VI.2 Elements for a Public Summary Fluticasone propionate / formoterol fumarate are available in pressarised metered dose inhalers (pmdi) under the brand names Flutiform, and in breath actuated inhalers under the brand names Flutiform K-Haler, Affera K-Haler, Abriff K-Haler. Within this sumamary these are referred to simply as Flutiform. VI.2.1 Overview of disease epidemiology Asthma, one of the most common chronic diseases in the world, affects around 300 million people worldwide. A recent study found that 4 out of 100 people will have been diagnosed with asthma worldwide. However, the estimates differ across countries and regions, ranging from 2 out of 1000 in China to 2 out of 10 people in Australia and Sweden. Around half of those diagnosed with asthma will have experienced an asthma attack in the past 12 months. The severity of asthma can be classified using a measure of how well the disease is treated and controlled, or the frequency and severity with which symptoms occur. A study looking at patients diagnosed with asthma found that only a third of patients in the UK had their asthma well controlled. VI.2.2 Summary of treatment benefits Overall, 22 clinical studies were conducted in approximately 6,000 patients. 225 of these patients were adolescents. In five 8 to 12-week studies in 2447 patients fluticasone propionate / formoterol fumarate showed better efficacy compared to fluticasone alone with regards to lung function, asthma symptoms, asthma exacerbations and study discontinuations due to lack of efficacy. Three of these studies also showed a better efficacy of compared to formoterol alone. In an 8-week study in 620 patients fluticasone propionate / formoterol fumarate showed comparable efficacy to the combination of fluticasone propionate and formoterol fumarate when administered as separate inhalers with regards to the same measurements. In two further 12- week studies in 481 patients the efficacy and safety of fluticasone propionate / formoterol fumarate was comparable to that of Seretide and Symbicort which are two commonly used medications in asthma. Two studies in 752 patients confirmed the long term efficacy and safety of fluticasone propionate / formoterol fumarate over 6 to 15 months. The rates of asthma exacerbations and discontinuations due to lack of efficacy were very low. Improvements in lung function were sustained over the entire treatment period. In a 12-week study including a 6-month extension phase in 210 children aged 4 to 12 years Fluticasone propionate / formoterol fumarate showed comparable efficacy and safety to Seretide. 205 patients completed the 6-month extension phase during which fluticasone propionate / formoterol fumarate was safe and well tolerated. An additional comparative study included a further 274 children aged 5 to 12 years providing further support that fluticasone propionate / formoterol fumarate was safe and well tolerated. VI.2.3 Unknowns relating to treatment benefits In studies most patients were white, aged between 4 and 81 and suffering from mild to severe asthma. It is unlikely that results would be different in non-white patients. No information is available for use in patients with liver or kidney disease. RMP Fluticasone propionate/formoterol fumarate breath-actuated inhaler Version 4.0, 29 Sep 2016 120
VI.2.4 Summary of safety concerns Important identified risks Part VI. Table 3 Summary of safety concerns Important identified risks Risk What is known Preventability An irregular heart beat (cardiac arrhythmias) Problems with the blood flow to your heart (Cardiac ischaemia / ischemic heart disease, IHD) Increase in the amount of sugar in the blood (hyperglycaemia) Asthma exacerbations are expected under treatment with fluticasone propionate / formoterol fumarate inhaler (Flutiform) since this medication is used in asthma and some patients may experience worsening of their asthma. Sleeping problems, depression or feeling worried, aggression, anxiety, restlessness, nervousness, overexcitment or irritability (psychological or behavioural effects). The term cardiac arrhythmia covers a very large number of very different conditions. Most arrhythmias are harmless, but some can be serious or even life threatening. Patients with underlying history of cardiovascular disease are an identified risk group. Probably less than 1 in 100 people using this inhaler experienced an irregular heartbeat or palpitations. And probably less than 1 in 1000 people using this inhaler are affected by fast heartbeat followingg use of this inhaler. Ischemic heart