Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions in patients with COPD or asthma are respectively: dysphonia (0.3% and 1.5%) and oral candidiasis (0.8% and 0.3%), which are normally associated with inhaled corticosteroids; muscle spasms (0.4% and 0.2%), which can be attributed to the long-acting beta2-agonist component; and dry mouth (0.4% and 0.5%), which is a typical anticholinergic effect.
In asthmatic patients, adverse reactions tend to cluster during the first 3 months following initiation of therapy and become less frequent with longer-term use (after 6 months of treatment).

Tabulated list of adverse reactions

Adverse reactions associated to beclometasone dipropionate/formoterol/glycopyrronium occurred during clinical studies and post-marketing experience as well as adverse reactions listed for the marketed individual components are provided below, listed by system organ class and frequency.
Frequencies are defined as: 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) and not known (cannot be estimated from available data).

MedDRA system organ
Adverse reaction                           Frequency class
Pneumonia (in COPD patients), pharyngitis, oral
Common candidiasis, urinary tract infection1, nasopharyngitis1
Influenza1, oral fungal infection, oropharyngeal
Infections and Infestations   candidiasis, oesophageal candidiasis, fungal Uncommon
(oro)pharyngitis, sinusitis1, rhinitis1, gastroenteritis1,
vulvovaginal candidiasis1
Lower respiratory tract infection (fungal)                   Rare
Blood and lymphatic           Granulocytopenia1                                            Uncommon system disorders              Thrombocytopenia1                                            Very rare Dermatitis allergic1                                         Uncommon Immune system disorders       Hypersensitivity reactions, including erythema, lips, Rare face, eye and pharyngeal oedema
Endocrine disorders           Adrenal suppression1                                         Very rare Metabolism and nutrition      Hypokalaemia, hyperglycaemia                                 Uncommon disorders                     Decreased appetite                                           Rare Restlessness1                                                Uncommon Psychomotor hyperactivity1, sleep disorders1, anxiety,
Frequency not
Psychiatric disorders         depression1, aggression1, behavioural changes known
(predominantly in children) 1
Insomnia                                                     Rare
MedDRA system organ
Adverse reaction                                   Frequency class
Headache                                                              Common Nervous system disorders            Tremor, dizziness, dysgeusia1, hypoaesthesia1                         Uncommon Hypersomnia                                                           Rare Frequency not
Vision, blurred1 (see also section 4.4)
Eye disorders                                                                                             known Glaucoma1, cataract1                                                          Very rare Ear and labyrinth disorders Otosalpingitis1                                                               Uncommon Atrial fibrillation, electrocardiogram QT prolonged,
Uncommon tachycardia, tachyarrhythmia1, palpitations
Cardiac disorders           Angina pectoris (stable1 and unstable), extrasystoles (ventricular1 and supraventricular), nodal rhythm,                            Rare sinus bradycardia
Hyperaemia1, flushing1, hypertension                                          Uncommon Vascular disorders
Extravasation blood                                                           Rare Dysphonia                                                                     Common Asthmatic crisis1, cough, productive cough1, throat
Uncommon irritation, epistaxis1, pharyngeal erythema
Respiratory, thoracic and
Bronchospasm paradoxical1, exacerbation of asthma,
mediastinal disorders oropharyngeal pain, pharyngeal inflammation, dry                              Rare throat
Dyspnoea1                                                                     Very rare Diarrhoea1, dry mouth, dysphagia1, nausea, dyspepsia1,
Gastrointestinal disorders  burning sensation of the lips1, dental caries1,                               Uncommon (aphthous) stomatitis
Skin and subcutaneous       Rash1, urticaria, pruritus, hyperhidrosis1                                    Uncommon tissue disorders            Angioedema1                                                                   Rare Muscle spasms, myalgia, pain in extremity1,
Musculoskeletal and                                                                                       Uncommon musculoskeletal chest pain1 connective tissue disorders
Growth retardation1                                                           Very rare Renal and urinary
Dysuria, urinary retention, nephritis1                                        Rare disorders
General disorders and       Fatigue1                                                                      Uncommon administration site                 Asthenia                                                              Rare conditions                          Oedema peripheral      1
Very rare
C-reactive protein increased1, platelet count increased1, free fatty acids increased1, blood insulin
Uncommon increased1, blood ketone body increased1, cortisol
Investigations decreased1
Blood pressure increased1, blood pressure decreased1                  Rare Bone density decreased1                                               Very rare 1 Adverse reactions reported in the SmPC of at least one of the individual components, but not observed as adverse reactions in the clinical development of Trimbow

Among the observed adverse reactions the following are typically associated with: 
Beclometasone dipropionate
Pneumonia, oral fungal infections, lower respiratory tract infection fungal, dysphonia, throat irritation, hyperglycaemia, psychiatric disorders, cortisol decreased, blurred vision.

Formoterol
Hypokalaemia, hyperglycaemia, tremor, palpitations, muscle spasms, electrocardiogram QT prolonged, blood pressure increased, blood pressure decreased, atrial fibrillation, tachycardia, tachyarrhythmia, angina pectoris (stable and unstable), ventricular extrasystoles, nodal rhythm.
Glycopyrronium
Glaucoma, atrial fibrillation, tachycardia, palpitations, dry mouth, dental caries, dysuria, urinary retention, urinary tract infection.

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
Additionally, you should also report to Kamada LTD to email address: pharmacovigilance@kamada.com