Adverse reactions : תופעות לוואי

4.8 Undesirable effects
Summary of the safety profile

Related adverse reactions of CTC grade 3 and 4 occurred in 37 % of relapsed/refractory APL patients in clinical trials. The most commonly reported reactions were hyperglycaemia, hypokalaemia, neutropenia, and increased alanine amino transferase (ALT). Leucocytosis occurred in 50 % of patients with relapsed/refractory APL, as determined by haematology assessments.
Serious adverse reactions were common (1-10 %) and not unexpected in the relapsed/refractory population.
Those serious adverse reactions attributed to arsenic trioxide included APL differentiation syndrome (3), leucocytosis (3), prolonged QT interval (4, 1 with torsade de pointes), atrial fibrillation/atrial flutter (1), hyperglycaemia (2) and a variety of serious adverse reactions related to haemorrhage, infections, pain, diarrhoea, nausea.

In general, treatment-emergent adverse events tended to decrease over time, in relapsed/refractory APL patients perhaps accounted for by amelioration of the underlying disease process. Patients tended to tolerate consolidation and maintenance treatment with less toxicity than in induction. This is probably due to the confounding of adverse events by the uncontrolled disease process early on in the treatment course and the myriad concomitant medicinal products required to control symptoms and morbidity.

In a phase 3, multicentre, non-inferiority trial comparing all-trans-retinoic acid (ATRA) plus chemotherapy with ATRA plus arsenic trioxide in newly diagnosed low-to-intermediate risk APL patients (Study APL0406; see also section 5.1), serious adverse reactions including hepatic toxicity, thrombocytopenia, neutropenia and QTc prolongation were observed in patients treated with arsenic trioxide.

Tabulated list of adverse reactions

The following undesirable effects have been reported in the APL0406 study in newly diagnosed patients and in clinical trials and/or post-marketing experience in relapsed/refractory APL patients. Undesirable effects are listed in table 2 below as MedDRA preferred term by system organ class and frequencies observed during ARSENIC TRIOXIDE clinical trials in 52 patients with refractory/relapsed APL. Frequencies are defined as: (very common ≥ 1/10), (common ≥ 1/100 to < 1/10), (uncommon ≥ 1/1,000 to < 1/100), not known (cannot be estimated from available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.



Table 2

All grades             Grades ≥ 3
Infections and infestations
Herpes zoster                                            Common                 Not known Sepsis                                                   Not known              Not known Pneumonia                                                Not known              Not known Blood and lymphatic system disorders                     All grades             Grades ≥ 3 Febrile neutropenia                                      Common                 Common Common                                                   Common                 Common Leucocytosis                                             Common                 Common Neutropenia                                              Common                 Common Pancytopenia                                             Common                 Common Thrombocytopenia                                         Common                 Common Anaemia                                                  Common                 Not known Leukopenia                                               Not known              Not known Lymphopenia                                              Not known              Not known All grades    Grades ≥ 3
Metabolism and nutrition disorders
Hyperglycaemia                                    Very Common   Very Common Hypokalaemia                                      Very Common   Very Common Hypomagnesaemia                                   Very Common   Common Hypernatraemia Common                             Common        Common Ketoacidosis                                      Common        Common Hypermagnesaemia                                  Common        Not known Dehydration                                       Not known     Not known Fluid retention                                   Not known     Not known Psychiatric disorders
Confusional state                                 Not known     Not known Nervous system disorders
Paraesthesia                                      Very Common   Common Dizziness                                         Very Common   Not known Headache                                          Very Common   Not known Convulsion                                        Common        Not known Encephalopathy Wernicke encephalopathy            Not known     Not known Eye disorders
Vision blurred                                    Common        Not known Cardiac disorders                                 All grades    Grades ≥ 3 Tachycardia                                       Very Common   Common Pericardial effusion                              Common        Common Ventricular extrasystoles                         Common        Not known Cardiac failure                                   Not known     Not known Ventricular tachycardia                           Not known     Not known Vascular disorders
Vasculitis                                        Common        Common Hypotension                                       Common        Not known Respiratory, thoracic and mediastinal disorders
Differentiation                                   Very Common   Very Common Dyspnoea                                          Very Common   Common Hypoxia                                           Common        Common Pleural effusion                                  Common        Common Pleuritic pain                                    Common        Common All grades    Grades ≥ 3
Pulmonary alveolar haemorrhage                    Common        Common Pneumonitis                                       Not known     Not known Gastrointestinal disorders
Diarrhoea                                         Very Common   Common Vomiting                                          Very Common   Not known Nausea                                            Very Common   Not known Abdominal pain                                    Common        Common Skin and subcutaneous tissue disorders
Pruritus                                          Very Common   Not known Rash                                              Very Common   Not known Erythema                                                Common                Common Face oedema                                             Common                Not known Musculoskeletal and connective tissue disorders

