Adverse reactions : תופעות לוואי

4.8   Undesirable effects
a.    Summary of the safety profile

Many of the listed undesirable effects can be assigned to the anticholinergic properties of tiotropium bromide or to the ß2-adrenergic properties of olodaterol, the components of Spiolto Respimat 

b.    Tabulated summary of adverse reactions
The frequencies assigned to the undesirable effects listed below are based on the crude incidence rates of adverse drug reactions (i.e. events attributed to Spiolto Respimat) observed in the tiotropium 5 microgram/olodaterol 5 microgram dose group (5646 patients), pooled from 8 active or placebo- controlled, parallel group clinical trials in COPD patients with treatment periods ranging between 4 and 52 weeks.

Adverse reactions reported in all clinical trials with Spiolto Respimat are shown below according to system organ class.
These also include all adverse reactions previously reported with one of the individual components.

Frequency is defined using the following convention:
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) 

System Organ Class              Adverse reaction                     Frequency 
Infections and infestations     Nasopharyngitis                      not known Metabolism and nutrition        Dehydration                          not known disorders
Nervous system disorders        Dizziness                            uncommon Insomnia                             Rare
Headache                             uncommon
Eye disorders                   Vision blurred                       rare Glaucoma                             not known
Intraocular pressure increased       not known
Cardiac disorders               Atrial fibrillation                  rare Tachycardia                          uncommon
Palpitations                         rare
Supraventricular tachycardia         rare
Vascular disorders              Hypertension                         rare 

Spiolto Respimat                                             Approved prescribing information Inhalation solution                                          May 2019 Respiratory, thoracic and           Cough                                  uncommon mediastinal disorders
Dysphonia                              uncommon
Laryngitis                             rare
Pharyngitis                            rare
Epistaxis                              rare
Bronchospasm                           rare
Sinusitis                              not known
Gastrointestinal disorders          Dry mouth                              Uncommon Constipation                            rare
Oropharyngeal candidiasis              rare
Gingivitis                             rare
Nausea                                 rare
Intestinal obstruction                 not known
Ileus paralytic
Dysphagia                            not known
Gastrooesophageal reflux               not known
disease
Glossitis                             not known
Stomatitis                             Rare
Dental caries                          not known
Skin and subcutaneous               Hypersensitivity                       rare tissue disorders, Immune
system disorders                    Angioedema                             rare Urticaria                              rare
Pruritus                               rare
Anaphylactic reaction                  not known

Rash                                   rare

Skin infection and skin ulcer          not known
Dry skin                               not known
Musculoskeletal and                 Arthralgia                             rare connective tissue disorders
Back pain1                             rare
Joint swelling                         rare
Renal and urinary                   Urinary retention                      rare disorders
Urinary tract infection                rare
Dysuria                                rare
1
undesirable effects reported with Spiolto Respimat, but not with the individual components 

Spiolto Respimat                                       Approved prescribing information Inhalation solution                                    May 2019

c.     Description of selected adverse reactions
Spiolto Respimat combines anticholinergic and ß2-adrenergic properties due to its components tiotropium and olodaterol.


Anticholinergic adverse reaction profile
In the long term 52-weeks clinical trials with Spiolto Respimat, the most frequently observed undesirable anticholinergic effect was dry mouth which occurred in approximately 1.3% of patients treated with Spiolto Respimat and in 1.7% and 1% in the tiotropium 5 microgram and olodaterol 5 microgram arms, respectively. Dry mouth led to discontinuation in 2 of 4,968 patients (0.04 %) treated with Spiolto Respimat.

Serious undesirable effects consistent with anticholinergic effects include glaucoma, constipation, intestinal obstruction including ileus paralytic and urinary retention.


ß-adrenergic adverse reaction profile
Olodaterol, one component of Spiolto Respimat is a member of the therapeutic class of long-acting beta2-adrenergic agonists. Therefore the occurrence of other undesirable effects related to the beta- adrenergic agonist class, which are not listed above, should be taken into consideration, such as, arrhythmia, myocardial ischaemia, angina pectoris, hypotension, tremor, nervousness, muscle spasms, fatigue, malaise, hypokalemia, hyperglycemia, and metabolic acidosis.

d. Other special populations
An increase in anticholinergic effect may occur with increasing age.

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.go v.il