Daunoxome Injection 2mg/Ml Concentrate For Solution For Infusion
GB 5649 4000 C 40
SUMMARY OF PRODUCT CHARACTERISTICS
DaunoXome®
1. NAME OF THE MEDICINAL PRODUCT
DaunoXome Injection 2mg/ml Concentrate for Solution for Infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Daunorubicin hydrochloride, Ph.Eur., present as citrate salt, equivalent to daunorubicin 2.0mg/ml,(50mg) encapsulated in liposomes. The liposomes are small unilamellar vesicles with mean diameter of about 45nm. The active ingredient is daunorubicin, an anthracycline antibiotic with antineoplastic activity originally obtained from Streptomyces peucetius. Daunorubicin has a four ring anthracycline moiety linked by a glycosidic bond to daunosamin, an amino sugar. Daunorubicin is currently isolated from Streptomyces coeruleorubidus and is described by the following chemical name:
(8S, 10S)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy]-6,8,11 -trihydroxy-1 -methoxy-7,8,9,10-tetrahydronaphthacene-5,12-dione.
Daunorubicin has a molecular weight of 527.5 and is represented by the formula C27H29NO10.
For the full list of excipients, see Section 6.1.
Each vial contains a sterile, pyrogen free, preservative-free liposomal emulsion. This emulsion is red and clear to slightly opalescent in appearance. The product is an injectable intended to be administered by intravenous infusion.
DaunoXome is indicated for the treatment of advanced HIV-related Kaposi's Sarcoma.
4.2 Posology and method of administration
DaunoXome should be administered by intravenous infusion. The recommended initial dose of DaunoXome in patients with AIDS-related Kaposi's sarcoma is 40mg/m2 every two weeks. The dosage of DaunoXome must be adjusted for each patient. Therapy should be continued as long as disease control can be maintained.
DaunoXome should be diluted with 5% dextrose for infusion before administration. The recommended concentration after dilution is between 0.2mg and 1 mg daunorubicin/ml of solution. DaunoXome should be administered intravenously over a minimum period of 30-60 minutes (See also Sections 6.2, 6.3 and 6.6).
DaunoXome must not be given by the intramuscular or subcutaneous route or as a bolus injection.
DaunoXome is a liposomal preparation and should not be used interchangeably with conventional daunorubicin.
Paediatric patients: DaunoXome is not recommended for use in children below 18 years of age due to insufficient data on safety and efficacy.
Elderly: The safety and effectiveness of DaunoXome in patients over 65 years of age have not been established. Cardiotoxicity may be more frequent in the elderly (see Section 4.4).
Hepatic impairment: Limited clinical experience exists in treating hepatically impaired patients with DaunoXome. Therefore, based on experience with conventional daunorubicin HCl, it is recommended that the dosage of DaunoXome be reduced if bilirubin is elevated as follows:
- Serum bilirubin 1.2 to 3mg/dl (20.3 to 50.8|jmol/l), give 75% of the normal dose
- Serum bilirubin > 3mg/dl (>50.8jmol/l), give 50% of the normal dose.
Renal impairment: Limited clinical experience exists in treating renally impaired patients with DaunoXome. Therefore, based on experience with conventional daunorubicin HCl, it is recommended that the dosage of DaunoXome be reduced if creatinine is elevated as follows:
Serum creatinine > 3mg/dl (>265jmol/l), give 50% of the normal dose.
Hypersensitivity to DaunoXome, any of its excipients or other anthracyclines/anthracenediones. Pregnancy and breast feeding.
4.4 Special warnings and precautions for use
The decision to treat must be based on an evaluation, by the physician, of the benefits and risks for the individual patient.
Cardiotoxicity
DaunoXome and other anthracyclines can cause cardiotoxicity, notably congestive heart failure due to cardiomyopathy. The onset of symptoms can be sudden and may not occur until weeks or months after discontinuation of therapy. Cardiac damage may be irreversible and there have been rare reports of fatalities, usually in patients with risk factors.
The risk of cardiotoxicity increases with total cumulative dosage of anthracyclines. Caution must therefore be exercised in patients previously treated with anthracyclines, or those with previous (or concomitant) therapy with other cardiotoxic compounds such as 5-fluorouracil (5-FU).
