Nutritional Perspective Cholesterol & the controversy continues Albert Cilia-Vincenti

recent widely publicised Lancet review of efficacy and the adverse effects (such as myopathy) can be reversed with no safety data generated more controversy than it resolved.1 Led residual ill-effects by stopping the statin, the effects of a heart Aby Professor Rory Collins of Oxford University, the review attack or stroke are often irreversible. claimed that the benefits of statins have been underestimated Dr Harlan Krumholz (Yale University), commenting on the and the risks exaggerated. Claims of statin intolerance in up to review in the BMJ,3 said that while the findings strongly support 20% of patients, the review argues, are not supported by large- the benefits of statins in comparison to modest risks, there is scale evidence from randomised trials. In fact, Collins et al. little consideration of the limitations of the trial evidence, most claim that statin therapy is no less well tolerated than placebo. notably a lack of robust data on elderly patients, individual trials Collins further claimed that the controversy about statin whose design prevented detection of many relevant harms, and intolerance and myopathy rates emerged only in the past 2 or inconsistent methods for adverse event data collection. 3 years as manufacturers began marketing newer and “very A vocal critic of the review, and an author of one of the expensive” cholesterol-lowering agents, such as, proprotein 2013 BMJ papers,4 Dr Aseem Malhotra (Lister Hospital, convertase subtilisin/kexin type 9 (PCSK9) inhibitors for Stevenage, UK) claims that the Clinical Trials Service Unit at patients classified as statin intolerant. He also pointed out that Oxford has received hundreds of millions of pounds in funding industry has funded reports on statin intolerance, as in the from statin manufacturers and that Collin’s group has not case of the European Society’s report2 which, released raw data on the major statin randomised controlled not only had funding from makers of PCSK9 inhibitors, but trials for independent scrutiny. He adds that by using also had its meetings coordinated by a commercial entity predominantly industry-sponsored trials designed for the funded by the manufacturers. purpose of determining the benefits of statins but minimising Collins claimed that one could side-effects, this review simply adds false precision to expect that 5 years of a statin regimen biased estimates. He also noted that Pfizer’s own patient that lowered LDL cholesterol by leaflet on atorvastatin states that common side-effects 2mmol/L would prevent major possibly affecting up to one in 10 people include vascular events in about 1000 of sore throat, nausea, digestive problems, muscle and 10,000 secondary-prevention joint pains. patients and about 500 of Malhotra has also co-authored a recent 10,000 primary-prevention systematic review revealing that in those patients, with a bigger patients over age 60, LDL- benefit to be expected cholesterol is not associated with lifelong statin use. with cardiovascular Moreover, he added, disease and is whereas many of inversely correlated

Volume 15, 2016 Issue 06 19 59% of children wake at Horton observed that more than 200,000 1 night due to their asthma ® ® patients were estimated to have stopped SeretideSere Evohaler taking a statin in the 6 months after 59% of children wake at 5050 mcgm from 4 years3 5 adverse media coverage following 1 with all-cause mortality. He is quick to admit that statins have publication of the disputed research a benefit, but adds that focusing on LDL lowering as if this was night due to their asthma SeretideSere ® Evohaler® the end in itself is counterproductive, especially when insulin resistance is a more important risk factor for myocardial Poppy is 50% less 5050 mcgm from 4 years3 infarction. He concludes that in his view, the Lancet review is likely to wake at night SeretideSe ® Diskus® a total whitewash, and agrees with the BMJ’s editor-in-chief, 1001 mcg from 4 years4 Fiona Godlee, who described it as “the trialists making their when using Seretide own homework”. compared to baseline2 It turns out that Godlee and Collins have been at odds ever since Collins called on the BMJ to correct and ultimately withdraw the two 2013 studies that repeated claims made in a 6 