SERETIDE EVOHALER. Salmeterol/fluticasone propionate

Transcription

1 Abbreviated Prescribing Information based on the International Prescribing Information and prepared to meet the requirements of the GSK International Pharmaceutical Promotional and Marketing Policy. SERETIDE EVOHALER Salmeterol/fluticasone propionate Composition: Each single actuation of Seretide provides: Salmeterol xinafoate equivalent to 25 micrograms of salmeterol and 50, 125 or 250 micrograms of fluticasone propionate. Indications: Seretide is recommended for regular asthma therapy, in cases where the administration by inhalation of a medicine combining a corticosteroid therapy and a long-term beta-2 agonist bronchodilator is justified: for patients insufficiently controlled by inhaled corticosteroid therapy and the use of a short-term beta-2 agonist bronchodilator by as needed inhalation or for patients controlled by the administration of inhaled corticosteroid therapy combined with a concurrent therapy by inhaled longterm beta-2 agonist. Dosage and Administration: By inhalation only. It is advisable to inform the patient that, in order to get an optimal effect of the therapy, Seretide must be administered daily even when the symptoms are improved.when the symptoms are controlled by the lowest effective dose twice a day, the administration of inhaled corticosteroid alone should be then considered. The dose may be reduced to be once a day, if the physician deems necessary to maintain a long acting beta-2 agonist therapy to control the symptoms. The delivery times of Seretide should be according to the frequency of symptoms. If the predominance of symptoms is at night, Seretide should be administered in the evening; and if it is during the day, Seretide should be administered in the morning. Asthma: Adults and adolescents of 12 years and above: Two inhalations of 50 µg of Fluticasone Propionate and 25 µg of Salmeterol twice a day Or Two inhalations of 125 µg of Fluticasone Propionate and 25 µg of Salmeterol twice a day. Seretide may be considered in a probationary short-term initiation therapy for adults and adolescents with mild persistent asthma and for those where it is necessary to receive a quick control of asthma. In such cases, the recommended initial dosage of the two inhalations of 25 mcg of Salmeterol and 50 mcg of Fluticasone Propionate, twice a day. When asthma is controlled, the therapy must be reassessed in order to reduce the therapy to inhaled corticosteroid alone. It is important to follow up on the patients regularly while reducing the therapy. The 50 mcg/ 25 mcg Seretide dose is not appropriate for adults and children suffering from severe asthma; the appropriate dose of inhaled corticosteroids must be asdjusted individually before establishing a therapy by fixed combination for patients suffering from severe asthma. Children of 4 years and above: Two inhalations of 50 µg of Fluticasone Propionate and 25 µg of Salmeterol twice a day. For children, the maximum recommended inhaled dose of Fluticasone Propionate is 100 mcg, twice a day. No data is available concerning the use of Seretide for children under 4 years. Children under 12 may encounter difficulties in coordinating the release of the inhalation device with their breathing. The use of an inhalation chamber with Seretide suspension for inhalation in a pressurized canister is recommended for patients suffering or likely to suffer from problems in coordinating their breathing with the release of the inhalation device. A recent clinical study showed that pediatric patients having used an inhalation chamber obtained a similar exposure to that of adults not having used an inhalation chamber and to that of pediatric patients having used a Diskus device, which confirms

