Adverse reactions : תופעות לוואי

4.8   Undesirable effects
Summary of the safety profile
The safety data provided in the sections below are based on the global, double-blind randomised pivotal phase 3 trial 1199.13 (LUME-Lung 1) comparing treatment with nintedanib plus docetaxel against placebo plus docetaxel in patients with locally advanced, or metastatic, or recurrent NSCLC after first-line chemotherapy and based on data observed during the post-marketing period. The most frequently reported adverse drug reactions (ADRs) specific for nintedanib were diarrhoea, increased liver enzyme values (ALT and AST) and vomiting. Table 3 provides a summary of the adverse reactions by System Organ Class (SOC). For the management of selected adverse reactions, see section 4.4. Information about selected adverse reactions observed from the LUME-Lung 1 trial are described below.

Tabulated list of adverse reactions
Table 3 summarizes the frequencies of adverse drug reactions that were reported in the pivotal study LUME-Lung 1 for patients with NSCLC of adenocarcinoma tumour histology (n = 320) or from the post-marketing period. The following terms are used to rank the ADRs by frequency: 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).
Within each frequency grouping adverse reactions are presented in order of decreased seriousness.


Table 3:        Summary of ADRs per frequency category

System Organ          Very common                 Common                   Uncommon               Not Class               (≥ 1/10)               (≥ 1/100 < 1/10)        (≥ 1/1,000 < 1/100)       known Infections and                               Febrile neutropenia,
infestations                                    Abscesses,
Sepsis
Blood and             Neutropenia          Thrombocytopenia lymphatic system       (includes febrile disorders             neutropenia)
Metabolism and           Decreased              Dehydration,
nutrition              appetite,            Weight decreased disorders              Electrolyte imbalance
Nervous system           Peripheral                Headache1) disorders             neuropathy
Cardiac disorders                                                            Myocardial infarction (see section 4.4)
Vascular           Bleeding1) (see             Venous                                       Aneurysms disorders           section 4.4)          thromboembolism3),                                and artery Hypertension                                   dissections

Gastrointestinal        Diarrhoea,                                         Perforation1)          Colitis disorders             Vomiting,                                          Pancreatitis2) Nausea,
Abdominal pain
Hepatobiliary            Alanine           Hyperbilirubinaemia,       Drug-induced liver disorders           aminotransferase           Gamma-                      injury (ALT)increased,       glutamyltransferase
Aspartate           (GGT) increased aminotransferase
(AST)increased,
Blood alkaline phosphatase
(ALKP) increased
Skin and             Mucositis                 Pruritus subcutaneous           (including tissue disorders        stomatitis),
Rash,
Alopecia1)
Renal and urinary                                 Proteinuria1)             Renal failure disorders                                                              (see section 4.4) 1)    In clinical trials the frequency was not increased in patients treated with nintedanib plus docetaxel as compared to placebo plus docetaxel.
2)
Events of pancreatitis have been reported in patients taking nintedanib for the treatment of IPF and NSCLC. The majority of these events were reported for patients in the IPF indication.
3)
Cases of pulmonary embolism have been reported.

Description of selected adverse reactions

Diarrhoea
Diarrhoea occurred in 43.4 % (≥ grade 3: 6.3 %) of adenocarcinoma patients in the nintedanib arm.
The majority of adverse reactions appeared in close temporal relationship with the administration of docetaxel. Most patients recovered from diarrhoea following treatment interruption, anti-diarrhoeal therapy and nintedanib dose reduction.

For recommended measures and dosing adjustments in case of diarrhoea, see sections 4.4 and 4.2, respectively.

Liver enzyme elevations and hyperbilirubinaemia
Liver-related adverse reactions occurred in 42.8 % of nintedanib-treated patients. Approximately one third of these patients had liver-related adverse reactions of ≥ grade 3 severity. In patients with increased liver parameters, the use of the established stepwise dose reduction scheme was the appropriate measure and discontinuation of treatment was only necessary in 2.2 % of patients. In the majority of patients, elevations of liver parameters were reversible.

For information about special populations, recommended measures and dosing adjustments in case of liver enzyme and bilirubin elevations, see sections 4.4 and 4.2, respectively.

Neutropenia, febrile neutropenia and sepsis
Sepsis and febrile neutropenia have been reported as subsequent complications of neutropenia. The rates of sepsis (1.3 %) and febrile neutropenia (7.5 %) were increased under treatment with nintedanib as compared to the placebo arm. It is important that the patient’s blood counts are monitored during therapy, in particular during the combination treatment with docetaxel (see section 4.4).

Bleeding
In the post-marketing period non-serious and serious bleeding events, some of which fatal, have been reported, including patients with or without anticoagulant therapy or other drugs that could cause bleeding. Post-marketing bleeding events include but are not limited to gastrointestinal, respiratory and central nervous system organs, with the most frequent being respiratory (see also section 4.4).

Perforation
As expected via its mechanism of action perforation might occur in patients treated with nintedanib.
However, the frequency of patients with gastrointestinal perforation was low.

Peripheral neuropathy
Peripheral neuropathy is also known to occur with docetaxel treatment. Peripheral neuropathy was reported in 16.5 % of patients in the placebo arm and in 19.1 % of patients in the nintedanib arm.

Reporting of suspected adverse reactions
You can report side effects to the Ministry of Health by following the link ‘Reporting Side Effects of Drug Treatment' on the Ministry of Health home page (www.health.gov.il) which links to an online form for reporting side effects. You can also use this link: https://sideeffects.health.gov.il