paper by Abramson et al. that side-effects of statins occur in 18% dense particle LDL – with only the latter being related to to 20% of people. The BMJ corrected the statements in the two Help Poppy by prescribing Seretide atherosclerosis. Routine LDL measurements do not indicate Poppy is 50% less studies, but Godlee passed the decision, on whether to retract, on whether moderately raised LDL is due to a raised large or Seretide is the only ICS/LABA proven to achieve to an independent expert panel, which rejected Collins’s request small sub-fraction. The surrogate marker for a raised small guideline-defi ned asthma control in children2 for retraction in June 2014. In October 2014, Collins and other co- LDL sub-fraction is raised triglyceride (TRG) combined SeretideSe ® Diskus® authors of the new Lancet review, sent a letter of complaint about with low HDL – the higher the TRG/HDL ratio, the likely to wake at night 4 the BMJ’s handling of the two papers to the UK’s Committee on higher the risk for atherosclerotic disease. 1001 mcg from 4 years Publication Ethics (COPE). In April 2016, COPE determined that 2. Another flaw in the review is the persistent belief that the whenSafety Informationusing Seretide the BMJ acted with due diligence and in line with the expectations benefit of statins is via their blood lipid–lowering action. It Very common side effects: Headache and nasopharyngitis. Candidiasis of mouth and throat, pneumonia, bronchitis, hypokalaemia and hoarseness/dysphonia under the COPE Code of Conduct. is now well-established that the essence of atherosclerosis Common side effects: Special warnings and precautions2 for use: Systemic effects may occur with any inhaled corticosteroid, particularly at high doses The Lancet editor-in-chief Dr Richard Horton, however, in is an inflammatory disease of arteries. Statins are now prescribed for long periods. These effects are much less likely to occur than with oral corticosteroids. 7 compared to baseline a comment accompanying the statin review, calls into question recognised to be potent anti-inflammatory-cytokine It is important that patients are reviewed regularly and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained. Monitor height of children on prolonged inhaled steroid therapy. the independence of the BMJ-appointed panel’s judgement, agents, and their clinical benefit is mainly via this anti- noting that the chair had previously written critically about inflammatory route. The high-sensitivity C-reactive protein statin use among older patients. Horton observed that more Seretide™ (salmeterol xinafoate and fluticasone propionate) of psychological or behavioural effects such as psychomotor hyperactivity, sleep disorders, anxiety, depression or (HsCRP) is the other valuable measurement of possible Kindly refer to full Summary of Product Characteristics (SPC) before prescribing. aggression (particularly in children) may develop on prolonged use. Monitor height of children on prolonged inhaled than 200,000 patients were estimated to have stopped taking a atherosclerotic inflammatory activity, particularly when Abridged prescribing information. Presentations: For Malta and Gibraltar: Seretide Diskus – Each dose steroid therapy. Transfer from oral steroids: Special care needed. Monitor adrenal function. Consider appropriate provides 50 microgram salmeterol xinafoate and 100 microgram, 250 microgram or 500 microgram respectively steroid therapy during periods of stress or elective surgery. Ritonavir can greatly increase the concentration of statin in the 6 months after adverse media coverage following combined with the TRG/HDL ratio. of fluticasone propionate. Seretide 50 Evohaler - Each dose provides 25 microgram salmeterol xinafoate and fluticasone propionate in plasma, therefore avoid concomitant use. There is also an increased risk of systemic side 50 microgram of fluticasone propionate. For Gibraltar only: Seretide 125, 250 Evohaler: Each dose provides 25 microgram effects with other potent CYP3A inhibitors. There was an increased reporting of lower respiratory tract infections publication of the disputed research, and drew parallels 3. As pointed out above by Dr Aseem Malhotra, insulin salmeterol xinafoate and 125 microgram or 250 microgram of fluticasone propionate. Therapeutic Indications: (particularly pneumonia