2 that inhalation chambers compensate a bad inhalation technique. Population at risk: It is not possible to adjust the doses for elderly or those suffering from renal failure. No data is provided concerning the use of Seretide by patients suffering from liver failure. Contraindications: Seretide is contraindicated in patients with a history of hypersensitivity to any of the ingredients. Warnings and Precautions: The adaptation of an anti-asthmatic therapy is ensured by levelling off according to the clinical status of the patient who will be regularly assessed in a medical follow-up and the control of the breathing function. Seretide is not adapted to the therapy of asthma crises and episodes of paroxysmal dyspnoea. In such cases, the patient should resort to a fast and short-acting bronchodilator to treat the acute symptoms. The patient should be advised to be provided at all times with a fast and short-acting bronchodilator medicine intended to be used in case of asthma crisis. The therapy using Seretide should not be initiated during the exacerbation phase, neither in case of significant aggravation nor of acute deterioration of asthma.unfavourable serious events associated with asthma and exacerbations may occur during therapy using Seretide. It is advisable to tell the patients that if the asthma symptoms continue or aggravate during the therapy using Seretide, they must continue the therapy and seek medical advice from their physician. An increase in the consumption of fast and short-acting bronchodilators for treatment of symptoms is a sign of destabilisation of the disease. In such case, the patient should consult his physician. A more or less quick deterioration of the symptoms control should raise concern about a development into an acute asthma that may put at stake the vital prognosis and, accordingly, require an urgent medical consultation. It is advisable then to increase the corticosteroids therapy. And if still insufficient control of symptoms following the therapy using Seredite, a medical consultation is required and the prescription of an additional corticosteroid therapy should be considered. Once the asthma symptoms are under control, a progressive decrease of the Seredite dose should be done. It is important that the patients be monitored regularly during the decrease of therapy. The minimum effective dose of Seredite must be used. The therapy using Seredite should not be abruptly interrupted. Just like other corticosteroids intended to be administered by inhalation, Seretide must be used carefully for patients suffering from pulmonary tuberculosis. Seretide may rarely cause disorders of the heart rhythm such as supra ventricular tachycardia, extra systolic and auricular fibrillation, as well as moderate and transitory hypokalemia in high therapeutic doses. Hence, Seretide must be used with care in case of serious cardiovascular pathology, disorders of heart rhythm, diabetes, hyperthyroidism, uncorrected hypokaliemia or patients likely to have hypokaliemia. Increase of glycemia is very rarely reported. This must be taken into account upon prescribing to diabetic patients. As it is with other inhaled products, the increase of bronchial wheeze, sign of bronchial spasm after the inhalation of the powder, should lead to stop the therapy using Seretide and the patient s clinical examination. The therapy should be re-evaluated, otherwise, a therapeutic alternative. Precautions should be taken during the relay of the general corticosteroids therapy using Seretide especially for patients likely to show signs of altered adrenal function. The inhaled corticosteroids therapy may cause systemic effects, particularly during long-term high dosage therapies. The occurrence of such effects remains however less probable than during oral corticosteroid therapy. Cushing syndrome may occur, Cushingoid features, inhibition of the adrenal function, decrease of the bones mineral density, cataract and glaucoma. Accordingly, the patient should be regularly monitored and the minimum effective dose must be always investigated. The extended administration of high doses of inhaled

