Adverse reactions : תופעות לוואי

4.8   Undesirable effects
Summary of the safety profile
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).

Tabulated list of adverse reactions
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- adverse reactions
Infections and infestations
Uncommon            Infection, sepsis
Neoplasms benign, malignant and unspecified (including cysts and polyps) Uncommon            Acute myeloid leukaemia
Blood and lymphatic system disorders
Very common         Anaemia, leukopenia
Common              Neutropenia, thrombocytopenia, febrile neutropenia, granulocytopenia, febrile bone marrow aplasia, white blood cell count decreased
Uncommon            Eosinophil count increased, neutrophil count increased, platelet count increased, white blood cell count increased, lymphocyte count decreased, monocyte count decreased
Immune system disorders
Not known           Anaphylactic reaction, hypersensitivity
Metabolism and nutrition disorders
Common              Anorexia
Nervous system disorders
Common              Paraesthesia, dizziness, headache, peripheral neuropathy Uncommon            Syncope
Ear and labyrinth disorders
Uncommon            Vertigo, ear infection
Cardiac disorders
Common              Ejection fraction decreased, tachycardia
Vascular disorders
Common              Phlebitis
Uncommon            Venous thrombosis, lymphoedema
Not known           Embolism
Respiratory, thoracic and mediastinal disorders
Common              Dyspnoea, cough, pharyngitis, respiratory tract infections Not known           Pulmonary embolism
Gastrointestinal disorders
Very common         Nausea, vomiting, stomatitis
Common              Diarrhoea, constipation, abdominal pain, dyspepsia Uncommon            Gingivitis, oral candidiasis
Hepatobiliary disorders
Common              Transaminases increased
Skin and subcutaneous tissue disorders
Very common         Alopecia
Common              Nail disorder, erythema
Uncommon            Cellulitis
General disorders and administration site conditions
Very common         Asthenia
Common              Mucosal inflammation, pyrexia, fatigue, malaise, injection site reaction (including pain, swelling, burning sensation, erythema, pruritus, thrombosis), oedema
Uncommon            Thirst

Clinical trial data
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):
•     Of these 76% were treated for breast cancer and 24% for a variety of advanced cancers.

•     Cardioxane treatment: a mean dose of 1010 mg/m² (median: 1000 mg/m²) in combination with doxorubicin, and a mean dose of 941 mg/m² (median: 997 mg/m²) in combination with epirubicin.
•     Chemotherapy treatment received by patients treated for breast cancer: 45% combination therapy with doxorubicin 50 mg/m² (mainly with 5-fluorouracil and cyclophosphamide): 17% with epirubicin alone; 14% combination therapy with epirubicin 60 or 90 mg/m² (mainly with 5-fluorouracil and cyclophosphamide).

Patients receiving chemotherapy alone (n=157)
•     All were treated for breast cancer
•     Chemotherapy treatment received: 43% single agent epirubicin 120 mg/m²; 33% combination therapy with 50 mg/m² doxorubicin (mainly with 5-fluorouracil and cyclophosphamide); 24% combination therapy with epirubicin at 60 or 90 mg/m² (mainly with 5-fluorouracil and cyclophosphamide).

Description of selected adverse drug reactions
Second primary malignancies
AML has been reported uncommonly in adult breast cancer patients post-marketing.

Safety profile at maximum tolerated dose
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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il