Doxorubin 0.2%
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Prescriber Information Leaflet
DOXORUBIN 0.2%
doxorubicin hydrochloride
Product Summary
1. Trade Name of the Medicinal Product
Doxorubin 0.2%
2. Qualitative and Quantitative Composition
Doxorubin 0.2% injection contains doxorubicin hydrochloride 2 mg/ml.
3. Pharmaceutical Form
Solution for Injection.
4. Clinical Particulars
4.1 Therapeutic Indications
In combination with other antineoplastic drugs, doxorubicin is intended for the treatment of acute lymphocytic leukaemia (except acute lymphatic leukaemia of low risk in children), acute myeloid leukaemia, Hodgkin- and non-Hodgkin lymphomas, osteosarcoma, Ewing sarcoma, adult soft tissue sarcoma, metastatic breast carcinoma, gastric carcinoma, small-cell lung cancer, neuroblastoma, Wilms tumour and bladder carcinoma. Doxorubicin may be used intravesically as a single agent for treatment and prophylaxis of superficial bladder carcinoma.
4.2 Posology and Method of Administration
Dosage depends on tumour type, hepatic function and concurrent chemotherapy. The commonly recommended dosage schedule as a single agent is 60-75 mg/m2 by intravenous injection once every 3 weeks. An alternative dose schedule is 20 mg/m2 intravenously, on 3 consecutive days, once every 3 weeks.
In combination with other cytotoxic agents doses of 50-75 mg/m2 are administered.
Myelosuppression may be more pronounced because of the additive effects of the drugs.
The risk of development of cardiomyopathy gradually increases with the dosage. A cumulative dose of 550 mg/m2 should not be exceeded. The administration of doxorubicin should be monitored by electrocardiography, echocardiography and carotid pulse curve: where the voltage of the QRS wave decreases by 30 % or at a fractional shortening of 5 %, it is recommended that treatment is stopped. If a patient has received mediastinal irradiation, has concomitant heart disease, or is also being treated with other cardiotoxic, non-anthracycline cytotoxic agents, a maximal cumulative dose of 400 mg/m2 is recommended.
Doxorubicin dosage should be reduced if the bilirubin is elevated as follows: serum bilirubin 12 to 30 mg/ml - give 1/2 of the normal dose, bilirubin > 30 mg/l - give 1/4 of the normal dose.
In general, impaired renal function does not require a dose reduction.
Doxorubicin may be given by intravenous bolus injection, or as a continuous infusion. Bolus injection causes higher peak plasma concentrations and therefore is probably more cardiotoxic.
Doxorubicin should not be administered intramuscularly or subcutaneously. Intravenous administration occurs preferably through a running intravenous infusion, over 3 to 5 minutes.
Patients at increased risk of cardiotoxicity should be considered for treatment with a 24 hours continuous infusion, rather than a bolus injection. In this way, cardiotoxicity may be less frequent, without a reduction in therapeutic efficacy. In these patients, the ejection fraction should be measured before each course.
Dosage in children:
Dosage in children may be lowered, since they have an increased risk for late cardiotoxicity. Myelotoxicity should be anticipated, with nadirs at 10 to 12 days after start of treatment, but is usually followed by a rapid recovery due to the large bone marrow reserve of children as compared to adults.
Superficial bladder carcinoma and bladder carcinoma in situ:
The recommended dosage is 50 mg in 50 ml normal saline, administered via a sterile catheter.
Initially, this dose is given weekly, later on, monthly. The optimal duration of treatment has not yet been determined; it ranges from 6 to 12 months. Restrictions regarding the maximal cumulative dose, as with intravenous administration, do not apply to intravesical administration, because systemic absorption of doxorubicin is negligible.
4.3 Contra-indications
Myelosuppression, pre-existing heart disease, previous treatment with complete cumulative doses of doxorubicin or other anthracyclines.
Doxorubicin should not be used intravesically for the treatment of bladder carcinoma in patients with urethral stenosis who cannot be catheterised.