3 corticosteroids may result in an inhibition of the adrenal function by favouring the occurrence of acute adrenal suppresion. Cases of inhibition of adrenal function and acute adrenal suppression have also been very rarely described with Fluticasone Propionate doses ranging between 500 and 1000 mcg. The adrenal suppresion crises may be caused by a trauma, surgery, infection or any quick reduction of dosage. The clinical table is generally atypical and may contain anorexia, abdominal ache, weight loss, fatigue, headaches, nausea, vomiting, hypotension, consciousness troubles, hypoglycemia and convulsions. In case of stress or when a surgery is planned, a corticosteroid therapy of general supplementation may be required. Fluticasone Propionate and salmeterol are essentially absorbed by the lungs. The use of an inhalation chamber associated to the metered inhaler may increase the dosage of the product delivered to the lung, which may increase the risk of occurrence of systemic undesirable effects. Kinetic data of single dose have shown a systemic exposure twice more significant when Seretide is administered using AeroChamber Plus inhalation chamber compared to the Volumatic inhalation chamber. The administration of Fluticasone Propionate by inhalation favours the reduction of resorting to oral corticosteroids to treat asthma, but it does not avoid the risk of adrenal suppresion during withdrawal using oral corticosteroid therapy for long-termtreatment patients. Such risk exists as well for patients having received strong doses of corticosteroids as a matter of urgency. The risk of persistent inhibition of adrenal functions should remain in mind in the emergency cases and/ or likely to set off in a stress condition. An adapted substitutive corticosteroid therapy should be envisaged. The advice of a specialist may be required. Ritonavir may significantly increase the plasma concentrations of Fluticasone Propionate. As a consequence, unless the expected benefit for the patient is not higher than the systemic effects of the corticosteroid therapy, it is advisable to avoid the concomitant administration. The risk of systemic effects of the corticosteroid therapy is also increased in case of concomitant administration of Fluticasone Propionate with other strong inhibitors of cytochrome P450 3A4. An increase in cases of low respiratory infections (particularly pneumonia and bronchitis) has been observed in a study carried over 3 years (TORCH study) for patients suffering from COPD and treated by Seretide, compared to those receiving a placebo. In this study, the risk of developing pneumonia, irrespective of the therapy, was at its highest levels at elderly patients, the patients with a low index of body mass (<25 Kg/m2) and those suffering from a very serious disease (VEMS < 30% of the theoretical value). It is advisable to stay alert to the possible occurrence of pneumonia or other low respiratory infections at patients suffering from chronic obstructive pulmonary disease (COPD) because the clinical manifestations of an infection are often mixed up with a simple exacerbation. The occurrence of pneumonia at a subject suffering from COPD at a serious stage should lead to re-evaluate the therapy by Seretide. Data resulting from a large-scale clinical trial ( Salmeterol Multi-Center Asthma Research Trial, SMART ) suggested an increase of the risk of occurrence of serious undesirable respiratory events or the death caused by respiratory reasons at Afro-American patients treated by salmeterol compared to placebo. One could not tell if such observations were originally pharmaco-genetic or resulting from other inter-current factors. If the symptoms of asthma persist or aggravate during the therapy by Seretide, the patients of black African or African Caribbean origin should continue their therapy by Seretide and should urgently seek the advice of their physician. The concomitant administration of ketoconazole systemically increases the systemic exposure to salmeterol significantly, which may result in an increase of the risk of occurrence of the systemic effects (for example:

4 extended QTc interval and palpitations). Consequently, it is advisable to avoid the concomitant administration of ketoconazole or other strong inhibitors of cytochrome P450 3Q4 unless the expected benefits are higher than the potential risk of occurrence of systemic effects of salmeterol. Athletics should pay attention to the fact that the product contains two active principles capable of inducing a positive reaction of the tests practiced during dope tests. Long acting Beta 2 adrenergic agonist (salmetrol) increases the risk of life threatening asthma episodes or asthma related deaths. Pediatric population Children and teenagers under 16 who receive strong doses of Fluticasone Propionate (generally 1000 mcg per day) are particularly at risk. Systemic effects may occur, particularly during therapy with strong long acting doses. Cushing syndrome may be observed, or Cushingoid features, inhibition of adrenal function, acute adrenal suppresion and growth delay for children and teenagers. The growth of children receiving a longterm inhaled corticosteroid therapy must be regularly monitored. The inhaled corticosteroid therapy must be reduced to the least dose ensuring an efficient control of asthma. Interactions: Beta-blockers, selective or not, must be avoided at patients suffering from asthma unless absolutely required. The concomitant administration of other beta-adrenergic may increase the potential beta-2-mimetic effects. Fluticasone Propionate: Under normal conditions of use, the plasma concentrations of Fluticasone Propionate reached after the inhaled administration are poor due to a significant due to extensive first pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the gut and live. Consequently, the risk of clinically significant interactions with Fluticasone Propionate are unlikely. Nevertheless, an interaction study with healthy volunteers receiving pernasal Fluticasone Propionate showed that ritonavir (very strong inhibitor of cytochrome P450 3A4) at the dose of 100 mg twice a day increased by several hundred times the plasma concentrations of Fluticasone Propionate, leading to a considerable decrease of concentrations in plasma cortisol. There are no data to document the interaction with Fluticasone Propionate administered by inhalation, but a considerable increase of plasma concentrations is expected; cases of Cushing and inhibition syndrome of the adrenal function have been reported. So, it is advisable to avoid the concomitant administration of Fluticasone Propionate and ritonavir, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects. A small-size study carried out on healthy volunteers showed that ketoconazol, a bit less strong inhibitor of cytochrome P450 3A4 increased by 150% the systemic exposure of an inhaled Fluticasone Propionate dosage. The reduction of plasma cortisol was more significant than that observed after the administration of Fluticasone Propionate alone. An increase of the systemic exposure and the systemic undesirable effects is expected in case of concomitant administration of other strong inhibitors of cytochrome P450 3A4 (eg: itraconazol). Discretion is recommended and long-term therapy associating this type of medicines must be avoided as much as possible. Salmeterol: Strong inhibitors of cytochrome P450 3A4: The concomitant administration of ketoconazol (400 mg orally once per day) and salmeterol (50 µg inhaled twice per day) at 15 healthy volunteers for 7 days resulted into a significant increase of plasma concentrations of salmeterol (Maximum concentration (Cmax) increased by 1.4 factor and area under (ASC) curve increased by 15 factor). This observation suggests an increase of the risk of occurrence of systemic effects of salmeterol, such as extended QT interval and palpitations, compared to the administration of salmeterol or ketoconazol alone. No significant clinical effect was observed on blood pressure, heart rate, glycemia and kaliemia. The concomitant administration of ketoconazol did not result from the extension of the elimination of the