The maximum cumulative dose of DaunoXome is not known. The pharmacokinetics of liposomal (DaunoXome) and conventional daunorubicin are different. However, based on experience with conventional daunorubicin, daunorubicin hydrochloride must not be used if the maximum cumulative dose of daunorubicin hydrochloride, 500-600mg/m2 in adults, or the maximum cumulative dose of other cardiotoxic anthracyclines (e.g idarubicin, epirubicin) or anthracenediones (e.g. mitoxantrone), has been previously administered, as the risk of life-threatening cardiac damage markedly increases. The total cumulative dose should be limited to 400mg/m2 in patients who have had previous radiation therapy to the chest or previous administration (at less than the maximum cumulative dose) of other potentially cardiotoxic drugs.
The risk of cardiotoxicity appears to be higher in those with pre-existing cardiovascular disease, a history of mediastinal radiation and the elderly. Caution must therefore be exercised when DaunoXome is given to these patients. DaunoXome should only be given to patients with cardiovascular disease when the benefit outweighs the risks.
Experience in patients treated with high dose DaunoXome (above 60mg/m2) for malignancies other than Kaposi's sarcoma indicates that the risk of cardiotoxicity may be higher in these patients.
Cardiac monitoring
Careful monitoring of cardiac function is essential in patients treated with DaunoXome.
Cardiomyopathy induced by anthracyclines is usually associated with a decreased left ventricular ejection fraction (LVEF) measured by echocardiography or by MUGA (Multiple Gated Acquisition). Measurement of LVEF provides a more specific method for monitoring cardiac function than ECG.
All patients should undergo baseline ECGs, echocardiography and measurement of LVEF prior to starting DaunoXome. These tests should be repeated regularly during treatment. Furthermore, in all patients, LVEF must be determined when a cumulative dose of 320mg/m2 has been reached, then every 160mg/m2 thereafter, in order to identify at an early stage any changes in LVEF that may be a precursor to cardiomyopathy if DaunoXome therapy is continued.
In patients with risk factors for cardiotoxicity with DaunoXome, or those receiving high dose DaunoXome per cycle (e.g. 120mg/m2 or above), decreases in cardiac function may occur at lower cumulative doses of DaunoXome, therefore consideration should be given to determination of LVEF after each treatment cycle and before any additional DaunoXome is administered.
Transient ECG changes such as T-wave flattening, S-T segment depression and benign arrhythmias are not considered mandatory indications for cessation of DaunoXome. A reduction of the QRS wave is considered more indicative of cardiac toxicity.
Whenever cardiomyopathy is suspected, and/or LVEF has decreased significantly as compared to pre-treatment values (e.g. 20% decline) and/or if the LVEF is lower than would be expected (e.g. <45%), the benefit of continued therapy must be carefully weighed against the risk of producing irreversible cardiac damage.
It is recommended that DaunoXome is stopped if signs or symptoms of heart failure occur.
Several long-term studies in children also suggest that after anthracycline treatment congestive cardiomyopathies with a latency of many years may occur.
Haematological toxicity
DaunoXome is a bone marrow suppressant. The most significant effect is usually neutropenia, which may be severe and result in fever and infection. Anemia and thrombocytopenia may also occur, but are usually less marked. Persistent severe myelosuppression may result in sepsis, or haemorrhage. Complete blood counts must be performed prior to each dose and frequently during the course of DaunoXome therapy.
Patients with malignancies or with HIV infection, whose immune system is already compromised, must be monitored carefully for evidence of intercurrent or opportunistic infections.
Anti-infective therapy should be employed in the presence of suspected or confirmed infection and during febrile neutropenia.
Haematological toxicity may require dose reduction of DaunoXome or suspension or delay of therapy. The colony stimulating factor GCSF has been used to manage patients with neutropenia.
Caution is warranted when combining DaunoXome with other agents which suppress bone marrow function.
Injection site reactions
Care should be taken to ensure that there is no extravasation of DaunoXome during administration. Paravenous administration has resulted in erythema, pain and swelling around the site of tissue infiltration. These changes are generally transitory, resolving within 6 months. However, localised tissue necrosis must still be regarded as a possible consequence of extravasation.
If any signs or symptoms of extravasation occur (e.g. stinging, erythema), the infusion should be stopped immediately and re-started in another vein. The affected limb should be elevated. It may be inappropriate to provide any measure that might cause release of the drug from the liposome (such as application of ice or corticosteroids, instillation of local antidotes, local compression, etc.)