Myalgia                                                 Very Common           Common Arthralgia                                              Common                Common Bone pain                                               Common                Common Renal and urinary disorders

Renal failure                                           Common                Not known General disorders and administration site conditions

Pyrexia                                                Very Common          Common Pain                                                   Very Common          Common Fatigue                                                Very Common          Not known Oedema                                                 Very Common          Not known Chest pain Common Common                               Common               Common Chills Common Not known                                Common               Not known Investigations
Alanine amino transferase increased                    Very Common          Common Aspartate amino transferase increased                  Very Common          Common Electrocardiogram QT prolonged                         Very Common          Common Hyperbilirubinaemia                                    Common               Common Blood creatinine increased                             Common               Not known Weight increased                                       Common               Not known Gamma-glutamyltransferase increased*                   Not known*           Not known* *In the CALGB study C9710, 2 cases of grade ≥3 increased GGT were reported out of the 200  patients who received ARSENIC TRIOXIDE consolidation cycles (cycle 1 and cycle 2) versus none in the control arm.

Description of selected adverse reactions

Differentiation syndrome
During ARSENIC TRIOXIDE treatment, 14 of the 52 patients in the APL studies in the relapsed setting had one or more symptoms of APL differentiation syndrome, characterised by fever, dyspnoea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leucocytosis (see section 4.4). Twenty-seven patients had leucocytosis (WBC ≥ 10 x 103/μl) during induction, 4 of whom had values above 100,000/μl.
Baseline white blood cell (WBC) counts did not correlate with development of leucocytosis on study, and WBC counts during consolidation therapy were not as high as during induction. In these studies, leucocytosis was not treated with chemotherapeutic medicinal products. Medicinal products that are used to lower the white blood cell count often exacerbate the toxicities associated with leucocytosis, and no standard approach has proven effective. One patient treated under a compassionate use program died from cerebral infarct due to leucocytosis, following treatment with chemotherapeutic medicinal products to lower WBC count.
Observation is the recommended approach with intervention only in selected cases.
Mortality in the pivotal studies in the relapsed setting from disseminated intravascular coagulation (DIC) associated haemorrhage was very common (> 10 %), which is consistent with the early mortality reported in the literature.

In newly diagnosed patients with low to intermediate risk APL, differentiation syndrome was observed in 19 % including 5 severe cases.

In post marketing experience, a differentiation syndrome, like retinoic acid syndrome, has also been reported for the treatment of malignancies other than APL with ARSENIC TRIOXIDE.

QT interval prolongation

Arsenic trioxide can cause QT interval prolongation (see section 4.4). QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging medicinal products, a history of torsade de pointes, pre-existing QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalaemia or hypomagnesaemia. One patient (receiving multiple, concomitant medicinal products, including amphotericin B) had asymptomatic torsade de pointes during induction therapy for relapsed APL with arsenic trioxide. She went onto consolidation without further evidence of QT prolongation.

In newly diagnosed patients, with low to intermediate risk APL, QTc prolongation was observed in 15.6 %. In one patient induction treatment was terminated because of severe prolongation of the QTc interval and electrolyte abnormalities on day 3.

Peripheral neuropathy

Peripheral neuropathy, characterised by paraesthesia/dysaesthisia, is a common and well known effect of environmental arsenic. Only 2 relapsed/refractory APL patients discontinued treatment early due to this adverse event and one went on to receive additional ARSENIC TRIOXIDE on a subsequent protocol. Forty-four per cent of relapsed/refractory APL patients experienced symptoms that could be associated with neuropathy; most were mild to moderate and were reversible upon cessation of treatment with ARSENIC TRIOXIDE.

Hepatotoxicity (grade 3-4)

In newly diagnosed patients with low to intermediate risk APL 63.2 % developed grade 3 or 4 hepatic toxic effects during induction or consolidation treatment with ARSENIC TRIOXIDE in combination with ATRA.
However, toxic effects resolved with temporary discontinuation of either ARSENIC TRIOXIDE, ATRA or both (see section 4.4).

Haematological and gastrointestinal toxicity

In newly diagnosed patients with low to intermediate risk APL, gastrointestinal toxicity, grade 3-4 neutropenia and grade 3 or 4 thrombocytopenia occurred, however these were 2.2 times less frequent in patients treated with ARSENIC TRIOXIDE in combination with ATRA compared to patients treated with ATRA + chemotherapy.

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