4.4 Special warnings and special precautions for use
Nausea, vomiting and mucositis are often severe and should be treated appropriately. Doxorubicin should not be administered intramuscularly or subcutaneously. 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, or sodium hydrogen carbonate solution (8.4%), and application of dimethylsulphoxide have been reported with varying success. The advice of the plastic surgery consultant should be asked for, and wide excision of the involved area should be considered. Exceeding the maximum cumulative dose of 550 mg/m2 increases the risk of severe, irreversible and therapy-resistant cardiomyopathy and resulting congestive heart failure.
Age over 70 or below 15 years 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. 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. The high incidence of bone marrow depression requires careful haematologic monitoring. 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.
Careful haematologic monitoring is also required because of the risk of secondary leukaemias after treatment with cytotoxic agents (see section 4.8: "Undesirable effects"). These leukaemias can be cured when detected at an early stage. Hepatic function should be evaluated before and during therapy.
Doxorubicin may induce hyperuricaemia. 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.
Men as well as women should take effective contraceptive measures during and for at least 3 months after doxorubicin therapy.
Doxorubicin may impart a red colouration to the urine.
4.5 Interaction with other medicaments and other forms of interaction
Doxorubicin cardiotoxicity is enhanced by previous or concurrent use of other anthracyclines, mitomycin C, dacarbazine, dactinomycin and, possibly, cyclophosphamide.
Doxorubicin may cause exacerbations of haemorrhagic cystitis caused by previous cyclophosphamide therapy.
The effects of radiation may be enhanced, and recall of these reactions may occur with doxorubicin therapy, even some time after termination of radiotherapy.
Inducers of the enzyme cytochrome P-450 (e.g. rifampicin and barbiturates) may stimulate the metabolism of doxorubicin, with a possible decrease in efficacy.
Inhibitors of cytochrome P-450 (e.g. cimetidine) may decrease the metabolism of doxorubicin, with a possible increase in toxic effects.
4.6 Pregnancy and lactation
Clinical evidence suggests a possible adverse effect on the foetus. In animals doxorubicin has embryotoxic and teratogenic effects. Doxorubicin is excreted in breast milk. Usage during pregnancy and lactation is therefore not recommended.
PACKAGE LEAFLET: INFORMATION FOR THE USER
DOXORUBIN 0.2% Doxorubicin Hydrochloride
Read all of this leaflet carefully before you start
using this medicine.
• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or nurse.
• If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse.
IN THIS LEAFLET:
1. What Doxorubin is and what it is used for 2. Before you receive Doxorubin 3. How to receive Doxorubin 4. Possible side effects 5. How to store Doxorubin 6. Further information
OWHAT DOXORUBIN IS AND WHAT IT IS USED FOR
Doxorubicin is an anthracycline glycoside, which belongs to a group of medicines called cytotoxics which are used to treat cancer.
Doxorubin is used to treat:
• acute lymphocytic leukaemia (cancer of the blood cells made by lymph glands)
• acute myeloid leukaemia (cancer of the blood cells made by bone marrow)
• Hodgkin and non-Hodgkin lymphoma (cancer of the lymph glands)
• osteosarcoma (bone cancer)
• Ewing sarcoma (bone cancer in teenagers)
• adult soft tissue sarcoma (cancer of the soft tissues)
• advanced breast cancer • stomach cancer • small-cell lung cancer • neuroblastoma (cancer of the nerve tissue)
• Wilms tumour (a kidney cancer)
• bladder cancer.
In all these types of cancer normal cell growth is disturbed. The cells grow uncontrolled which causes your cancer. The types of cancer listed above depends on the place in your body where these cells grow.
Leukaemia is a cancer of the cells in your body which produce the various components of your blood.
Doxorubicin attacks and destroys the diseased cells. Unfortunately, the growth of normal cells is also affected. This may result in some of the side effects which are discussed later in this leaflet. Before treatment, you should discuss the risks and benefits of this medicine with your doctor.
^ BEFORE YOU RECEIVE DOXORUBIN
Do NOT receive Doxorubin if you:
• are allergic (hypersensitive) to doxorubicin hydrochloride or any of the other ingredients of this medicine
• have problems with your bone marrow not working properly (a problem with blood cell production)
• have heart problems • have previously received treatment with doxorubicin or similar medicines e.g. epirubicin
• have problems urinating
• are pregnant, planning to become pregnant or breast-feeding.
Please discuss any worries you may have about the above warnings with your doctor immediately. Your doctor may, however, decide that your treatment is essential.