Acute infusion-associated reactions
Acute infusion-related reactions have been reported in patients treated with DaunoXome. Symptoms typically include back pain, flushing, chest tightness and dyspnoea. These infusion reactions may occur during the patient's first exposure to DaunoXome, or during re-exposure in a patient who had previously received DaunoXome without incident. Infusion-related reactions generally occur within the first 10 minutes of the infusion and subside when the infusion is slowed or halted. Acute allergic/ anaphylactic reactions, sometimes associated with hypotension, have also been reported.
Caution is also required with preceding, concurrent or planned radiotherapy as these patients, during treatment with daunorubicin hydrochloride, have an increased risk of local reactions in the radiation area (recall phenomena).
Liver and renal function
Daunorubicin hydrochloride is metabolised predominantly in the liver and is excreted via the bile. Monitoring of liver and renal function before starting and during treatment with DaunoXome, is recommended. For advice on dosage adjustment in patients with liver or renal impairment, see Section 4.2.
Immunosuppressant effects/increased susceptibility to infections
Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including daunorubicin, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving daunorubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Reproductive system and breast disorders
Daunorubicin hydrochloride inhibits fertility. Based on experience with conventional daunorubicin, amenorrhoea and azoospermia may occur. Irreversible disorders of fertility are possible (see Section 4.6).
Birth defects
Daunorubicin may cause serious birth defects when used during pregnancy (see Section 4.6). DaunoXome is contra-indicated in pregnancy (see Section 4.3).
4.5 Interaction with other medicinal products and other forms of interaction
Daunorubicin hydrochloride is mainly metabolised in the liver; concomitant medication influencing liver function may also therefore influence the metabolism or pharmacokinetics of daunorubicin hydrochloride and, as a consequence, influence efficacy and/or toxicity.
Protease Inhibitors (PIs) and Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are known inhibitors of Cytochrome P450 IIIA (CYP-3A) and may also have a role in the inhibition of the drug transporting protein, P-glycoprotein (P-gp). Daunorubicin and other anthracyclines may undergo some metabolism by CYP-3A and are known substrates of P-gp. There is therefore a theoretical possibility of interaction between DaunoXome and these two groups of antiviral therapy. To date however, a single study has indicated that there is no effect of PIs or NNRTIs on DaunoXome's pharmacokinetic properties. Limited data from one small study where patients were treated with and without protease inhibitors indicate that there were no major changes in DaunoXome associated toxicity.
Caution should be exercised when DaunoXome is used concomitantly with other myelosuppressive or cardiotoxic agents. The risk of gastrointestinal side-effects increases with the concurrent administration of other cytotoxics. Mucositis (oral and gastrointestinal) occurring in association with daunorubicin-containing chemotherapy may impair the absorption of oral medicinal products. Live vaccines should be avoided. Killed or inactivated vaccines should be used with caution (see Section 4.4).
Caution should be taken when DaunoXome is administered concurrently with antiplatelet drugs such as aspirin (acetylsalicylic acid), clopidogrel, dipyridamole, eptifibatide and other agents which inhibit platelet/thrombocyte aggregation. Thrombocytopenic patients will be at increased risk of bleeding disorders.
4.6 Fertility, pregnancy and lactation
Fertility and Contraceptive Measures
Daunorubicin could induce chromosomal damage in human spermatozoa. Men should receive counselling on sperm cryopreservation before the start of daunorubicin treatment because of the possibility of irreversible infertility. Men undergoing treatment with daunorubicin should use effective contraceptive methods during and for 6 months after treatment.
Women of childbearing potential have to use effective contraception while they or their male partner is receiving DaunoXome, and for 6 months following discontinuation of treatment with DaunoXome. For women who want to become pregnant after completing DaunoXome treatment, genetic counselling is also recommended.
Pregnancy
Studies in animals have shown reproductive toxicity (see Section 5.3 Preclinical safety data). Like most other anticancer drugs, daunorubicin has shown embryotoxic, teratogenic, mutagenic and carcinogenic potential in animals. There are no or limited amount of data from the use of daunorubicin in pregnant women, although a few women who received daunorubicin during the second and third trimesters of pregnancy have delivered apparently normal infants.
According to experimental data, the drug must be considered as a potential cause of foetal malformations when administered to a pregnant woman. Daunorubicin should not be used during pregnancy unless the clinical condition of the woman requires treatment with daunorubicin and justifies the potential risk to the foetus. Women of child-bearing potential who have to undergo daunorubicin therapy should be informed about the potential hazard to the foetus and should be advised to avoid becoming pregnant during treatment. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the woman should be informed of the potential hazard to the foetus. The possibility of genetic counselling should also be utilised. In any case, cardiologic examination and a blood count are recommended in foetuses and newborns born to mothers who received treatment with daunorubicin during pregnancy.
