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). Leukocytosis 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), leukocytosis (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, multicenter, noninferiority 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 Leukocytosis                                  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 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
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
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 leukocytosis (see section 4.4). Twenty-seven patients had leukocytosis (WBC  10 x 103/l) during induction, 4 of whom had values above 100,000/l. Baseline white blood cell (WBC) counts did not correlate with development of leukocytosis on study, and WBC counts during consolidation therapy were not as high as during induction. In these studies, leukocytosis 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 leukocytosis, and no standard approach has proven effective. One patient treated under a compassionate use program died from cerebral infarct due to leukocytosis, 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, preexisting 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 paresthesia/dysesthesia, 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 percent 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 http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.he alth.gov.il .