disease or myocardial ischaemia is potentially lifethreatening. Patients with underlying history of ischaemic heart disease are an identified risk group. Probably less than 1 in 1000 people using this inhaler are affected by chest pain associated with heart disease. Patients with underlying history of diabetes mellitus are an identified risk group. An increase in the amount of sugar in the blood affects probably less than 1 in 100 people using this inhaler. Probably less than 1 in 100 people using this inhaler experience worsening of asthma. Some psychological and behavioural effects have been associated with use of the steroid component fluticasone propionate in fluticasone propionate / formoterol fumarate inhaler. These have not been reported with Flutiform and the frequency these effects occur with is not known. These effects are more likely to occur in children. Yes: before treatment with this inhaler tell your doctor, pharmacist or asthma nurse if you have an irregular heart beat (cardiac arrhythmia) Yes: before treatment with this inhaler tell your doctor, pharmacist or asthma nurse if you have problems with the blood flow to your heart Yes: before treatment with this inhaler tell your doctor, pharmacist or asthma nurse if you have diabetes. If you are diabetic you may need to check your blood sugar more often and adjust your usual diabetic treatment. Your doctor may need to monitor you more closely. Yes: It is advised that you should use this medicine every day as directed by your doctor or asthma nurse. This medicine helps to prevent breathing problems such as asthma and helps to stop you becoming breathless and wheezy. However, it does not work if you are already having an asthma attack i.e. you are already breathless and wheezing. You will need to use a fast acting reliever medicine such as salbutamol if this happens. Yes, adhere to the guidance provided in the patient information leaflet for Flutiform inhaler, especially sections 3. How to use Flutiform inhaler and 4. Possible side effects. If any of the side effects become serious, or if you notice any other side effects affecting your behaviour or mood not listed in the patient information leaflet, please RMP Fluticasone propionate/formoterol fumarate breath-actuated inhaler Version 4.0, 29 Sep 2016 121
tell your doctor, pharmacist or asthma nurse. Important potential risks Part VI. Table 4 Summary of safety concerns Important potential risks Risk What is known (including reason why it is considered a potential risk) Allergic reactions with characteristic All medicines can cause allergic reactions, although serious symptoms of sudden swelling of the allergic reactions are reported rarely. Some drugs may cause eyelids, face, throat, tongue or lips, rash allergic reactions when people are first exposed to them. or itching especially those covering the whole body, symptoms such as dizziness, light-headedness or fainting or any sudden changes in breathing pattern such as increased wheezing or shortness of breath Poor adrenal gland function (adrenal suppression) Slowing of the rate of growth of children and adolescents (growth retardation) Changes in bone mineral density with thinning of the bones (decrease in bone mineral density) An abnormal heart trace potentially leading to an abnormal heart rhythm (QTc interval prolongation) Serious asthma- related events with severe breathlessness and wheezing. Constriction of the airways after treatment with a bronchodilator (paradoxical bronchospasm) Clouding of the lens in the eye (cataract) Increased pressure in the eye (glaucoma) Decrease in the amount of potassium in the blood (hypokalaemia) developing decreased adrenal gland function. Poor adrenal gland function means that your adrenal gland is not working properly and you may have symptoms such as headaches, weakness, tiredness, abdominal pain, loss of appetite, weight loss, dizziness, very low blood pressure, diarrhoea, feeling or being sick or fits. Flutiform inhaler contains a steroid. Children and adolescents treated with steroids may be at an increased risk of slowing of the rate of their growth. Flutiform inhaler contains a steroid. This risk is more likely to occur after oral use of steroids or prolonged high doses. developing changes in bone mineral density with thinning of the bones which means having a higher risk for fractures. Flutiform inhaler contains a steroid. The risk is more likely to occur after oral use of steroids or prolonged high doses. Patients treated with ß- agonists such as formoterol are at an increased