and bronchitis) in the TORCH study in patients with COPD receiving Seretide compared between “this statin scare” and the MMR vaccine scare that For Malta and Gibraltar: Seretide Diskus and Evohaler: is indicated in the regular treatment of asthma where use of with placebo; older patients, patients with a lower body mass index (<25kg/m2) and patients with very severe resistance (chronic hyperinsulinaemia) is a more potent a combination (long-acting beta-2-agonist and inhaled corticosteroid) is appropriate. Seretide Diskus is indicated for disease (FEV1<30% predicted) were at greatest risk of developing pneumonia regardless of treatment. Concomitant began with a now-retracted research paper that had led to the symptomatic treatment of patients with COPD with a FEV1<60% predicted normal (pre-bronchodilator) and a use of systemic ketoconazole significantly increases systemic exposure to salmeterol. This may lead to an increase indicator of myocardial infarction risk than LDL. This has history of repeated exacerbations, who have significant symptoms despite regular bronchodilator therapy. Seretide in the incidence of systemic effects (e.g. prolongation in the QTc interval and palpitations). Concomitant treatment widespread vaccine hesitancy. been highlighted in a previous instalment of this Synapse 50 Evohaler is used in patients not adequately controlled with inhaled corticosteroids and ‘as needed’ inhaled with ketoconazole or other potent CYP3A4 inhibitors should therefore be avoided unless the benefits outweigh the shortHelp acting beta-2-agonist Poppy or patients already adequatelyby prescribingcontrolled on both inhaled corticosteroid andSeretide long- potentially increased risk of systemic side effects of salmeterol treatment. Drug Interactions: Avoid beta-blockers. Horton’s comment about COPE’s conduct prompted Godlee’s series, which also pointed out that the TRG/HDL ratio is a acting beta-2-agonist. For Gibraltar only: Seretide 125, 250 Evohaler: is indicated in the regular treatment of asthma Concomitant use with other beta-adrenergic containing drugs can have a potentially additive effect. Potent CYP3A4 8 where use of a combination (long-acting beta-2-agonist and inhaled corticosteroid) is appropriate. Used in patients inhibitors: Co-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 mcg inhaled twice daily) rapid response letter of 14th September 2016, that COPE did not surrogate marker for insulin-resistance/hyperinsulinaemia. not adequately controlled with inhaled corticosteroids and ‘as needed’ inhaled short acting beta-2-agonist or resulted in a significant increase in plasma salmeterol exposure which may lead to an increase in the incidence of patients already adequately controlled on both inhaled corticosteroid and long-acting beta-2-agonist. Dosage and other systemic effects of salmeterol treatment (e.g. prolongation of QTc interval and palpitations) compared with decline to act but deliberated on the concerns raised by Collins Some private laboratories in Malta will be adopting the administration:Seretide Seretide is isthe for inhalation only use ICS/LABAonly. Seretide Diskus: Asthmaproven – Adults andto adolescents achieve 12 years salmeterol or ketoconazole treatment alone. The concomitant administration of ketoconazole should be avoided, et al., and on the BMJ’s response, and came to a clear conclusion and over: one puff twice daily of Seretide 100 or Seretide 250 or Seretide 500 (each containing 50 mcg of salmeterol unless the benefits outweigh the potentially increased risk of systemic side effects of salmeterol treatment. There TRG/HDL ratio and the HsCRP as the main markers of xinafoate and 100 mcg, 250 mcg or 500 mcg respectively of fluticasone propionate). Patients should be given the is likely to be a similar risk of interaction with other potent CYP3A4 inhibitors (e.g. itraconazole, telithromycin, that the BMJ had acted appropriately. Godlee has also written atherosclerotic activity risk. strength of Seretide containing the appropriate, lowest fluticasone propionate dosage for the severity2 of their ritonavir). Pregnancy and Lactation: Experience limited. Balance risks against benefits. Undesirable effects: disease.guideline-defi A short term trial of Seretide ned may asthma be considered ascontrol initial maintenance in therapy children in