5 salmeterol half-life or the accumulation thereof after repeated administrations. It is advisable to avoid the association of ketoconazol with a therapy using salmeterol unless the expected benefits are higher than the potential risk of occurrence of systemic effects of the salmeterol. A risk of interaction of the same class is expected with other strong inhibitors of cytochrome P450 3A4 (for example with itraconazol, telithromycine, ritonavir). Moderate inhibitors of cytochrome P450 3A4: The concomitant administration of erythromycine (500 mg orally three times per day) and salmeterol (50 µg inhaled twice per day) at 15 healthy volunteers for 6 days has resulted into a slight increase, but not statistically significant, plasma concentrations of salmeterol (Cmax increased by 1.4 factor and ASC increased by 1.2 factor). No serious undesirable effect has been associated with the concomitant administration with erythromycine. Pregnancy and Lactation: Seretide should not be used during pregnancy unless the expected benefit for the mother outweighs any eventual risk for the foetus. It is advisable for pregnant women to always seek the minimal effective dosage of Fluticasone Propionate ensuring a satisfactory control of the asthma symptoms. A risk for breastfed new born/infants may not be excluded. The decision to interrupt breastfeeding or treating by Seretide should be made according to the expected benefit of maternal breastfeeding for the child compared to that of the therapy for the breastfeeding mother. Effects on Ability to Drive and Use Machines: No studies to assess the effects of this medicine on the aptitude to drive vehicles and use machines. Adverse Reactions: Organic classes Undesirable effects Frequency Infections and Infestations Mouth and pharyngeal candida Pneumonia 1,3,5 Bronchitis 1,3 Immunity system disorders Hypersensitivity reactions of the following types: Hypersensitivity cutaneous reactions Angi-oedema (mainly facial and oropharyngeal oedema), breathing symptoms (dyspnea and/or broncho-spasm), anaphylactic reactions including anaphylactic shock. Endocrine disorders Cushing Syndrome, Cushingoid features, inhibition of adrenal function, growth retardation in children and teenagers, reduction of the bones mineral density uncommon 4 Metabolic and nutritional disorders Hypokaliemia 3 Hyperglycemia 4 Psychiatric disorders Anxiety, sleep disorders and behaviour changes including hyperactivity and irritability (especially in children)

6 Neural system disorders Head aches Very common 1 Shaking Ocular disorders Cataract, glaucoma 4 Heart disorders Palpitations Tachycardia Heart arrhythmia (including auricular fibrillation, supraventricular and extrasystol tachycardia) uncommon Breathing, thoracic and mediastinal disorders Rhino-pharyngitis Very common 2,3 Pharyngeal discomfort Voice hoarseness/ dysphonia Sinus 1,3 Paradoxal bronchospasm 4 Cutaneous and sub-cutaneous disorders Muscle-skeletal and systemic disorders Contusion 1,3 Muscle cramps Traumatic fractures 1,3 Arthralgia Myalgia Storage: should not be stored above 30 C. Protect from frost and direct sunlight. Full Prescribing Information is available on request. Please read the full prescribing information prior to administration. AFSAPS/2013.