risk of developing an abnormal heart trace potentially leading to an abnormal heart rhythm. Flutiform inhaler contains a ß- agonist (formoterol). Since Flutiform inhaler is used in asthma some patients may experience a severe worsening of their asthma. These events can be potentially life threatening and require immediate medical consultation and therapy. Paradoxical bronchospasm with an immediate increase in wheezing and shortness of breath after dosing has been reported with other asthma inhalation products. developing clouding of the lens in the eye. Flutiform inhaler contains a steroid. The risk is more likely to occur after oral use of steroids or prolonged high doses. developing increased pressure in the eye. Flutiform inhaler contains a steroid. The risk is more likely to occur after oral use of steroids or prolonged high doses. Patients treated with ß- agonists such as formoterol are at an increased risk of developing decrease in the amount of potassium in the blood which can cause muscle weakness, RMP Fluticasone propionate/formoterol fumarate breath-actuated inhaler Version 4.0, 29 Sep 2016 122
Use of fluticasone propionate / formoterol fumarate inhaler (Flutiform) in other indications such as chronic obstructive lung disease, younger children or for acute asthma attacks (Off-label use) twitching or abnormal heart rhythm. Flutiform inhaler contains a ß- agonist (formoterol). Children below 5 years should not use Flutiform inhaler as there is limited data on the safety of use in children. Currently Flutiform inhaler is not approved for use in children aged 5 to 12 years of age. The same applies to patients suffering from chronic obstructive lung disease. Flutiform inhaler should further not be used as treatment of acute asthma attacks (reliever treatment). Missing information Part VI. Table 5 Summary of safety concerns Missing information Risk What is known Limited information on use in patients with liver impairment Limited information on use in patients with kidney impairment Current smoking history Long-term safety and efficacy of the new combination of fluticasone and HFA 227 (propellant) The use of Flutiform inhaler in subjects with liver impairment has not been investigated during its clinical development programme. Such patients should be regularly monitored. The use of Flutiform inhaler in subjects with kidney impairment has not been investigated during its clinical development programme. Such patients should be regularly monitored. Smokers may require higher doses of steroids to achieve the same effect of the asthma treatment than non- smokers. The use of Flutiform inhaler in smokers has not been investigated during its clinical development programme. Flutiform inhaler is the first asthma inhaler product using the propellant component HFA227 together with the corticosteroid fluticasone. VI.2.4 Summary of risk minimisation measures by safety concern All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PL). The measures in these documents are known as routine risk minimisation measures. The Summary of Product Characteristics and the Package leaflet for Flutiform can be found on the Flutiform EPAR page, and for Flutiform K-Haler in the Flutiform K-Haler EPAR page, on the EMA website. There are no additional risk minimisation measures. RMP Fluticasone propionate/formoterol fumarate breath-actuated inhaler Version 4.0, 29 Sep 2016 123
VI.2.5 Planned post authorisation development plan Part VI. Table 7 List of studies in post authorisation development plan Study/ activity Objectives Safety concerns addressed Status PASS: FLT9501 Title: Flutiform a new combination in the treatment of asthma in real life setting. Noninterventional study on safety and effectiveness Short title: ffairness Primary objectives: Safety and effectiveness of Flutiform [fluticasone propionate / formoterol fumarate] prescribed for outpatients aged 12 years with asthma: Evaluation of the safety and effectiveness (efficacy under real life conditions) of fluticasone propionate / formoterol fumarate in routine clinical practice by Collection of data on the exposure to Flutiform [fluticasone propionate / formoterol fumarate] and evaluation of asthma control and the frequency of adverse events associated with Flutiform [fluticasone propionate / formoterol fumarate], or which are known to be side effects of treatment with ICS/LABA combination drugs. All adverse events reported spontaneously or after physicians open question by the patients as well as adverse events detected by diagnostic procedures during routine