Take special care with Doxorubin
Tell your doctor or nurse before you start to take this medicine if you:
• have received radiation therapy to the chest
• have liver problems
• have a history of gout.
You should also talk to your doctor before you receive Doxorubin if you are over 70 or under 15 years of age.
Your doctor will want to monitor you with heart, blood and liver tests before and during your treatment with Doxorubin.
Men and women should use an effective method of contraception during therapy and for at least 3 months afterwards.
Taking other medicines
Talk to your doctor or nurse if you are taking any of the following:
• rifampicin (an antibiotic)
• barbiturates e.g. phenobarbital
• cimetidine (used to treat certain conditions caused by too much acid being produced in the stomach).
Talk to your doctor or nurse if you:
• have previously been treated with cyclophosphamide, mitomycin C, dactinomycin or dacarbazine (used to treat cancer).
Please tell your doctor or nurse if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
Pregnancy and breast-feeding
Doxorubin is not recommended if you are pregnant, trying to become pregnant or breast-feeding. If you become pregnant or suspect that you may be pregnant during therapy, you must tell your doctor immediately.
Driving and using machines
Doxorubin may cause frequent nausea and vomiting. If affected do not drive or operate machinery.
^ HOW TO RECEIVE DOXORUBIN
Your medicine will be administered by a doctor or nurse as an injection into one of your veins. The injection should never be given under the skin or into a muscle. The site of injection should not be covered or bandaged. In the case of cancer of the bladder, Doxorubin is administered through a catheter. Doxorubin may be given alone or in combination with other medicines.
If you experience any pain, swelling or warmth around the vein where Doxorubin is being injected, tell your nurse or doctor immediately. This may be a sign that the injection has leaked into the surrounding tissue.
If you notice that your face is red while the injection is being given to you, tell your doctor or nurse immediately. This may be a sign that the injection is being given too quickly.
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How much Doxorubin will you receive and how • allergic reactions e.g. fever, nettle rash, often: increased heartbeat, breathing problems, Adults dizziness • The dosage will depend on the type of cancer • stomach problems, nausea, vomiting, being treated, other medicines you are diarrhoea receiving, your age, height, weight and your • kidney and bladder problems e.g. general medical condition inflammation and bleeding of the bladder, • The most commonly used dosage is blood in the urine, changed pattern of 60 - 75 mg/m2 every 3 weeks urination, pain during urination • If you are being treated for cancer of the • liver problems, e.g. yellow eyes and skin, bladder the usual dose is 50 mg/50 ml every abnormal liver enzymes, inflamed liver. week and later on, every month • Your treatment schedule may be modified There is a chance that Doxorubin might cause depending on your body's response or other unwanted effects that may not occur until medication you are receiving months or years after the medicine is used. These • While you are being given Doxorubin your delayed effects may include certain types of doctor may want to monitor your heart cancer, such as leukaemia. Discuss these possible function. Your condition will also be closely effects with your doctor. monitored during treatment. This will involve blood tests Doxorubin may cause your urine to turn red in • Other medicines may be given during a course colour for a couple of days after each dose. of Doxorubin to treat or prevent side effects. Medicines like Doxorubin often cause temporary Children hair loss. After treatment your normal hair Children may be given lower doses than those growth should return. used in adults. If any of the side effects get serious, or if you If you have any questions about your treatment notice any side effects not listed in this leaflet, ask your doctor or nurse. please tell your doctor or nurse. If you receive more Doxorubin than you should As a doctor or nurse will be giving you your HOW TO STORE DOXORUBIN medicine, it is unlikely that you will receive an incorrect dose. If you receive too much Doxorubin Keep out of the reach and sight of children. you may suffer from side effects sooner. Tell your The vials should be stored in a fridge and be doctor or nurse if you have any concerns about protected from light. Diluted solutions of the amount of medicine that you receive. Doxorubin should be stored in a fridge for 24 hours, and be protected from light. Do not use If you miss a dose of Doxorubin