Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: Pfizer Laboratories (Pty) Ltd, 85 Bute Lane, Sandton 2196, South Africa Tel: +27 (0)11) 320 6000 / 0860 734 937 (Toll-free South Africa)
DAUNOBLASTIN is contraindicated in:
DAUNOBLASTIN should not be repeated in the presence of buccal ulceration. This condition is sometimes preceded by a premonitory buccal burning sensation and the repetition of DAUNOBLASTIN therapy in the presence of this symptom is not advised.
DAUNOBLASTIN is intended for use only by those experienced in the use of cytostatics. The patient must be closely monitored, and electrocardiogram examination should be made regularly to detect signs of cardiotoxicity.
Initial treatment with DAUNOBLASTIN requires close observation of the patient and extensive laboratory monitoring. It is recommended, therefore, that patients be hospitalised at least during the first phase of treatment. Blood counts and monitoring of parameters of renal and liver function should be performed prior to each treatment with DAUNOBLASTIN.
Administration of myelosuppressive medicines such as DAUNOBLASTIN may lead to an increased frequency of infections and haemorrhagic complications. These complications are potentially fatal therefore patients should be instructed to notify the medical practitioner if fever, sore throat, or unusual bruising or bleeding occurs.
Patients should recover from acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia, and generalised infections) before beginning treatment with DAUNOBLASTIN.
DAUNOBLASTIN may transiently impart a red discolouration to the urine after administration.
Special attention must be given (by close cardiac monitoring) to the cardiac toxicity exhibited by DAUNOBLASTIN, especially in infants and children.
DAUNOBLASTIN has a cardiotoxic effect, which can be manifested under two distinct sets of circumstances:
Firstly, daily administration of large doses of ≥2 mg/kg (or ≥55 mg/m²) will result in transient reversible electrocardiogram (ECG) changes in a proportion of cases. This can be avoided by administering the medicine at longer intervals.
Secondly, exceeding the total cumulative dose of 20 mg/kg (or 550 mg/m²) may result in irreversible cardiac failure. This can occur with very little warning and after only a short period of tachycardia.
Cardiomyopathy usually appears within 1 to 6 months after initiation of therapy. It may develop suddenly and may not be detected by routine ECG. It may be irreversible and fatal but responds to treatment if detected early.
Cardiotoxicity may be manifested by early (i.e. acute) or late (i.e. delayed) events.
Early cardiotoxicity of DAUNOBLASTIN consists mainly of sinus tachycardia and/or ECG abnormalities such as non-specific ST-T wave changes. Tachyarrhythmias, including premature ventricular contractions, as well as heart block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not a consideration for discontinuation of DAUNOBLASTIN treatment.
Delayed cardiotoxicity usually develops late in the course of therapy with DAUNOBLASTIN or within 2 to 3 months after treatment termination, but later events (several months to years after completion of treatment) have also been reported.
Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF) such as dyspnoea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Lifethreatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the medicine.
There is increased risk of cardiac toxicity (and lower cumulative dosage limit) in patients previously treated with doxorubicin or in those who received prior or concomitant radiation therapy that encompassed the heart (mediastinal/pericardial area).
Pre-existing active or dormant heart disease, concomitant use of medicines with the ability to suppress cardiac contractility and previous therapy with other anthracyclines or anthracenediones are suspected co-factors of increased risk of DAUNOBLASTIN-induced cardiac toxicity. It is probable that the toxicity of DAUNOBLASTIN and other anthracyclines or anthracenediones is additive.
Anthracyclines including DAUNOBLASTIN should not be administered in combination with other cardiotoxic medicines (e.g. trastuzumab) unless the patient’s cardiac function is closely monitored. Patients receiving anthracyclines after stopping treatment with other cardiotoxic medicines, especially those with long half-lives such as trastuzumab (variable half-life; washout period up to 7 months), may also be at an increased risk of developing cardiotoxicity. Under these conditions, a total cumulative dose of 400 mg/m² in adults should be exceeded only with extreme caution.
It has also been suggested, but is not clearly established, that concurrent therapy with cyclophosphamide or some other antineoplastic medicines (e.g. dacarbazine, dactinomycin, mitomycin) may increase the risk of DAUNOBLASTIN-induced cardiotoxicity. Cardiac function must be carefully monitored in all patients receiving high cumulative doses and in those with risk factors. However, cardiotoxicity with DAUNOBLASTIN may occur at lower cumulative doses whether or not cardiac risk factors are present.
In infants and children there appears to be a greater susceptibility to anthracycline-induced cardiac toxicity, and a long-term periodic evaluation of cardiac function has to be performed.