Lactation
It is unknown whether daunorubicin/metabolites are excreted in human milk; other anthracyclines are excreted in breast milk. DaunoXome is contraindicated during breast-feeding (see Section 4.3 Contraindications).
4.7 Effects on ability to drive and use machines
No studies have been performed on the effects of DaunoXome on the ability to drive and use machines. However, patients should be informed that dizziness, nausea and vomiting have been reported with DaunoXome and may affect the ability to drive and operate machinery.
2|
PACKAGE LEAFLET: INFORMATION FOR THE USER
DaunoXome
Injection 2mg/ml concentrate for solution for infusion
Daunorubicin
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.
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor. See section 4.
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1 |
What DaunoXome is and what it is used for |
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2 |
Before you use DaunoXome |
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3. |
How DaunoXome is used |
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4. |
Possible side effects |
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5 |
How to store DaunoXome |
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6 |
Further information |
What DaunoXome is and what it is used for
DaunoXome is an anti-cancer medicine (a cytotoxic agent) which reduces tumour cell growth. The active substance of DaunoXome is daunorubicin. DaunoXome is a special formulation of daunorubicin (in liposome form), which is used to treat a type of cancer known as Kaposi's sarcoma. Kaposi's sarcoma is a form of cancer that mainly affects the skin, but which can also affect the lungs and intestines.
DaunoXome is used for the treatment of a severe form of Kaposi's sarcoma in patients with AIDS.
Before you use DaunoXome
■ if you are allergic (hypersensitive) to daunorubicin or any of the other ingredients of DaunoXome, or any other medicines belonging to the same group (these are called anthracyclines or anthracenediones).
■ if you are pregnant or breastfeeding.
*+■ If any of these applies to you, you must not be given DaunoXome.
If in doubt, ask your doctor or pharmacist for advice.
Take special care with DaunoXome
This medicine can cause heart problems (cardiac failure) because of its effects on heart muscle. Rarely, these heart problems can be fatal. Heart problems can develop suddenly and may occur weeks or months after the end of treatment. Damage to the heart may be irreversible. As a precaution, your doctor will carry out tests to monitor your heart's performance, before and during the treatment.
**• Make sure your doctor knows
about any heart problems you have had
*+■ Tell your doctor if you have been treated before with any medicines in the same class as DaunoXome
(anthracyclines or anthracenediones). The risk of heart problems is higher in some situations:
■ if you have existing heart problems
■ if you are over 65 years old
■ if you have been given high doses of DaunoXome, or high total doses of other anthracycline/ anthracenedione medicines as well as DaunoXome
■ if you have been treated with other medicines that may damage the heart
■ if you have received radiation therapy to the chest.
DaunoXome can suppress bone marrow activity, which can cause fever; infections, including infection in the blood (sepsis); bleeding problems and reduced red blood cells (anaemia). Your doctor will carry out regular blood monitoring. The risk of bone marrow problems with DaunoXome is higher if you already have a weakened immune system.
Daunoxome may also cause tissue damage such as redness, swelling or pain at the site of infusion if the product leaks from the vein. This damage usually resolves within 6 months.
W Tell your doctor if you notice a stinging pain, redness or leakage of fluid in the area of the infusion site.
Tell your doctor before treatment with DaunoXome if you have received, are receiving or are due to receive radiation therapy.
If you have impaired kidney or liver function, your doctor may reduce your dose of DaunoXome.
DaunoXome is not usually recommended for children or older people. Its safety and efficacy has not yet been studied in these two groups.
Tell your doctor if you are taking any other medicines, or have recently taken any. This includes medicines and herbal products you bought without a prescription.
Daunorubicin can cause inflammation of the lining of the mouth and gastrointestinal tract which may affect the absorption of other medicines taken orally (by mouth).
Other medicines that affect the heart or bone marrow
Your doctor will be especially careful if DaunoXome is given at the same time as any medicine which reduces the function of the heart or of the bone marrow, and with medicines that suppress the immune system. This includes medicines in the same class as DaunoXome (anthracyclines or anthracenediones).
