Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: Novartis Pharmaceuticals UK Limited Frimley Business Park Frimley Camberley Surrey GU16 7SR
Myelosuppressive effects that may be additive to those of chemotherapy were reported with CARDIOXANE (see section 4.8). Cell counts at nadir may be lower in patients treated with dexrazoxane. Haematological monitoring is thus necessary. Leucopenia and thrombocytopenia generally reverse quickly upon cessation of treatment with CARDIOXANE.
At higher doses of chemotherapy, where the CARDIOXANE dose exceeds 1000mg/m2, myelosuppression may increase significantly.
Since dexrazoxane is a cytotoxic agent, with topoisomerase II inhibition activity, combination of dexrazoxane with chemotherapy may lead to an increased risk of second primary malignancy.
In clinical trials, second primary malignancies, in particular acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS), have been reported in paediatric patients with Hodgkin’s disease and acute lymphoblastic leukaemia receiving chemotherapy regimes including several cytotoxics (e.g. etoposide, doxorubicin, cyclophosphamide) (see section 4.8).
AML has been reported uncommonly in adult breast cancer patients in post-marketing (see section 4.8).
In some studies, a higher incidence of death has been observed in the groups treated with dexrazoxane plus chemotherapy compared to those treated with chemotherapy alone. The possibility that dexrazoxane was a contributing factor to the imbalance cannot be ruled out (see section 5.1).
A significant decrease in tumour response rate has been reported in one study in advanced breast cancer patients treated with doxorubicin and dexrazoxane compared to patients treated with doxorubicin and placebo. Since both dexrazoxane and doxorubicin are topoisomerase inhibitors, it is possible that dexrazoxane may interfere with the anti-tumour efficacy of doxorubicin. Use of dexrazoxane in combination with adjuvant breast cancer therapy or chemotherapy intended as curative is therefore not recommended.
Clearance of dexrazoxane and its active metabolites may be reduced in patients with decreased creatinine clearance.
Liver dysfunction was occasionally observed in patients treated with CARDIOXANE (see section 4.8).
Standard cardiac monitoring associated with doxorubicin or epirubicin treatment should be continued.
There are no data that support the use of dexrazoxane in patients with myocardial infarction within the past 12 months, pre-existing heart failure (including clinical heart failure secondary to anthracycline treatment), uncontrolled angina or symptomatic valvular heart disease.
Combination of dexrazoxane with chemotherapy may lead to an increased risk of thromboembolism (see section 4.8).
Since dexrazoxane is a cytotoxic agent, sexually active men should continue using effective methods of contraception for at least 3 months after cessation of treatment with dexrazoxane (see section 4.6).
Anaphylactic reaction including angiodema, skin reactions, bronchospasm, respiratory distress, hypotension and loss of consciousness have been observed in patients treated with CARDIOXANE and anthracyclines (see section 4.8). Previous history of allergy to dexrazoxane or razoxane should be carefully considered prior to administration.
CARDIOXANE may increase haematological toxicity induced by chemotherapy or radiation, requiring careful monitoring of haematological parameters during the first two treatment cycles (see section 4.4).
Interaction studies with dexrazoxane are limited. Effects on CYP450 enzymes or drug transporters have not been studied.
CARDIOXANE should not be mixed with any other medicinal products during infusion.
Both sexually active men and women should use effective methods of contraception during treatment. For men the contraception should be continued for at least 3 months after cessation of treatment with CARDIOXANE (see section 4.4).
There are no adequate data from the use of dexrazoxane in pregnant women. Animal studies showed embryotoxic and teratogenic effects (see section 5.3). The potential risk for humans is unknown. CARDIOXANE should not be used during pregnancy unless clearly necessary.
There are no animal studies on the transfer of the active substance and/or its metabolites into milk. It is unknown whether dexrazoxane and/or its metabolites are excreted in human milk. Because of the potential for serious adverse reactions in infants exposed to CARDIOXANE, mothers should discontinue breast-feeding during CARDIOXANE therapy (see section 4.3).
The effects of CARDIOXANE on the fertility of humans and animals have not been studied.
Patients should be advised to be cautious when driving or using machines if they experience fatigue during treatment with CARDIOXANE.