The incidence of cardiotoxicity is more frequent in adults receiving a total cumulative dose over 550 mg/m² (or over 20 mg/kg body weight) or over 400 mg/m² in patients who have received concurrent cyclophosphamide or previous chest irradiation, in the elderly, and in patients with a history of cardiac disease or mediastinal radiation. In adults, at total cumulative doses less than 550 mg/m², acute congestive cardiac failure is seldom encountered, although rare instances of pericarditis-myocarditis, not dose related, have been reported.
Children may be more susceptible to the development of cardiomyopathy than adults. However, the risk of developing cardiomyopathy is reduced with a total dose less than 300 mg/m² in children over 2 years of age or at a total dosage of less than 10 mg/kg in children younger than 2 years of age with a body surface area of less than 0,5 m².
Cardiac function should be assessed before patients undergo treatment with DAUNOBLASTIN and must be monitored throughout therapy to minimise the risk of incurring severe cardiac impairment. There is no absolutely reliable method of predicting the patients in whom acute congestive heart failure will develop as a result of DAUNOBLASTIN therapy. However, certain changes in the ECG and a decrease in the left ventricular ejection fraction (LVEF) from pre-treatment baseline may help to recognise those patients at greatest risk. On the basis of the ECG, a decrease equal to or greater than 30 % in limb lead QRS voltage has been associated with a significant risk of medicine-induced cardiomyopathy. The appropriate quantitative method for repeated evaluation of LVEF includes multigated radionuclide angiography (MUGA) or echocardiography (ECHO).
A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up.
The risk of cardiotoxicity may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of DAUNOBLASTIN at the first sign of impaired cardiac function. Early clinical diagnosis of medicine-induced congestive heart failure appears to be essential for successful treatment with digoxin, diuretics, sodium restriction and bed rest.
Bone marrow depression and consequent marked cytopenia will occur in all patients who receive DAUNOBLASTIN and requires careful monitoring. The severity being dependent on the dose received and the regenerative capacity of the bone marrow. Evaluation of response based on bone marrow status cellularity is necessary to guide DAUNOBLASTIN treatment.
Myelosuppression is manifested primarily by leukopenia, which is usually severe, and thrombocytopenia. Anaemia may also occur. Leucocyte and platelet nadirs usually occur around days 10-14, with recovery around day 21 following therapy.
Haematologic profiles must be carefully assessed before and during each cycle of DAUNOBLASTIN therapy, including differential white blood cell counts.
Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia, or death. During a course of therapy special attention should be devoted to patients with severe neutropenia and fever (febrile neutropenia), a condition that can be possibly followed by septicaemia and death.
In a variable proportion of cases, a severe aplasia will develop which must be anticipated in every case by eliminating infection before treatment, by isolating the patient from infection during the treatment and by the use of supportive therapy, including the continuous administration of anti-infective medicines, the administration of platelet rich plasma or fresh whole blood transfusion and, under some circumstances, the transfusion of blood or white cells from cases of hyper-leukocytic chronic myeloid leukaemia. Therapy with DAUNOBLASTIN should not be started in patients with pre-existing medicineinduced bone marrow depression unless the benefit from such treatment warrants the risk.
Secondary leukaemia, with or without a preleukaemic phase, has been reported in patients treated with anthracyclines, including DAUNOBLASTIN. Secondary leukaemia is more common when such medicines are given in combination with DNA-damaging antineoplastic medicines, in combination with radiotherapy, when patients have been heavily pre-treated with cytotoxic medicines, or when doses of the anthracyclines have been escalated. These leukaemias can have a 1- to 3-year latency period.
DAUNOBLASTIN possesses immunosuppressive properties. Appropriate measures should be taken to prevent secondary infection.
Administration of live or live-attenuated vaccines in patients immuno-compromised by chemotherapeutic medicines including DAUNOBLASTIN may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving DAUNOBLASTIN. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished (see section 4.5).
DAUNOBLASTIN may enhance the toxicity of other cytotoxic medicines when administered concurrently and dosage should be suitably reduced (see section 4.5).
Nausea and vomiting are usually mild and transient, occurring soon after administration and lasting 24 to 48 hours. Severe nausea and vomiting may produce dehydration. Nausea and vomiting may be prevented or alleviated by the administration of appropriate antiemetic therapy.