adults or adolescents Very Common/Common - candidiasis of mouth and throat, pneumonia, bronchitis, hypokalaemia, headache, hoarseness/ to England’s chief medical officer asking for an inquiry into the with moderate persistent asthma (defined as patients with daily symptoms, daily rescue use and moderate to severe dysphonia, throat irritation (uncommon with Seretide 50 Evohaler), nasopharyngitis, sinusitis, contusions, traumatic airflow limitation) for whom rapid control of asthma is essential. In these cases, the recommended initial dose is fractures, arthralgia and myalgia, muscle cramps (uncommon with Seretide 50 Evohaler). See SPC for information statins saga and for an independent review of the evidence on References one inhalation of 50 micrograms salmeterol and 100 micrograms fluticasone propionate twice daily. Once control of on all adverse events. Overdose: due to Salmeterol: tremor, headache, tachycardia; due to Fluticasone propionate: asthma is attained treatment should be reviewed and consideration given as to whether patients should be stepped temporary adrenal suppression. statins. She claims that an independent third-party scrutiny of the 1. Collins R, Reith C, Emberson J, et al. Interpretation of evidence for the down to an inhaled corticosteroid alone. Regular review of patients as treatment is stepped down is important. MA Holder (Malta): GlaxoSmithKline (Ireland) Ltd. Trading as: Allen & Hanburys Ltd. MA Numbers (Malta): efficacy and safety of statin therapy. Lancet 2016; 388: 2532-61. Seretide is not intended for the initial management of mild asthma. Seretide 50/100 micrograms strength is not Seretide Diskus: MA 192/00901-3; Seretide 50 Evohaler: AA 192/00904. Legal category: POM. Not all pack sizes may statins trial data remains an essential next step if this increasingly appropriate in adults and children with severe asthma. Children 4-11 years: Seretide 100 Diskus (50 mcg salmeterol be marketed. Date of revision of text: August 2013. 2. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle and 100 mcg fluticasone propionate) – one puff twice daily. Seretide Diskus: COPD: Seretide 500 Diskus (50 mcg bitter and unproductive dispute is to be resolved. symptoms: impact on statin therapy: European Atherosclerosis Society of salmeterol xinafoate and 500 mcg fluticasone propionate) – one puff twice daily. Seretide 50 Evohaler: Adults In order to ensure that this product information reflects the most up-to-date clinical and Consensus Panel Statement on assessment; aetiology and management. and children 4 years and older: Two inhalations twice daily. For Gibraltar only: Seretide 125, 250 Evohaler: Adults post-marketing surveillance data, please always refer to the latest Summary of Product Eur Heart J 2015; 36: 1021-22. and adolescents 12 years and older: Two inhalations twice daily. Contra-indications: Hypersensitivity. Warnings Characteristics which is available from GlaxoSmithKline (Malta) Ltd (Tel: +356 21238131) and Precautions: Seretide should not be used to treat acute asthma symptoms for which a fast- and short-acting Take home messages 3. Krumholz HM. Statins evidence: When answers also raise questions. Safety Information bronchodilator is required. Patients should not be initiated on Seretide during an exacerbation, or if they have REPORTING ADVERSE EVENTS (AEs): 1. Apart from the above claims of drug-company funding and BMJ 2016; 354: i4963. significantly worsening or acutely deteriorating asthma. Serious asthma-related events and exacerbations can occur If you become aware of any AEs, medication errors and/or use during pregnancy in association 4. Malhotra A. is not the major issue. BMJ 2013; 347: i6340. during Seretide therapy; sudden and progressive deterioration in control or increased use of bronchodilator therapy with GSK products, please report the event promptly to: GSK (Malta) Limited, 1, De la Cruz Avenue, dubious research quality, the Lancet review in question, 5. Ravnskov U, Diamond DM, Hama R, et al. Lack of an association or warrants urgent medical assessment especially in patients of African-American origin (SMART). As with all inhaled Qormi QRM 2458, Malta (Tel: +356 21238131) or e-mail: [email protected] Verymedication common containing corticosteroids, side effects: Seretide should Headache be administered and with nasopharyngitis. caution