If you are being treated with other cytotoxics (anti-cancer medicines) at the same time as DaunoXome, you are likely to be at an increased risk of gastrointestinal side effects.
There is a possibility that DaunoXome may interact with two groups of anti-HIV medicines, protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs).
Antiplatelet medicines to prevent blood clots
You should tell your doctor if you are taking an antiplatelet medicine to prevent blood clots. Some examples of antiplatelet medicines are aspirin (acetylsalicylic acid), clopidogrel, dipyridamole, eptifibatide; there are other antiplatelet medicines also available, so you should check with your doctor if you are not sure.
Medicines that affect the liver
Some medicines may have an effect on how your liver works and may, therefore, have an effect on DaunoXome. Please tell your doctor about all other medicines that you are taking or that you have taken recently.
Tell your doctor or nurse that you are taking DaunoXome if you are due to receive any vaccination, as some vaccines cannot be given to patients being treated with DaunoXome.
W Tell your doctor if you are taking or have recently taken any of these.
Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
DaunoXome can cause serious birth defects if it is used during pregnancy. Therefore, DaunoXome must not be used during pregnancy, unless your doctor considers it to be vital.
In this case, your doctor should discuss the possible risks for your unborn child with you. If you become pregnant during treatment, you should seek genetic advice.
DaunoXome should not be used in mothers who are breast-feeding.
Treatment with DaunoXome may affect your fertility (female and male). You should speak to your doctor about the possible effects on fertility before your treatment starts.
Men who are treated with daunorubicin should have counselling about sperm cryopreservation before the start of treatment. It is recommended that men who are treated with daunorubicin should not father a child during treatment or for 6 months afterwards.
Women of childbearing potential have to use effective contraception during treatment with daunorubicin and for 6 months after treatment. For women who want to become pregnant after treatment with daunorubicin, genetic counselling is also recommended.
The adverse reactions considered at least possibly related to treatment with DaunoXome are listed below, by body system organ class and absolute frequency. Frequencies are defined as follows: very common > 10%; common > 1% and < 10%; uncommon > 0.1% and < 1%; rare > 0.01% and < 0.1%, very rare < 0.01%, not known (cannot be estimated from the available data).
Daunorubicin is then released over time in the cytoplasm, where it is able to exert its antineoplastic activity over a longer period.
5.2 Pharmacokinetic properties
DaunoXome has a pharmacokinetic profile significantly different from that of conventional daunorubicin. DaunoXome was administered intravenously over approximately 30 minutes as a single dose of 10, 20, 40, 60, or 80mg/m2. Plasma pharmacokinetic profiles for most patients demonstrated monoexponential declines, although biexponential or Michaelis-Menton (saturation) kinetics occurred in some instances. Peak plasma levels at 40mg/m2 ranged from 14.8 to 22.0pg/ml with a mean peak plasma level of 18.0pg/ml. The mean terminal half-life at this dose was 4.0 hours and mean total body clearance was 10.5ml/minute. This resulted in a mean area under the plasma curve of 120pg.hr/ml. Metabolism of DaunoXome appeared not to be significant at lower doses. At 60mg/m2 and above, three metabolites were observed, although they have not yet been identified.
DaunoXome pharmacokinetic parameters were also compared to published values for conventional daunorubicin. At 80mg/m2, peak plasma levels ranged from 33.4 to 52.3pg/ml for DaunoXome compared to 0.40pg/ml for conventional drug. At this dose, DaunoXome plasma levels decline monoexponentially with a terminal half-life of 5.2 hours versus an initial half-life of 0.77 hours and a final half-life of 55.4 hours for conventional daunorubicin. Mean clearance for DaunoXome is 6.6ml/min versus 223ml/minute for daunorubicin. When combined, these parameters indicate that DaunoXome produces a 36-fold increase in mean area under the plasma curve compared to conventional drug (375.3 versus 10.33pg.hr/ml).
