed on the label.
Chemical and physical in-use stability of the reconstituted solution in 0.9% sodium chloride solution has been demonstrated for 7 days at 15-25 C and for 14 days under refrigeration (2-8 C).
Chemical and physical in-use stability of a 0.5 mg/ml solution in water for injections has been demonstrated for 24 hours at temperatures below 25 C.
Chemical and physical in-use stability of solutions in the range 0.05 mg/ml to 5 mg/ml in 0.9% sodium chloride solution has been demonstrated for 7 days at room temperature (15-25 C).
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 C, unless reconstitution has taken place in controlled and validated aseptic conditions.
Lactose
There are no preclinical safety data of relevance to the prescriber which are additional to those already stated in other sections of the SPC.
April 2005
Pharmachemie B.V.
Swensweg 5
PO Box 552
2003 RN Haarlem
The Netherlands.
Doxorubin 10 mg: PL 4946/0001
Doxorubin 50 mg: PL 4946/0002
General precautions
Doxorubicin should only be used under supervision of a physician who is experienced in cytotoxic therapy. Nausea, vomiting and mucositis are often severe and should be treated appropriately.
Doxorubicin should not be administered intramuscularly or subcutaneously.
The total dose of doxorubicin administered to the individual patient should take into account any previous or concomitant therapy with related compounds such as daunorubicin.
Extravasation
Extravasation results in a severe and progressive tissue necrosis. If extravasation occurs, the injection should be terminated immediately and restarted in another vein. Flooding with normal saline, local infiltration with corticosteroids with or without sodium hydrogen carbonate solution (8.4%), and application of dimethylsulfoxide have been reported with varying success. The advice of a plastic surgeon should be sought, and wide excision of the involved area should be considered.
Cardiotoxicity
Congestive heart failure and/or cardiomyopathy may be encountered several weeks after discontinuation of doxorubicin therapy. Severe cardiac failure may occur precipitously without antecedent ECG change.
The risk of severe, irreversible and therapy-resistant cardiomyopathy and resulting congestive heart failure gradually increases with increasing dosages. A cumulative dose of 450 mg/m2 should not be exceeded.
Age over 70 or below 15 years and female gender in children should be considered a risk factor, as well as concomitant heart disease. In addition, ECG changes may occur including a reduction in the voltage of the QRS wave, and a prolongation of the systolic time interval, and the ejection fraction may be reduced.
In patients previously treated with other anthracyclines or cyclophosphamide, mitomycin C or dacarbazine, and patients who received radiotherapy to the mediastinal area, cardiotoxicity may occur at doses lower than the recommended cumulative limit. The concurrent use of trastuzumab and anthracyclines (like doxorubicin) is not recommended.
Acute severe arrhythmias have been reported to occur during or within a few hours after doxorubicin administration.
Heart function should be assessed before, during and after doxorubicin therapy, e.g., by ECG, echocardiography or determination of the ejection fraction. If test results indicate change in cardiac function associated with doxorubicin the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage.
Myelosuppression
The high incidence of bone marrow depression requires careful haematologic monitoring. The nadir is reached between 10-14 days after administration. Blood values usually return to normal within 21 days after administration. Doxorubicin therapy should not be started or continued when polynuclear granulocyte counts are below 2000/mm3, except in the treatment of acute leukaemia, where lower limits may be applied, depending on the circumstances.
Careful haematologic monitoring is also required because of the risk of secondary leukaemias after treatment with cytotoxic agents. A remission of acute leukaemia can be achieved when detected at an early stage.
Hepatic impairment
Hepatic function (SGOT, SGPT, alkaline phosphatase and bilirubin) should be evaluated before and during therapy.
Hyperuricaemia
Doxorubicin may induce hyperuricemia. The blood uric acid level should be monitored. Sufficient fluid intake should be ascertained (with a daily minimum of 3 l/m2). If necessary, a xanthine-oxidase inhibitor (allopurinol) may be administered.
Discoloration of urine
Doxorubicin may impart a red coloration to the urine.
Due to the frequent occurrence of nausea and vomiting, driving cars and operation of machinery should be discouraged.
The drug can not be administered in a jet or undiluted form.
Do not use for the administration of the drug Kelix
every 3-4 weeks.
Instructions for reconstitution:
For intravenous injection, Doxorubicin powder for solution for injection should be reconstituted to a concentration of 2 mg/ml in water for injections immediately before use. Alternatively, sodium chloride for injections may be used as a solvent, however, the product may take longer to dissolve.
In order to reconstitute the product, ensure the powder, solutions and equipment are at room temperature, add 5 (25) ml to the 10 (50) mg vial and shake for at least 60 seconds and leave to stand at room temperature for at least 5 minutes before administration to get a clear red mobile liquid. If gelatinous fragments are seen, leave the solution to stand for 5 minutes and shake again. Should the fragments still be visible, discard the solution.
When water for injections is used, immediate dilution to a concentration of less than 0.4mg/ml doxorubicin with 0.9% sodium chloride solution or 5% glucose solution is needed in order to obtain an isotonic solution.
Due to the toxic nature of doxorubicin it is recommended that the following protective measures be taken:
-General instructions for safe use of cytotoxics:
- Training in good techniques for reconstitution and handling should be given to relevant personnel.
- Pregnant staff should be excluded from working with this drug
- Protective clothing should be worn while administering, handling or reconstituting doxorubicin
- Contact with skin or eyes should be avoided. If it occurs, the affected area should be washed immediately with water, soap and water or sodium bicarbonate solution.
- Any spillages should be cleaned with dilute sodium hypochlorite solution.
- All equipment used for the handling, preparation and administration of doxorubicin should be incinerated.
Unused products should be disposed of in a suitable labelled container, marked as hazardous waste.
12-July-1993