in patients with pulmonary an inverse association between low-density-lipoprotein cholesterol and Malta: any suspected AEs and medication errors can also be reported via the national Adverse penned by several professors of medicine and cardiology, tuberculosis, severe cardiovascular disorders, including heart rhythm abnormalities, mellitus, untreated Drug Reactions (ADRs) reporting system: is flawed for at least another two reasons. One is the fact mortality in the elderly: A systematic review. BMJ 2016; 6: e010401. Commonhypokalaemia/patients side predisposed effects: to hypokalaemia Candidiasis or thyrotoxicosis. of mouth In case and of paradoxicalthroat, bronchospasmpneumonia, Report bronchitis, forms can be hypokalaemia downloaded from www.medicinesauthority.gov.mt/adrportal and hoarseness/dysphonia and posted to the Malta 6. Abramson JD, Rosenberg HG, Jewell N, et al. Should people at low risk discontinue Seretide, assess patient and give alternative therapy if necessary. Systemic effects may occur with any Medicines Authority, Post-licensing Directorate, 203, Level 3, Rue D’Argens, Gżira GŻR 1368, MALTA, or sent that all the data is based on routine LDL measurements. of cardiovascular disease take statin? BMJ 2013; 347: 16123. inhaled corticosteroid, particularly at high doses prescribed for long periods, but are less likely than with oral by email to [email protected] Specialsteroids. It is important, warnings therefore, andthat the precautionspatient is reviewed regularly for and use: the dose Systemic of inhaled corticosteroid effects is mayGibraltar: occur any with suspected any AEs inhaled and medication corticosteroid, errors can also be particularlyreported via the UKat regulatoryhigh doses Previous instalments in this Synapse series have put 7. Horton, R. Offline: Lessons from the controversy over statins. Lancet reduced to the lowest dose at which effective control of asthma is maintained. Prolonged treatment of patients authority (MHRA): https://yellowcard.mhra.gov.uk/ 2016; 388: 1040. prescribedwith high doses of inhaledfor long corticosteroids periods. may result These in adrenal effects suppression are and much acute adrenal less crises. likely Rarely, to a range occur than with oral corticosteroids. forward evidence for LDL having two biologically different 8. Godlee F. Rapid response re COPE complaint. BMJ 2016; Letter (14 September). sub-fractions – a large light particle LDL and a small It is important that patients areReferences reviewed regularly and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective 1. Wildhaber, J et al. Pediatr. Pulmonol 2012; 47:346–357. 2. DeBlic J et al. Pediatr Allergy Immunol 2009: 20:763–771 control of asthma is maintained.3. Monitor Seretide Evohaler height ( uticasone of children propionate/salmeterol on prolonged xinafoate) inhaled steroid therapy. Summary of Product Characteristics, Allen & Hanburys Ltd. October 2014. 4. Seretide Accuhaler ( uticasone propionate/salmeterol xinafoate) 20 Volume 15, 2016 Issue 06 Summary of Product Characteristics, Allen & Hanburys Ltd. October 2014. Date of Preparation: January 2015 ZINC CODE: MLT_GIB/SFC/0002/15 Seretide™ (salmeterol xinafoate and fluticasone propionate) of psychological or behavioural effects such as psychomotor hyperactivity, sleep disorders, anxiety, depression or

Seretide-LP-Night-GSKDC-PT-ADI-2015-0034_D1.inddKindly refer to full Summary of Product Characteristics (SPC) 2 before prescribing. aggression (particularly in children) may develop on prolonged use. Monitor height of children on1/23/2015 prolonged inhaled 9:53:02 PM Abridged prescribing information. Presentations: For Malta and Gibraltar: Seretide Diskus – Each dose steroid therapy. Transfer from oral steroids: Special care needed. Monitor adrenal function. Consider appropriate provides 50 microgram salmeterol xinafoate and 100 microgram, 250 microgram or 500 microgram respectively steroid therapy during periods of stress or elective surgery. Ritonavir can greatly increase the concentration of of fluticasone propionate. Seretide 50 Evohaler - Each dose provides 25 microgram salmeterol xinafoate and fluticasone propionate in plasma, therefore avoid concomitant use. There is also an increased risk of systemic side 50 microgram of fluticasone propionate. For Gibraltar only: Seretide 125, 250 