Animal studies with tumour models in mice have demonstrated that DaunoXome can increase daunorubicin tumour exposure ten-fold (in terms of area under the tumour concentration vs. time curve, AUC) when compared with equivalent doses of conventional (free) drug. The rate of drug accumulation in tumour tissues, however, appears to be slower for DaunoXome than for conventional daunorubicin. This difference is thought to be due to a slow diffusion process by which DaunoXome extravasates through the tumour neovasculature into the extracellular space while free drug, in contrast, is able to rapidly equilibrate from the circulation to both normal and neoplastic tissues. Since tumour accumulation of DaunoXome-delivered daunorubicin is a gradual process, it is important that DaunoXome remains in the circulation at high levels for prolonged periods. This has been shown to occur in animal studies where plasma AUC values for daunorubicin were approximately 200-fold greater for DaunoXome than for conventional drug. In contrast to tumour tissue, however, AUC values for normal tissues were only moderately elevated in DaunoXome-treated animals, relative to conventional daunorubicin. Exclusive of reticuloendothelial tissues (liver and spleen, AUC values increased by 110% and 60%, respectively) and brain tissue (AUC value increased by 3.5 fold) AUC increases ranged from 10% for heart and lungs to 30% for kidney and small intestines.
Liposome:
Distearoylphosphatidylcholine Cholesterol, USNF Citric acid, Ph.Eur.
Buffer:
Sucrose, Ph.Eur.
Glycine, B.P.
Calcium chloride, Ph.Eur.
q.s. to approximately 25ml with Water for Injection, Ph.Eur.
To date, no incompatibilities of DaunoXome with other drugs have been reported. However, it is known that the active component daunorubicin is physically incompatible with heparin sodium and with dexamethasone phosphate when directly admixed. A precipitate is produced with either drug. Additionally, because of the chemical instability of the glycosidic bond of daunorubicin, admixture into a highly alkaline media (pH > 8.0) is not recommended. DaunoXome should not be mixed with saline; aggregation of the liposomes may result.
Admixtures containing bacteriostatic agents such as benzyl alcohol or other detergent like molecules should be avoided because such compounds can rupture the bilayer wall of the liposomes causing premature leakage of the active drug.
The shelf-life is 52 weeks when stored at 2° - 8°C.
Chemical and physical in-use stability has been demonstrated for DaunoXome diluted with 5% dextrose, see table below for details.
From a microbial point of view, diluted DaunoXome should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2-8°C for the 5% dextrose dilutions. This recommendation is made on the assumption that dilution has taken place in controlled and validated aseptic conditions.
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System Organ Class |
Frequency of adverse reactions | ||||
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Very Common |
Common |
Uncommon |
Rare |
Not Known | |
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Infections and infestations |
Infections |
Sepsis Septic shock* | |||
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Blood and lymphatic system disorders |
Bone marrow suppression, Bone marrow failure, Agranulocytosis, Neutropenia, Febrile neutropenia, Leucopenia, Pancytopenia, Thrombocytopenia and Anaemia* | ||||
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Immune system disorders |
Infusion-associated reactions (including back pain, flushing, chest tightness, dyspnoea, allergic reactions)* |
Anaphylactic reaction | |||
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Metabolism and nutritional disorders |
Dehydration | ||||
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Psychiatric disorders |
Depression | ||||
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Nervous system disorders |
Headache |
Dizziness | |||
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Cardiac disorders* |
Decreased left ventricular ejection fraction |
Congestive heart failure, Cardiomyopathy |
Atrial fibrillation, Myocardial infarction | ||
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Vascular disorders |
Haemorrhage |
Shock | |||
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Respiratory, thoracic and mediastinal disorders |
Dyspnoea | ||||
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Gastrointestinal disorders |
Stomatitis, Mucous ulcerations, Nausea, Vomiting, Diarrhoea, Abdominal pain |
Colitis | |||
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Hepatobiliary disorders |
Transient elevations in serum bilirubin, aspartate aminotransferase (AST) and alkaline phosphatase (ALP) concentrations, Hepatitis, Hepatic failure | ||||
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Skin and subcutaneous tissue disorders |
Alopecia |
Palmar-plantar erythrodysaes- thesia syndrome** | |||
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Renal and urinary disorders |
Red discolouration of urine | ||||
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Reproductive system and breast disorders |
Amenorrhoea, Azoospermia | ||||
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General disorders and administration site conditions |
Asthenia, Fatigue, Fever, Chills |
Extravasation at the injection site may result in erythema, pain and swelling* | |||
* See Section 4.4
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Diluent |
Dilution Ratio mL to mL |
Final Concentration Daunorubicin mg/mL |
Duration of Chemical Stability at 25°C |
Duration of Chemical Stability at 2° - 8°C |
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5% Dextrose |
1:2 |
1.0 |
24 hours |
24 hours |
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1:4 |
0.5 |
24 hours |
24 hours | |
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1:8 |
0.25 |
24 hours |
24 hours | |
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1:10 |
0.2 |
24 hours |
24 hours |
** Palmar-plantar erythrodysaesthesia syndrome (hand-foot syndrome) has been reported rarely in patients treated with high dose DaunoXome and cytarabine for leukaemia.The condition is characterised by swelling, pain, tingling and erythema of the palms and soles, which may lead to desquamation of the skin in some patients. Dose reduction or delayed dosing may be required to manage the condition.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
From experience with non-liposomal anthracycline preparations, the primary anticipated toxicity from overdose would be myelosuppression. Other side effects may occur in more pronounced form, like cardiomyopathy. In the event of overdose, bone marrow function and cardiac function should be carefully monitored with appropriate therapy for any severe side-effects.