CARDIOXANE is administered together with anthracycline chemotherapy and, consequently, the relative contributions of anthracycline and CARDIOXANE to the adverse reaction profile may be unclear. The most common adverse reactions are haematological and gastroenterological reactions, primarily anaemia, leukopenia, nausea, vomiting and stomatitis, as well as asthenia and alopecia. Myelosuppressive effects of CARDIOXANE may be additive to those of chemotherapy (see section 4.4). An increased risk of the development of second primary malignancies, particularly AML, has been reported.
The following table includes reactions from clinical trials and from post-marketing use. Due to the spontaneous nature of post-marketing reporting, such events are listed with frequency “not known” if they were not already identified as reactions from clinical trials.
Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); not known (cannot be estimated from the available data).
Table 1:
Uncommon: Infection, sepsis
Uncommon: Acute myeloid leukaemia
Very common: Anaemia, leukopenia
Common: Neutropenia, thrombocytopenia, febrile neutropenia, granulocytopenia
Uncommon: Febrile bone marrow aplasia, eosinophil count increased, neutrophil count increased, platelet count increased, white blood cell count increased, lymphocyte count decreased, monocyte count decreased
Not known: Anaphylactic reaction, hypersensitivity
Common: Anorexia
Common: Paraesthesia, dizziness, headache, peripheral neuropathy
Uncommon: Syncope
Common: Conjunctivitis
Uncommon: Vertigo, ear infection
Common: Ejection fraction decreased, tachycardia
Common: Phlebitis
Uncommon: Venous thrombosis, lymphoedema
Not known: Embolism
Common: Dyspnoea, cough, pharyngitis
Uncommon: Respiratory tract infection
Not known: Pulmonary embolism
Very common: Nausea, vomiting, stomatitis
Common: Diarrhoea, constipation, abdominal pain, dyspepsia
Uncommon: Gingivitis, oral candidiasis
Common: Transaminases increased
Very common: Alopecia
Common: Nail disorder, erythema
Very common: Asthenia
Common: Mucosal inflammation, pyrexia, fatigue, malaise, injection site reaction (including pain, swelling, burning sensation, erythema, pruritus, thrombosis)
Uncommon: Oedema, thirst
The above table shows adverse reactions reported in clinical studies and having a reasonable possibility of a causal relationship with CARDIOXANE. These data are derived from clinical trials in cancer patients where CARDIOXANE was used in combination with anthracycline-based chemotherapy, and where in some cases a control group of patients receiving chemotherapy alone can be referred to.
Patients receiving chemotherapy and CARDIOXANE (n=375):
Patients receiving chemotherapy alone (n=157):
Secondary acute myeloid leukaemia (AML) / myelodysplastic syndrome (MDS) has been observed in paediatric patients with Hodgkin’s disease or acute lymphoblastic leukaemia receiving dexrazoxane in combination with chemotherapy (see section 4.4). AML has been reported uncommonly in adult breast cancer patients post-marketing.
Dexrazoxane’s maximum tolerated dose (MTD) when given as monotherapy by short infusion every three weeks for cardioprotection has not been specifically studied. In studies of dexrazoxane as a cytotoxic, its MTD is shown to be dependent on posology and dosing schedule, and varies from 3750 mg/m² when short infusions are given in divided doses over 3 days to 7420 mg/m² when given weekly for 4 weeks, with myelosuppression and abnormal liver function tests becoming dose-limiting. The MTD is lower in patients who have been heavily pre-treated with chemotherapy, and those with pre-existing immunosuppression (e.g. AIDS).
The following are adverse reactions reported when CARDIOXANE was given at doses around the MTD: neutropenia, thrombocytopenia, nausea, vomiting, and increase in hepatic parameters. Other toxic effects were malaise, low grade fever, increased urinary clearance of iron and zinc, anaemia, abnormal blood clotting, transient elevation of serum triglyceride and amylase levels, and a transient decrease in serum calcium level.
Incompatibilities with other medicinal products or materials are not known. However CARDIOXANE should not be mixed with other medicinal products during infusion, other than the diluents mentioned in section 6.6.
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