Mucositis (mainly stomatitis, less often oesophagitis) may occur in patients undergoing DAUNOBLASTIN therapy. Mucositis/stomatitis generally appear early after medicine administration (burning and erythema of the oral mucosa; sores in the mouth and/or lips occurring 3 to 7 days after administration) and if severe, may progress over a few days to mucosal ulcerations (7 to 10 days after administration). Most patients recover from this adverse event by the third week of therapy.
Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimise the risk of phlebitis/thrombophlebitis at the injection site (see section 4.2).
Extravasation of DAUNOBLASTIN at the site of intravenous administration can cause local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. Should signs or symptoms of extravasation occur during intravenous administration of DAUNOBLASTIN, the medicine infusion should be immediately stopped.
DAUNOBLASTIN may induce hyperuricaemia as a consequence of the extensive purine catabolism that accompanies rapid medicine-induced destruction of a large number of leukaemia cells (tumourlysis syndrome).
It is recommended to check the blood uric acid, urea, potassium, calcium phosphate and creatinine levels, three or four times a week during the first week of treatment. Hydration, urine alkalinisation and prophylaxis with allopurinol to prevent hyperuricemia may minimise potential complications of tumourlysis syndrome.
There is little evidence of neurotoxic effects.
Complete alopecia involving beard growth and the scalp, axillary and pubic hair occurs almost always with full doses of DAUNOBLASTIN. This side effect may cause distress to patients but is usually reversible, with regrowth of hair, which usually occurs within two to three months from the termination of therapy.
Adverse effects may be enhanced by radiotherapy. Skin reactions previously induced by radiotherapy may recur.
Increased radiation toxicities such as skin reactions and mucositis may result from concurrent radiotherapy and DAUNOBLASTIN therapy.
Hepatotoxic effects have been reported resulting from DAUNOBLASTIN treatment. DAUNOBLASTIN should be used with caution and in reduced doses in the treatment of patients with impaired liver function and the elderly.
The major route of elimination of DAUNOBLASTIN is the hepatobiliary system. Serum total bilirubin should be evaluated before and during treatment with DAUNOBLASTIN. Patients with elevated bilirubin may experience slower clearance of the medicine with an increase in overall toxicity. Lower doses are recommended in these patients (see section 4.2).
Patients with severe hepatic impairment must not receive DAUNOBLASTIN (see section 4.3).
Renal impairment can enhance the toxicity of recommended doses of DAUNOBLASTIN. Prior to administration, it is recommended that renal function be evaluated using conventional clinical laboratory tests. Dosage should be reduced in patients with impaired renal function (see section 4.3 and section 4.2).
DAUNOBLASTIN has been implicated as causing renal failure and should therefore be used with caution when renal damage exists.
No data available.
No data available.
No data available.
DAUNOBLASTIN is mainly used in combination with other cytotoxic medicines. Additive toxicity may occur especially with regard to bone marrow/haematologic and gastrointestinal effects (see section 4.4). The use of DAUNOBLASTIN in combination chemotherapy with other potentially cardiotoxic medicines as well as the concomitant use of other cardioactive compounds (e.g. calcium channel blockers) requires monitoring of cardiac function throughout treatment. Changes in hepatic or renal function induced by concomitant therapies may affect daunorubicin metabolism, pharmacokinetics, therapeutic efficacy and/or toxicity.
The cardiotoxic effects of DAUNOBLASTIN may be enhanced by concurrent treatment with cyclophosphamide. DAUNOBLASTIN may exacerbate cyclophosphamide induced haemorrhagic cystitis. It is recommended that the total dose of DAUNOBLASTIN not exceed 400 mg/m² of body surface area when administered concurrently with cyclophosphamide.
Previous treatment with doxorubicin increases the risk of DAUNOBLASTIN induced cardiotoxicity. DAUNOBLASTIN should not be administered to patients who have received the complete cumulative dose of doxorubicin.
DAUNOBLASTIN may raise the concentration of uric acid in the blood. Control of hyperuricaemia and gout may require dosage adjustments to be made for antigout medicines for better control. Allopurinol may be preferred to prevent or reverse DAUNOBLASTIN induced hyperuricaemia because of the risk of uric acid nephropathy with uricosuric antigout medicines.
Reduced dosage of DAUNOBLASTIN may be required.
Concurrent administration may increase the risk of hepatotoxicity.
Due to its immunosuppressive properties, concurrent use of DAUNOBLASTIN with a live virus vaccine may potentiate the replication of the vaccine, increase the adverse effects of the vaccine virus, or decrease the patient’s antibody response to the virus.
DAUNOBLASTIN should only be used in women of childbearing potential if the expected benefits outweigh the risks of therapy and adequate contraception is used. If the patient becomes pregnant whilst receiving the medicine, she should be advised of the potential hazard to the foetus.