5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties
DaunoXome is a liposomal preparation of daunorubicin formulated to maximise the selectivity of daunorubicin for solid tumours in situ. This tumour selectivity has been demonstrated for transplanted tumours in animal models. While in the circulation, the DaunoXome formulation protects the entrapped daunorubicin from chemical and enzymatic degradation, minimises protein binding, and generally decreases uptake by normal tissues, as well as by the non-reticuloendothelial system. The specific mechanism by which DaunoXome is able to deliver daunorubicin to solid tumours in situ is not known. However, it is believed to be a function of increased permeability of the tumour neovasculature to some particulates in the size range of DaunoXome. Thus, by a decrease in distribution and uptake of normal tissues and binding to plasma proteins and by selective extravasation in tumour neovasculature, the pharmacokinetics of daunorubicin are favourably shifted towards an accumulation of DaunoXome in tumour tissue. Once within the tumour environment, DaunoXome vesicles enter the tumour cells intact.
6.4 Special precautions for storage
Store at 2° - 8°C. Do not freeze. Protect against exposure to light. Do not store partially used vials for future patient use. Vials are for single use only.
6.5 Nature and contents of container
DaunoXome is presented in 50ml, sterile, Type I glass vials. The closure consists of a butyl rubber stopper and aluminium ring seal fitted with a removable plastic cap. Each single dose vial is packed in a white chipboard carton. Included in each carton are directions for use.
6.6 Instruction for Use/Handling
Use Aseptic Technique. Aseptic technique must be strictly observed in all handling, since no preservative or bacteriostatic agent is present in DaunoXome or in the materials recommended for dilution. Withdraw the calculated volume of DaunoXome into a sterile syringe. Instill the DaunoXome preparation into a sterile container with the correct amount of 5% Dextrose Injection. The recommended concentration after dilution is between 0.2mg and 1mg daunorubicin/ml of solution. Infuse over a 30-60 minute period. As with all parenteral drug products, inspect the solution visually for particulate matter prior to administration. Caution: The only fluid which may be mixed with DaunoXome is 5% Dextrose Injection; DaunoXome should not be mixed with saline, bacteriostatic agents such as benzyl alcohol, or any other solution.
An in-line filter is not recommended for the intravenous infusion of DaunoXome. However, if such a filter is used, the mean pore diameter of the filter should not be less than 5pm.
Procedures for proper handling and disposal of anticancer drugs should be followed.
7. MARKETING AUTHORISATION HOLDER
Galen Limited
Seagoe Industrial Estate
Craigavon
BT63 5UA
UK
8. MARKETING AUTHORISATION NUMBER(S)
PL 27827/0007
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
12 October 1995
10. DATE OF REVISION OF THE TEXT
20 May 2016
W Do not drive a car, or use any tools or machines immediately after treatment with DaunoXome, because the side effects of this medicine could stop you doing this safely. In particular, the medicine can cause dizziness, nausea or sickness (see also section 4, Possible side effects).
How DaunoXome is used
DaunoXome is always given to you by a doctor or nurse. It is given as an infusion into a vein (a drip). DaunoXome must not be given by any other method.
Before use, DaunoXome will first be diluted with a solution of glucose (5%), and it will then be administered as an infusion into a vein (intravenously). Normally, DaunoXome should be used straight after it has been diluted. However, your doctor or pharmacist may decide to store the diluted DaunoXome for a maximum of 24 hours before use, depending on the solution.
The infusion will usually take 30 to 60 minutes.
The dose of DaunoXome is calculated on the basis of your body surface area (which is related to your height and weight). The starting dose is 40 milligrams per m2, given every two weeks.