Doxorubin after the expiry date that is stated on It is important that you do not miss an the outer packaging. The expiry date refers to appointment/injection. If you do miss an the last day of that month. injection, you should ensure that you receive your missed dose as soon as possible. FURTHER INFORMATION If you have any further questions on the use of this product, ask your doctor or nurse. What Doxorubin contains: • The active ingredient is doxorubicin hydrochloride POSSIBLE SIDE EFFECTS • The other ingredients are sodium chloride, hydrochloric acid/sodium hydroxide and water Like all medicines, Doxorubin can cause side for injections. effects. You should discuss them with your doctor who will explain the risks and benefits of What Doxorubin looks like and contents of the your treatment. Some of the side effects can be pack: lessened or treated by other medicines or • Doxorubin 0.2% comes as a red-orange therapy. solution for injection in vials of 5 ml (10 mg doxorubicin hydrochloride per vial), 10 ml Although not all of these side effects may occur, (20 mg doxorubicin hydrochloride per vial), if they do occur, they may need medical 25 ml (50 mg doxorubicin hydrochloride per attention. vial) and 100 ml (200 mg doxorubicin hydrochloride per vial) Tell your doctor immediately if any of the • Doxorubin 0.2% is supplied in packs of 1 or following occur: 10 vials. • blood problems, characterised by fever or chills, sore throat, ulcers in the mouth or Marketing Authorisation Holder and throat, tiredness or weakness, unusual Manufacturer bleeding or unexplained bruising Marketing Authorisation holder and company • heart problems, characterised by irregular responsible for manufacture: Pharmachemie B.V., heartbeat, problems with the heart muscle. Haarlem, The Netherlands. After you have completed your course of This leaflet was last revised: September 2011 treatment, you should tell your doctor or nurse immediately if you notice difficulty in breathing, PL 04946/0016 swelling of the feet or legs, or an irregular or rapid heart beat. The following side effects have also been reported: • inflammation, ulceration or swelling of the nose, mouth, or throat • flushing of the face • inflammation of a vein with a blood clot • conjunctivitis • pain, swelling or warmth around the vein where Doxorubin is being injected |
r 4.7 Effects on ability to drive and use machines 5.2 Pharmacokinetic properties Due to the frequent occurrence of nausea and The intravenous administration of doxorubicin is vomiting, driving and operation of machinery should followed by a rapid plasma clearance (t1/2 = 10 min.) be discouraged. and significant tissue binding. The terminal half-life is approximately 30 hours. Doxorubicin is partly 4.8 Undesirable effects metabolised, mainly to doxorubicinol and to a lesser Dose limiting toxicities of therapy are extent, to the aglycon, and is conjugated to the myelosuppression and cardiotoxicity. glucuronide and sulphate. Biliary and faecal excretion Myelosuppression includes a transient leukopenia, presents the major excretion route. About 5 % of anaemia and thrombocytopenia, reaching its nadir at the dose is eliminated by renal excretion. Plasma 10 to 14 days after treatment. protein binding of doxorubicin ranges from 50-85 %. Cardiotoxicity may occur as arrhythmias directly The volume of distribution is 800-3500 l/irP. following drug administration; eCg changes, Doxorubicin is not absorbed after oral including T-wave flattening and S-T depression, may administration; it does not cross the blood-brain last up to 2 weeks after administration. barrier. Impairment of liver function may decrease The risk of cardiomyopathy increases at cumulative the clearance of doxorubicin and its metabolites. doses higher than 550 mg/m2. Age over 70 or below 15 years should be regarded as a risk factor. Also, 5.3 Preclinical safety data concomitant or previous treatment with mitomycin None stated. C, cyclophosphamide or dacarbazine has been reported to potentiate doxorubicin induced 6. Pharmaceutical Particulars cardiomyopathy. 6.1 List of excipients Cardiotoxicity may be encountered several weeks or Sodium chloride, hydrochloric acid/sodium months after discontinuation of doxorubicin therapy. hydroxide, water for injections. Other adverse reactions reported are: a generally reversible alopecia; gastrointestinal disturbances, 6.2 Incompatibilities including nausea, vomiting and diarrhoea. Mucositis Doxorubicin should not be mixed with 5-fluorouracil (stomatitis or oesophagitis) may occur 5 to 10 days or heparin. Contact with aluminium should be after administration. avoided. Hypersensitivity reactions, such as fever, urticaria and anaphylaxis have been occasionally reported. 