Evohaler: Each dose provides 25 microgram effects with other potent CYP3A inhibitors. There was an increased reporting of lower respiratory tract infections salmeterol xinafoate and 125 microgram or 250 microgram of fluticasone propionate. Therapeutic Indications: (particularly pneumonia and bronchitis) in the TORCH study in patients with COPD receiving Seretide compared For Malta and Gibraltar: Seretide Diskus and Evohaler: is indicated in the regular treatment of asthma where use of with placebo; older patients, patients with a lower body mass index (<25kg/m2) and patients with very severe a combination (long-acting beta-2-agonist and inhaled corticosteroid) is appropriate. Seretide Diskus is indicated for disease (FEV1<30% predicted) were at greatest risk of developing pneumonia regardless of treatment. Concomitant the symptomatic treatment of patients with COPD with a FEV1<60% predicted normal (pre-bronchodilator) and a use of systemic ketoconazole significantly increases systemic exposure to salmeterol. This may lead to an increase history of repeated exacerbations, who have significant symptoms despite regular bronchodilator therapy. Seretide in the incidence of systemic effects (e.g. prolongation in the QTc interval and palpitations). Concomitant treatment 50 Evohaler is used in patients not adequately controlled with inhaled corticosteroids and ‘as needed’ inhaled with ketoconazole or other potent CYP3A4 inhibitors should therefore be avoided unless the benefits outweigh the short acting beta-2-agonist or patients already adequately controlled on both inhaled corticosteroid and long- potentially increased risk of systemic side effects of salmeterol treatment. Drug Interactions: Avoid beta-blockers. acting beta-2-agonist. For Gibraltar only: Seretide 125, 250 Evohaler: is indicated in the regular treatment of asthma Concomitant use with other beta-adrenergic containing drugs can have a potentially additive effect. Potent CYP3A4 where use of a combination (long-acting beta-2-agonist and inhaled corticosteroid) is appropriate. Used in patients inhibitors: Co-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 mcg inhaled twice daily) not adequately controlled with inhaled corticosteroids and ‘as needed’ inhaled short acting beta-2-agonist or resulted in a significant increase in plasma salmeterol exposure which may lead to an increase in the incidence of patients already adequately controlled on both inhaled corticosteroid and long-acting beta-2-agonist. Dosage and other systemic effects of salmeterol treatment (e.g. prolongation of QTc interval and palpitations) compared with administration: Seretide is for inhalation use only. Seretide Diskus: Asthma – Adults and adolescents 12 years salmeterol or ketoconazole treatment alone. The concomitant administration of ketoconazole should be avoided, and over: one puff twice daily of Seretide 100 or Seretide 250 or Seretide 500 (each containing 50 mcg of salmeterol unless the benefits outweigh the potentially increased risk of systemic side effects of salmeterol treatment. There xinafoate and 100 mcg, 250 mcg or 500 mcg respectively of fluticasone propionate). Patients should be given the is likely to be a similar risk of interaction with other potent CYP3A4 inhibitors (e.g. itraconazole, telithromycin, strength of Seretide containing the appropriate, lowest fluticasone propionate dosage for the severity of their ritonavir). Pregnancy and Lactation: Experience limited. Balance risks against benefits. Undesirable effects: disease. A short term trial of Seretide may be considered as initial maintenance therapy in adults or adolescents Very Common/Common - candidiasis of mouth and throat, pneumonia, bronchitis, hypokalaemia, headache, hoarseness/ with moderate persistent asthma (defined as patients with daily symptoms, daily rescue use and moderate to severe dysphonia, throat irritation (uncommon with Seretide 50 Evohaler), nasopharyngitis, sinusitis, contusions, traumatic airflow limitation) for whom rapid control of asthma is essential. In these cases, the recommended initial dose is fractures, arthralgia and myalgia, muscle cramps (uncommon with Seretide 50 Evohaler). See SPC for information one inhalation of 50 micrograms salmeterol and 100 micrograms fluticasone propionate twice daily. Once control of on all adverse events. Overdose: