Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Undesirable effects which have been associated with Flutiform inhaler during clinical development are given in the table below, listed by system organ class. The following frequency categories form the basis for classification of the undesirable effects as: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1,000 and <1/100), rare (≥1/10,000 < 1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.



System Organ Class               Adverse Event                         Frequency 
Infections and Infestations      Oral candidiasis                      Rare Oral fungal infections
Sinusitis
Metabolism and Nutrition         Hyperglycaemia                        Rare Disorders
Psychiatric Disorders            Sleep disorders including insomnia    Uncommon 

Abnormal dreams                       Rare
Agitation


Psychomotor hyperactivity, anxiety,   Not known depression, aggression, behavioural changes (predominantly in children)
Nervous System Disorders         Headache                              Uncommon Tremor
Dizziness
Dysgeusia                             Rare

Eye disorders                    Vision blurred                        Not known 
Ear and labyrinth disorders      Vertigo                               Rare Cardiac Disorders                Palpitations                          Uncommon Ventricular extrasystoles
Angina pectoris                       Rare
Tachycardia
Vascular disorders               Hypertension                          Rare Respiratory, Thoracic and        Exacerbation of asthma                Uncommon Mediastinal Disorders            Dysphonia
Throat irritation
Dyspnoea                              Rare
Cough
Gastrointestinal disorders       Dry mouth                             Uncommon 
Diarrhoea                             Rare
Dyspepsia
Skin and subcutaneous tissue     Rash                                  Uncommon disorders
Pruritus                              Rare
Musculoskeletal and              Muscle spasms                         Rare Connective Tissue Disorders
General disorders and            Peripheral oedema administration site conditions   Asthenia                              Rare 


As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid- acting inhaled bronchodilator and should be treated straight away. Flutiform inhaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Since Flutiform inhaler contains both fluticasone propionate and formoterol fumarate, the same pattern of undesirable effects as reported for these substances may occur. The following undesirable effects are associated with fluticasone propionate and formoterol fumarate, but have not been seen during the clinical development of Flutiform inhaler:

Fluticasone propionate:
Hypersensitivity reactions including, urticaria, pruritus, angiooedema (mainly facial and oropharyngeal), anaphylactic reactions. Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These may include Cushing’s Syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma, contusion, skin atrophy and susceptibility to infections. The ability to adapt to stress may be impaired. The systemic effects described, however, are much less likely to occur with inhaled corticosteroids than with oral corticosteroids. Prolonged treatment with high doses of inhaled corticosteroids may result in clinically significant adrenal suppression and acute adrenal crisis. Additional systemic corticosteroid cover may be required during periods of stress (trauma, surgery, infection).

Formoterol fumarate:
Hypersensitivity reactions (including hypotension, urticaria, angioneurotic oedema, pruritus, exanthema), QTc interval prolongation, hypokalaemia, nausea, myalgia, increased blood lactate levels. Treatment with β2 agonists such as formoterol may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.

Hypersensitivity reactions have been reported in patients using inhaled sodium cromoglicate as an active ingredient. Whilst Flutiform inhaler contains only a low concentration of sodium cromoglicate as an excipient, it is unknown if hypersensitivity reactions are dose dependent.

In the unlikely event of a hypersensitivity reaction to Flutiform inhaler, treatment should be initiated in accordance with standard treatment for any other hypersensitivity reaction, which may include the use of antihistamines and other treatment as required. Flutiform inhaler may need to be discontinued immediately and an alternative asthma therapy may need to be initiated if necessary.



Dysphonia and candidiasis may be relieved by gargling or rinsing the mouth with water or brushing the teeth after using the product. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst continuing the treatment with Flutiform inhaler.

Paediatric population
Possible systemic effects as reported for the individual components of Flutiform inhaler include Cushing's syndrome, Cushingoid features, adrenal suppression and growth retardation in children and adolescents. Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability. Studies conducted with Flutiform inhaler demonstrated similar safety and tolerability profile as compared to fluticasone monotherapy in children aged 5-12 years and fluticasone/salmeterol in children aged 4-12. Long term treatment with Flutiform inhaler for 24 weeks in 208 children did not show any indication of growth retardation or adrenal suppression. Another pharmacodynamic study conducted in children aged 5-12 years showed similar lower leg growth rate as measured by knemometry after treatment with Flutiform inhaler as compared to fluticasone monotherapy for 2 weeks.


Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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