clinical practice at the physicians discretion will be recorded. The primary efficacy parameter will be asthma control under therapy with Flutiform [fluticasone propionate / formoterol fumarate], assessed by comparing the ACTTM, total score, between baseline and end of study. Secondary objectives: Secondary objectives are to evaluate the effectiveness of Flutiform [fluticasone propionate / formoterol fumarate] treatment on asthma control by further parameters (e.g. daytime/nighttime symptoms, exacerbation rate, use of asthma related rescue medication) and by lung function parameters. In addition, the NIS shall provide deeper insights in the course of the therapy with Flutiform [fluticasone propionate / formoterol fumarate] over one year with regard to dose adjustments, changes in asthma-related co-medication and discontinuation due to lack of efficacy as well as the patients and the physicians satisfaction with the Flutiform [fluticasone propionate / formoterol fumarate]therapy. All important identified and potential risks and missing information Current smoking history and Long-term safety and efficacy of the new combination of fluticasone and HFA 227 (propellant). Ongoing Date for submission of interim or final reports Submission of data within 6 months after LPLV. (Q2 2016). RMP Fluticasone propionate/formoterol fumarate breath-actuated inhaler Version 4.0, 29 Sep 2016 124
Study/ activity Objectives Safety concerns addressed Status PASS: FLT9503 Title: A Non interventional post authorisation study to determine the safety and effectiveness of Flutiform (Affirm Study). Short title Assessment of fluticasone/ formoterol In Real life Maintenance treatment (Affirm). Primary objectives: Evaluation of the safety of Flutiform in routine clinical practice by Collection of data on the exposure to Flutiform and the frequency of adverse events associated with Flutiform, or which are known to be side effects of treatment with ICS/LABA combination drugs. Recording all adverse events reported spontaneously or after physicians open question by the subjects as well as adverse events detected by diagnostic procedures during routine clinical practice at the physicians discretion. Secondary objectives: Secondary objectives are to evaluate the effectiveness of Flutiform treatment under real life conditions on asthma control by comparing the Asthma Control Test (ACTTM) total score between baseline and end of study and further parameters (e.g. exacerbation rate, use of asthma related rescue medication, asthma symptoms and sleep disturbance from the ACT sub scores, consultations and hospitalisations due to asthma, days of absence from work/school/college or inability to perform everyday activities due to asthma) and by lung function parameters. In addition, the study shall provide deeper insights in the course of the therapy with Flutiform over one year with regard to dose adjustments, changes in asthma-related co-medication and discontinuation due to lack of efficacy as well as the subjects and the physicians satisfaction with the Flutiform therapy. All important identified and potential risks and missing information Current smoking history and Long-term safety and efficacy of the new combination of fluticasone and HFA 227 (propellant). Finished recruiting Date for submission of interim or final reports 30SEP2016 RMP Fluticasone propionate/formoterol fumarate breath-actuated inhaler Version 4.0, 29 Sep 2016 125
Study/ activity Objectives Safety concerns addressed Status Evaluation of realworld prescribing of fixed-dose combination inhaled corticosteroid / long-acting ß2- agonist (ICS/LABA) fluticasone propionate / formoterol (FP/FOR) and adverse events in routine primary care Sub-title: Characterisation of real-world FP/FOR prescribing and adverse events [CPRD study] (1) To characterise real-world prescribing of FP/FOR [fluticasone propionate / formoterol fumarate] as used in clinical practice and to identify and quantify prevalence of off-label prescribing. (2) To evaluate the adverse event rates in patients prescribed FP/FOR on and off label (3) To compare adverse event rates in patients prescribed FP/FOR on and off label with rates in appropriate matched controls. All important identified and potential risks and missing information Off-label use and Long-term safety and efficacy of the new combination of fluticasone and HFA 227 (propellant). Date for submission of interim or final reports Ongoing Final Q4 2016 RMP Fluticasone propionate/formoterol fumarate breath-actuated inhaler Version 4.0, 29 Sep 2016 126