During your treatment, your doctor may also decide to raise or lower the amount you are given. Normally, he or she will treat you with DaunoXome for as long as it has a positive effect.
If you are given too much DaunoXome
As your infusion is administered by a doctor or nurse, it is very unusual to be given too much of this medicine.
Tell your doctor at once if you suspect that you have been given too much DaunoXome. In the event of an overdose, the side effects listed in section 4 may appear more pronounced.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4. Possible side effects
Like all medicines, DaunoXome can
cause side effects, although not
everybody gets them.
Tell your doctor at once if you
notice any of these side effects, or any others not listed in this leaflet.
(may affect more than 1 in 10 people
treated):
■ disease of the bone marrow. Signs include frequent infections and bleeding, reduced levels of red blood cells (anaemia)
■ infusion reactions. Signs include back pain, flushing, a tight feeling in the chest and shortness of breath. These reactions generally occur within the first 10 minutes of the infusion and subside when the infusion is slowed or stopped
■ allergic reactions. These may include rash or wheezing
■ headaches
■ tiredness
■ difficulty breathing
■ chills, fever
■ nausea, vomiting, diarrhoea, tummy ache
■ hair loss
■ inflammation of the mucous membranes (such as the lining of the mouth, throat, nose, rectum and vagina).
(may affect up to 1 in 10 people treated)
■ dehydration
■ depression
■ dizziness
■ decreased ability of the left chamber of the heart to pump blood
■ redness of the skin, pain and swelling around the infusion site, caused by leakage from a vein into surrounding tissue.
(may affect up to 1 in every 100 people treated)
■ an infection in the blood (sepsis) which can cause fever or chills, rapid heartbeat or rapid breathing; and/or septic shock (a life-threatening form of sepsis) which also causes low blood pressure.
■ disease of the heart muscle and heart failure. Your doctor may order some special heart function tests, both before and during your treatment.
(may affect up to 1 in every 1,000 people treated)
■ anaphylactic reactions (life-threatening type of allergic reaction). Signs include flushing, itching, wheezing, and swelling of the mouth, tongue or throat that can prevent breathing.
■ heart attack; abnormal rhythm of the heart (atrial fibrillation)
■ hand-foot syndrome, which is also known as Palmar-Plantar Erythrodysaesthesia (PPE). Signs are swelling, redness, pain, and tingling of the hands and feet, which may lead to peeling of the skin.
Side effects of unknown frequency
(frequency cannot be estimated from the available data)
■ shock, which may cause a sudden drop in blood pressure, faint or collapse
■ transient/temporary increases in the blood levels of some liver enzymes and bilirubin in laboratory tests
■ hepatitis, or inflammation (swelling) of the liver which can cause different symptoms including jaundice (yellowing of the whites of the eyes and skin) and lead to hepatic (liver) failure. Your doctor will be able to tell you if you are suffering from these conditions
■ red discolouration of the urine
■ amenorrhoea, which is the absence of a menstrual period in females of child-bearing potential
■ azoospermia, which is a reduction in the sperm count in males
■ inflammatory disease of the (large) bowel.
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at:
By reporting side effects you can help provide more information on the safety of this medicine.
DaunoXome
Keep out of the reach and sight of children.
Do not use DaunoXome after the expiry date which is stated on the label {Expiry Date}. The product must be used within 24 hours after dilution with 5% glucose.
Store at 2°C to 8°C (in a refrigerator). Do not freeze. Keep the vial in the outer carton. Vials are for single use only.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.
6. Further information
The active substance is daunorubicin (as citrate salt) equivalent to 2 mg/mL (total 50 mg) daunorubicin base, encapsulated in liposomes.
The other ingredients in the liposome are
distearoylphosphatidylcholine, cholesterol, citric acid (E330).
The other ingredients in the buffer are sucrose, glycine (E640), calcium chloride (E509), water for injection.
What DaunoXome looks like and contents of the pack
DaunoXome is a red, clear or slightly cloudy solution in a 50 ml glass vial containing 25 ml of concentrate.
Each vial contains daunorubicin hydrochloride, corresponding to 50 mg of daunorubicin.
Marketing Authorisation Holder
Galen Limited
Seagoe Industrial Estate
Craigavon
BT635UA
UK
Almac Pharma Services Limited Almac House
20 Seagoe Industrial Estate
Craigavon
BT63 5QD
UK
DaunoXome is registered under the number PL 27827/0007.
This leaflet was last updated in May 2016
GALEN
28/04/16