due to Salmeterol: tremor, headache, tachycardia; due to Fluticasone propionate: asthma is attained treatment should be reviewed and consideration given as to whether patients should be stepped temporary adrenal suppression. down to an inhaled corticosteroid alone. Regular review of patients as treatment is stepped down is important. MA Holder (Malta): GlaxoSmithKline (Ireland) Ltd. Trading as: Allen & Hanburys Ltd. MA Numbers (Malta): Seretide is not intended for the initial management of mild asthma. Seretide 50/100 micrograms strength is not Seretide Diskus: MA 192/00901-3; Seretide 50 Evohaler: AA 192/00904. Legal category: POM. Not all pack sizes may appropriate in adults and children with severe asthma. Children 4-11 years: Seretide 100 Diskus (50 mcg salmeterol be marketed. Date of revision of text: August 2013. and 100 mcg fluticasone propionate) – one puff twice daily. Seretide Diskus: COPD: Seretide 500 Diskus (50 mcg of salmeterol xinafoate and 500 mcg fluticasone propionate) – one puff twice daily. Seretide 50 Evohaler: Adults In order to ensure that this product information reflects the most up-to-date clinical and and children 4 years and older: Two inhalations twice daily. For Gibraltar only: Seretide 125, 250 Evohaler: Adults post-marketing surveillance data, please always refer to the latest Summary of Product and adolescents 12 years and older: Two inhalations twice daily. Contra-indications: Hypersensitivity. Warnings Characteristics which is available from GlaxoSmithKline (Malta) Ltd (Tel: +356 21238131) and Precautions: Seretide should not be used to treat acute asthma symptoms for which a fast- and short-acting bronchodilator is required. Patients should not be initiated on Seretide during an exacerbation, or if they have REPORTING ADVERSE EVENTS (AEs): significantly worsening or acutely deteriorating asthma. Serious asthma-related events and exacerbations can occur If you become aware of any AEs, medication errors and/or use during pregnancy in association during Seretide therapy; sudden and progressive deterioration in control or increased use of bronchodilator therapy with GSK products, please report the event promptly to: GSK (Malta) Limited, 1, De la Cruz Avenue, warrants urgent medical assessment especially in patients of African-American origin (SMART). As with all inhaled Qormi QRM 2458, Malta (Tel: +356 21238131) or e-mail: [email protected] medication containing corticosteroids, Seretide should be administered with caution in patients with pulmonary Malta: any suspected AEs and medication errors can also be reported via the national Adverse tuberculosis, severe cardiovascular disorders, including heart rhythm abnormalities, diabetes mellitus, untreated Drug Reactions (ADRs) reporting system: hypokalaemia/patients predisposed to hypokalaemia or thyrotoxicosis. In case of paradoxical bronchospasm Report forms can be downloaded from www.medicinesauthority.gov.mt/adrportal and posted to the Malta discontinue Seretide, assess patient and give alternative therapy if necessary. Systemic effects may occur with any Medicines Authority, Post-licensing Directorate, 203, Level 3, Rue D’Argens, Gżira GŻR 1368, MALTA, or sent inhaled corticosteroid, particularly at high doses prescribed for long periods, but are less likely than with oral by email to [email protected] steroids. It is important, therefore, that the patient is reviewed regularly and the dose of inhaled corticosteroid is Gibraltar: any suspected AEs and medication errors can also be reported via the UK regulatory reduced to the lowest dose at which effective control of asthma is maintained. Prolonged treatment of patients authority (MHRA): https://yellowcard.mhra.gov.uk/ with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crises. Rarely, a range

References 1. Wildhaber, J et al. Pediatr. Pulmonol 2012; 47:346–357. 2. DeBlic J et al. Pediatr Allergy Immunol 2009: 20:763–771 3. Seretide Evohaler ( uticasone propionate/salmeterol xinafoate) Summary of Product Characteristics, Allen & Hanburys Ltd. October 2014. 4. Seretide Accuhaler ( uticasone propionate/salmeterol xinafoate) Summary of Product Characteristics, Allen & Hanburys Ltd. October 2014.

Date of Preparation: January 2015 ZINC CODE: MLT_GIB/SFC/0002/15

Seretide-LP-Night-GSKDC-PT-ADI-2015-0034_D1.indd 2 1/23/2015 9:53:02 PM