Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2014 Publisher: Galen Limited, Seagoe Industrial Estate, Craigavon, BT63 5UA, UK
The decision to treat must be based on an evaluation, by the physician, of the benefits and risks for the individual patient.
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, 500-600 mg/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 400 mg/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 60 mg/m²) for malignancies other than Kaposi’s sarcoma indicates that the risk of cardiotoxicity may be higher in these patients.
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) scan. 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 320 mg/m² has been reached, then every 160 mg/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. 120 mg/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 treatment with DaunoXome is stopped if clinical signs of cardiotoxicity appear.
Several long-term studies in children also suggest that after anthracycline treatment congestive cardiomyopathies with a latency of many years may occur.
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 monitored, as medically appropriate, during the course of DaunoXome therapy.
Patients must be observed carefully for evidence of intercurrent or opportunistic infections.
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.
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. 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-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 should be exercised when DaunoXome is used concomitantly with other myelosuppressive or cardiotoxic agents (see Section 4.5). 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).
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. DaunoXome is not recommended in patients with liver or renal impairment, see Section 4.2.
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.
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).
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, Pglycoprotein (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.
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.
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.
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).
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 has been reported during treatment with DaunoXome.
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).
Very common: Infections
Uncommon: Sepsis, Septic shock*
Very common: Bone marrow suppression, Agranulocytosis, Neutropenia, Febrile neutropenia, Leucopenia, Pancytopenia, Thrombocytopenia and Anemia*
Very common: Allergic reactions
Rare: Anaphylactic reaction
Common: Dehydration
Common: Depression
Very common: Headache
Common: Dizziness
Common: Decreased left ventricular ejection fraction
Uncommon: Congestive heart failure, Cardiomyopathy
Rare: Atrial fibrillation, Myocardial infarction
Very common: Haemorrhage
Not known: Shock
Very common: Dyspnoea
Very common: Stomatitis, Mucous ulcerations, Nausea, Vomiting, Diarrhoea, Abdominal pain
Not known: Transient elevations in serum bilirubin, aspartate aminotransferase (AST) and alkaline phosphatase (ALP) concentrations Hepatitis, Hepatic failure
Very common: Alopecia
Rare: Palmar-plantar erythrodysaesthesia syndrome**
Not known: Red discolouration of urine
Not known: Amenorrhoea, Azoospermia
Very common: Infusion-associated reactions (including back pain, flushing, chest tightness, and dyspnoea)*, Asthenia, Fatigue, Fever, Chills
Common: Extravasation at the injection site may result in erythema, pain and swelling*
* See Section 4.4
** 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 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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.
DaunoXome may only be mixed with 5% dextrose for infusion. If DaunoXome is 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 as well because such compounds can rupture the bilayer wall of the liposomes causing premature leakage of the active drug.
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.
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