Daunorubicin has shown teratogenic, mutagenic and carcinogenic potential in animals. The medicine must be considered as a potential cause of foetal malformations when administered to a pregnant woman. DAUNOBLASTIN should not be used during pregnancy (see section 4.3).
It is not known whether daunorubicin is excreted in breast milk therefore breastfeeding is not recommended during DAUNOBLASTIN therapy in lactating women. It is recommended that DAUNOBLASTIN is not administered to mothers who are breastfeeding (see section 4.3).
DAUNOBLASTIN could induce chromosomal damage in human spermatozoa. Men undergoing treatment with DAUNOBLASTIN should use effective contraceptive methods
No studies have been assessed with regard to the influence of DAUNOBLASTIN on the ability to drive or use machines. There have been no reports explicitly relating to effects of DAUNOBLASTIN treatment on the ability to drive or use machines. However, DAUNOBLASTIN may cause episodes of nausea and vomiting, which sometimes can indirectly lead to impairment of the ability to drive or use machines. Patients should not drive or use machines before they know how treatment with DAUNOBLASTIN affects their ability to drive and use machines.
The below adverse effects are listed by system organ class and frequency category. Frequency categories are defined as: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (cannot be estimated from the available data) (see also section 4.4).
| System organ class | Frequency | Adverse effects |
|---|---|---|
| Infections and infestations | Very common | Sepsis/septicaemia, infection |
| Not known | Septic shock | |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | Uncommon | Acute myeloid leukaemia |
| Not known | Myelodysplastic syndrome | |
| Blood and lymphatic system disorders | Very common | Bone marrow failure, leukopenia, granulocytopenia, neutropenia, thrombocytopenia, anaemia |
| Immune system disorders | Not known | Anaphylactic reaction/anaphylactoid reaction |
| Metabolism and nutrition disorders | Not known | Dehydration, acute hyperuricaemiaa |
| Cardiac disorders | Very common | Cardiomyopathy (clinically manifested by dyspnoea, cyanosis, dependent oedema, hepatomegaly, ascites, pleural effusion and congestive cardiac failure) |
| Uncommon | Myocardial infarction | |
| Not known | Myocardial ischaemia (angina pectoris), endomyocardial fibrosis, pericarditis/myocarditis, supraventricular tachydysrhythmias (such as sinus tachycardia, ventricular extrasystoles, atrioventricular block) | |
| Vascular disorders | Very common | Haemorrhage |
| Not known | Flushing, shock, thrombophlebitis, phlebosclerosisb | |
| Respiratory, thoracic and mediastinal disorders | Not known | Hypoxia |
| Gastrointestinal disorders | Very common | Nausea/vomiting, diarrhoea, oesophagitis, mucositis/stomatitisc |
| Common | Abdominal pain | |
| Not known | Colitis | |
| Skin and subcutaneous tissue disorders | Very common | Alopecia, erythema, rash |
| Not known | Contact dermatitis, recall phenomenon, pruritus, skin hyperpigmentation, nail pigmentation, urticaria | |
| Renal and urinary disorders | Not known | Chromaturiad |
| Reproductive system and breast disorders | Not known | Amenorrhoea, azoospermia |
| General disorders and administration site conditions | Very common | Pyrexia, pain |
| Common | Infusion site phlebitis | |
| Not known | Death, hyperpyrexia, infusion site extravasatione, chills | |
| Investigations | Very common | Increased blood bilirubin, increased aspartate aminotransferase, increased blood alkaline phosphatase |
| Common | Abnormal electrocardiogram, (electrocardiogram ST-T change, abnormal electrocardiogram QRS complex, abnormal electrocardiogram T wave) |
a With possible impairment of renal function especially in the presence of elevated pre-treatment white blood cell counts.
b Venous sclerosi may result from injection of the medicine into a small vessel or from repeated injections into the same vein.
c Pain or burning sensation, erythema, ulcer, haemorrhage infection.
d Red color of urine for 1–2 days after administration.
e Infusion site pain/burning sensation, cellulitis, skin ulcer, necrosis.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.
Heparin sodium and aluminium are incompatible with DAUNOBLASTIN and will precipitate in solution. Incompatibility has also been reported when DAUNOBLASTIN is mixed with a solution of dexamethasone sodium phosphate, aztreonam, allopurinol sodium, fludarabine and piperacillin/tazobactam. DAUNOBLASTIN can be used in combination with other cytotoxic medicines, but should not be administered mixed with other medicines.
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