Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Summary of the safety profile
Two parallel, 24-week, randomised, double-blind, placebo-controlled clinical studies were conducted with TOBI in 520 cystic fibrosis patients ranging in age from 6 to 63 years.

The most commonly (≥ 10%) reported adverse events in the placebo-controlled studies with TOBI were cough, pharyngitis, productive cough, asthenia, rhinitis, dyspnoea, pyrexia, lung disorder, headache, chest pain, sputum discoloured, haemoptysis, anorexia, pulmonary function test decreased, asthma, vomiting, abdominal pain, dysphonia, nausea, and weight loss.

Most events were reported at similar or higher frequencies in patients receiving placebo.
Dysphonia and tinnitus were the only undesirable effects reported in significantly more patients treated with TOBI; (12.8% TOBI vs. 6.5% placebo) and (3.1% TOBI vs. 0% placebo) respectively. These episodes of tinnitus were transient and resolved without discontinuation of TOBI therapy, and were not associated with permanent loss of hearing on audiogram testing.
The risk of tinnitus did not increase with repeated cycles of exposure to TOBI (see section 4.4 Ototoxicity).

Tabulated summary of adverse reactions

In the 24-week placebo-controlled studies and their open-label extensions on active treatment, a total of 313, 264 and 120 patients completed treatment with TOBI for 48, 72 and 96 weeks respectively.

Table 1 provides the incidence of treatment-emergent adverse drug reactions, according to the following criteria: reported with an incidence of ≥ 2% for patients receiving TOBI, occurring at a higher rate in the TOBI arm, and assessed as drug-related in ≥ 1% of patients.

Adverse drug reactions from clinical trials are listed according to system organ classes in MedDRA. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each adverse drug reaction: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports.

Table 1 Adverse reactions in clinical trials

Adverse reactions                                                             Frequency category
Infections and infestations
Laryngitis                                                                    Common Ear and labyrinth disorders
Tinnitus                                                                      Common Respiratory, thoracic, and mediastinal disorders
Lung disorder                                                                 Very common Rhinitis                                                                      Very common Dysphonia                                                                     Very common Sputum discoloured                                                            Very common Musculoskeletal and connective tissue disorders
Myalgia                                                                       Common General disorders and administration site conditions
Malaise                                                                       Common Investigations
Pulmonary function test decreased                                             Very common 
As the duration of exposure to TOBI increased over the two open-label extension studies, the incidence of productive cough and pulmonary function test decreased appeared to increase; however, the incidence of dysphonia appeared to decline. Overall, the incidence of adverse events related to the following MedDRA System Organ Class (SOC) decreased with increasing exposure to TOBI: Respiratory, thoracic, and mediastinal disorders, Gastrointestinal disorders, and General disorders and administration site conditions.

Adverse reactions derived from spontaneous reports

Spontaneously reported adverse reactions, presented below, are reported voluntarily and it is not always possible to reliably establish frequency or a causal relationship to drug exposure.

Nervous system disorders
Aphonia, dysgeusia
Ear and labyrinth disorders
Hearing loss
Respiratory, thoracic, and mediastinal disorders
Bronchospasm, oropharyngeal pain
Skin and subcutaneous tissue disorders
Hypersensitivity, pruritus, urticaria, rash

In open label studies and post-marketing experience, some patients with a history of prolonged previous or concomitant use of intravenous aminoglycosides have experienced hearing loss (see 4.4). Parenteral aminoglycosides have been associated with hypersensitivity, ototoxicity and nephrotoxicity (see 4.3, 4.4).

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