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 TRISENOX 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
Febrile neutropenia                                  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 Metabolism and nutrition disorders
Hyperglycaemia                                    Very Common           Very Common Hypokalaemia                                      Very Common           Very Common Hypomagnesaemia                                   Very Common             Common Hypernatraemia                                      Common                Common Ketoacidosis                                        Common                Common Hypermagnesaemia                                    Common               Not known Dehydration                                        Not known             Not known Fluid retention                                    Not known             Not known All grades          Grades ≥ 3
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
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 syndrome                    Very Common           Very Common Dyspnoea                                    Very Common             Common Hypoxia                                        Common               Common Pleural effusion                               Common               Common Pleuritic pain                                 Common               Common 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 Chills                                        Common               Not known All grades           Grades ≥ 3
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 TRISENOX consolidation cycles (cycle 1 and cycle 2) versus none in the control arm.

Description of selected adverse reactions

Differentiation syndrome
During TRISENOX 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 TRISENOX.

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 TRISENOX 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 TRISENOX.

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 TRISENOX in combination with ATRA.
However, toxic effects resolved with temporary discontinuation of either TRISENOX, 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 TRISENOX 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