Adverse reactions : תופעות לוואי

4.8         Undesirable effects

Summary of the safety profile

The most serious side effects with mitoxantrone are myocardial toxicity and myelosuppression.
The most common side effects with mitoxantrone (seen in more than 1 patient in 10) are anaemia, leucopenia, neutropenia, infections, amenorrhoea, alopecia, nausea and vomiting.
Tabulated list of adverse reactions

The table below is based on safety data derived from clinical trials and spontaneous reporting in oncological indications and from clinical trials, post authorisation safety studies and spontaneous reporting for patients treated for multiple sclerosis. Frequencies are defined according to the following convention: 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).
Frequency                      Oncology                            Multiple Sclerosis 
Infections and Infestations
Very common                    Infection (including fatal          Infection (including fatal outcome)                            outcome)
Urinary tract infection
Upper respiratory tract infection

Uncommon                       Urinary tract infection             Pneumonia Upper respiratory tract infection   Sepsis
Sepsis                              Opportunistic infections
Opportunistic infections

Rare                           Pneumonia

Neoplasms benign and malignant (including cysts and polyps)
Uncommon                       Acute myeloid leukaemia,            Acute myeloid leukaemia, myelodysplastic syndrome,           myelodysplastic syndrome,
acute leukaemia                     acute leukaemia

Blood and lymphatic system disorders
Very common                    Anaemia
Neutropenia
Leukopenia

Common                         Thrombocytopenia                    Anaemia Granulocytopenia                    Leukopenia
Granulocytopenia
White blood cell count abnormal

Uncommon                       Myelosuppression                    Bone marrow failure Bone marrow failure                 Myelosuppression
White blood cell count              Thrombocytopenia abnormal                            Neutropenia

Immune system disorders
Uncommon                       Anaphylaxis/anaphylactoid           Anaphylaxis/anaphylactoid reactions (including shock)         reactions (including shock)

Metabolism and nutrition disorders
Common                         Anorexia
Uncommon                       Weight fluctuations                 Anorexia Tumour lysis syndrome*              Weight fluctuations

* Acute T and B lymphoblastic leukaemia and non-Hodgkin lymphomas (NHL) are most commonly associated with TLS
Nervous system disorders
Common                         Lethargy                     Headache
Uncommon                       Anxiety                      Anxiety
Confusion                    Confusion
Headache                     Paraesthesia
Paraesthesia                 Lethargy

Eye disorders
Uncommon                       Scleral discolouration       Scleral discolouration Cardiac disorders
Common                         Congestive heart failure     Arrhythmia Myocardial infarction        Electrocardiogram abnormal
(including fatal events)     Left ventricular ejection fraction decreased


Uncommon                       Arrhythmia                   Congestive heart failure Sinus bradycardia            Cardiomyopathy
Electrocardiogram abnormal   Sinus bradycardia
Left ventricular ejection    Myocardial infarction fraction decreased           (including fatal events)

Rare                           Cardiomyopathy
Vascular disorders
Uncommon                       Contusion                    Contusion Haemorrhage                  Haemorrhage
Hypotension                  Hypotension

Respiratory, thoracic and mediastinal disorders
Common                         Dyspnoea
Uncommon                                                    Dyspnoea
Gastrointestinal disorders
Very common                    Nausea                       Nausea
Vomiting

Common                         Constipation                 Constipation Diarrhoea                    Diarrhoea
Stomatitis                   Stomatitis
Vomiting


Uncommon                       Abdominal pain               Abdominal pain Gastrointestinal             Gastrointestinal haemorrhage Mucosal          haemorrhage Mucosal inflammation                 inflammation
Pancreatitis                 Pancreatitis
Hepatobiliary disorders
Common                                                                Elevated aspartate aminotransferase levels
Uncommon                           Hepatotoxicity                     Hepatotoxicity Elevated aspartate aminotransferase levels
Skin and subcutaneous tissue disorders
Very common                        Alopecia                           Alopecia Uncommon                           Erythema                           Nail disorders Nail disorders                     Rash
Rash                               Skin discolouration
Skin discolouration                Tissue necrosis
Tissue necrosis                    (after extravasation)
(after extravasation)

Renal and urinary disorders
Uncommon                           Elevated serum creatinine          Elevated serum creatinine Elevated blood urea nitrogen       Elevated blood urea nitrogen levels                             levels
Nephropathy toxic                  Nephropathy toxic
Urine discolouration               Urine discolouration

Reproductive system and breast disorders
Very common                                                           Amenorrhoea* Uncommon                           Amenorrhoea
* Amenorrhea may be prolonged and may be consistent with premature menopause General disorders and administration site conditions
Common                             Asthenia
Fatigue
Pyrexia
Uncommon                           Oedema                             Asthenia Extravasation*                     Fatigue
Dysgeusia                          Oedema
Pyrexia
Extravasation*
Sudden death**

* Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning and/or blue discolouration of the skin. Extravasation can result in tissue necrosis with resultant need for debridement and skin grafting. Phlebitis has also been reported at the site of infusion.

** The casual relationship to mitoxantrone administration is uncertain.
Description of selected adverse reactions

Myocardial toxicity, manifested in its most severe form by potentially irreversible and fatal congestive heart failure (CHF), may occur either during therapy with mitoxantrone or months to years after termination of therapy. This risk increases with cumulative dose. In clinical trials cancer patients who received cumulative doses of 140 mg/m2 either alone or in combination with other chemotherapeutic agents had a cumulative 2.6% probability of clinical congestive heart failure.
Myelosuppression is a dose-limiting undesirable effect of mitoxantrone. Myelosuppression can be more pronounced and longer-lasting in patients who have previously received chemotherapy or radiotherapy. In a clinical trial with acute leukaemia patients, significant myelosuppression occurred in all patients who were given mitoxantrone therapy. Amongst the 80 enrolled patients the median values for the lowest white blood cell count and platelet count were 400/μl (WHO grade 4), and 9.500/μl (WHO grade 4), respectively. Haematological toxicity is difficult to evaluate in acute leukaemia because traditional parameters of bone marrow depression such as white blood cell and platelet counts are confounded by marrow replacement with leukemic cells.
Multiple sclerosis population

Haematological toxicity

A neutropenia can occur after each administration. This is in general a transient neutropenia with the lowest count of leucocytes at day 10 after the infusion and recovered around day 20. A reversible thrombocytopenia can also be observed. Haematological parameters should be regularly monitored (see section 4.4).
Fatal cases of Acute Myeloid Leukaemia (AML) have been reported (see section 4.4).
Cardiac toxicity

Cases of ECG anomalies have been reported. Cases of congestive heart failure with left- ventricular ejection fraction (LVEF) < 50 % have also been reported (see section 4.4).
Paediatric population

Treatment with mitoxantrone is not recommended in the paediatric population. Safety and efficacy have not been established.
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. 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/