6.3 Shelf-life Doxorubicin influences and potentiates normal tissue Following the special precautions for storage (see reactions to radiation. Also, late ("recall") reactions section 6.4) the shelf-life of the 5 ml, and 25 ml vials may occur when doxorubicin is administered some is 36 months and the shelf-life of the 100 ml vial is time after irradiation. Facial flushing may occur if the 24 months as printed on the label. injection is given too rapidly Thrombophlebitis and The injection may be diluted with 0.9% sodium conjunctivitis have been reported. chloride solution or 5% glucose solution. Chemical Slight transient increases of liver enzymes have been and physical in-use stability has been demonstrated reported. Concomitant irradiation of the liver may for 7 days at room temperature (15-25°C) and cause severe hepatoxicity, sometimes progressing to protected from light. cirrhosis. From a biological point of view, the product should As with other cytotoxic agents, myelodysplastic be used immediately. If not used immediately, in-use syndrome and acute myeloid leukaemia have been storage times and conditions prior to use are the observed after treatment with combination therapy responsibility of the user and would normally not be including doxorubicin. With topoisomerase II longer than 24 hours at 2 to 8°C, unless inhibitors, secondary leukaemias have been reported reconstitution/dilution (etc) has taken place in more frequently than expected in the form of acute controlled and validated aseptic conditions. myeloid leukaemia classification 2, 3 and 4. These forms of leukaemia can have a short period of 6.4 Special precautions for storage latency (1 to 3 years). They can be cured when Doxorubin 0.2%, injection should be stored at detected at an early stage and with an appropriate 2-8°C, protected from light. curative treatment (see section 4.4 "Special warnings and special precautions for use"). 6.5 Nature and contents of container Intravesical administration may cause the following Doxorubicin 0.2%, injection is supplied as a red-adverse reactions: haematuria, vesical and urethral orange, sterile solution in injection vials containing irritation, stranguria and pollakisuria. These reactions 5 ml (10 mg), 25 ml (50 mg), or 100 ml (200 mg), are usually of moderate severity and of short respectively, of doxorubicin hydrochloride 2 mg/ml. duration. Intravesical administration of doxorubicin may cause a sometimes haemorrhagic cystitis; this 6.6 Instructions for use/handling may cause a decrease in bladder capacity. Any contact with the solution should be avoided. Doxorubicin may impart a red colouration to the During preparation and reconstitution a strictly urine. aseptic working technique should be used; protective measures should include the use of gloves, mask, 4.9 Overdosage safety goggles and protective clothing. Acute overdosage of doxorubicin enhances the toxic Use of a vertical laminar airflow (LAF) hood is effects of mucositis, leukopenia and recommended. thrombocytopenia. Gloves should be worn during administration. Overdosage at intravesical administration may cause Waste-disposal procedures should take into account severe cystitis. Treatment of acute overdosage the cytotoxic nature of this substance. consists of treatment of the severely myelosuppressed If the doxorubicin solution contacts skin, mucosae or patient with hospitalisation, antibiotics and eyes, immediately wash thoroughly with water. Soap transfusions after consultation with an oncologist. may be used for skin cleansing. Chronic overdosage with cumulative doses exceeding 550 mg/m2 increases the risk of cardiomyopathy and 7. Marketing Authorisation Holder resultant congestive heart failure. Treatment consists Pharmachemie B.V., of vigorous management of congestive heart failure Swensweg 5, with digitalis preparations and diuretics. Postbus 552, Administration of a very high single dose may cause 2003 RN Haarlem, myocardial degeneration within 24 hours. The Netherlands. 5. Pharmacological Properties 8. Marketing Authorisation Number 5.1 Pharmacodynamic properties PL 04946/0016 Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. 9. Date of First Authorisation/Renewal of caesius. Animal studies have shown a cytotoxic Authorisation action in several solid and haematologic tumours. 4 January 1996. The mechanism of action is not completely elucidated. A major mechanism is probably inhibition of 10. Date of (Partial) Revision of the Text topoisomerase II, resulting in DNA breakage. January 2001. Intercalation and free-radical formation is probably of minor importance. Drug resistance, due to Distributed by TEVA UK Uirrite^ Eastbourne, increased expression of the MDR-1 gene encoding BN22 9AG. for a multidrug efflux pump, has been reported regularly. 67918-K 93.130.570-D |