Zyban | THE FACTS MAY 2002 | EDITORIAL Despite all the health warnings, which have been around for many years now, smoking remains the world’s leading cause of preventable death. There have been advances in treatments, but there is no miracle cure for tobacco addiction. Stopping smoking requires the commitment and motivation of the smoker and in many cases, the help and advice of healthcare professionals. The much welcomed recent guidance from the National Institute for Clinical Excellence reaffirms the important role of pharmaceutical intervention in significantly increasing smokers’ A medicine that saves lives chances of stopping. Both nicotine replacement therapies Since its launch in the US in 1997, it is whether there was an increased risk (NRT) and Zyban have been estimated that Zyban (bupropion associated with Zyban use. shown to be twice as effective hydrochloride), has helped over two million in helping patients stop smokers worldwide to stop smoking. The review included a comprehensive smoking compared to will evaluation of the reports of death and power alone. Zyban is the first non-nicotine prescription the pattern of reporting between countries, treatment designed to help smokers quit. as well as an epidemiological analysis of It is important for health care It was first launched in Europe in the reported death rates in the UK and US. This professionals to remember the Netherlands in late 1999, with most other has enabled the company to compare the tremendous toll smoking is European countries launching this tablet- number of deaths expected in the general taking: smoking kills one in two form medicine during the year 2000. population and the more ‘at risk’ smoking of all lifelong smokers. In the population. UK alone, more than 120,000 The product had a promising launch in the people will die this year from UK in June 2000 and attracted a great deal The review has not revealed any new safety smoking related illnesses (NICE of positive media coverage. From around issues and the evidence available does not 2002) – nearly 14 people every February 2001, however, its safety has suggest that Zyban carries any increased hour of every day. been questioned in some newspapers, risk of death, if used in accordance with through reports on a number of deaths the labelling. It indicates that treatment As with any medicine, it is that have been supposedly associated with with bupropion for smoking cessation is important to balance the its use. not associated with any greater risk of benefit versus the risks. In the death than smokers are exposed to case of smoking cessation GSK’s mission is to improve the quality of through their use of tobacco products. treatments, it is clear that the human life by enabling people to do more, And, finally, it has confirmed that treatment benefits far outweigh the risks feel better and live longer. As with all its with bupropion for all indications carries no for the vast majority of smokers medicines, the company is fully committed greater risk of death compared to the and they are among the most to understanding the safety profile of general population. cost effective of all health Zyban and it closely monitors reports of all interventions. adverse events, regardless of severity. More details of the review can be found Indeed, GSK has conducted a thorough inside this document. Gay Sutherland review of all spontaneous reports of death Tobacco Research Section, up to December 2001, to determine GSK is confident in the role of Zyban in Institute of Psychiatry, National CONTINUES OVERLEAF Addiction Centre and Hon. Consultant Clinical Psychologist at Maudsley Hospital Smoking Cessation Clinic Zyban THE FACTS Science against smoking Smoking kills OVER 2 MILLION 4 million people die each year from a smoking related PEOPLE GLOBALLY disease – equivalent to 10,000 each day. This number will HAVE STOPPED reach 10 million by the late 2020s. worldwide, 33% of all deaths among 40 to 69-year-olds and SMOKING USING 30% of all cancer deaths are caused by smoking. ZYBAN more people die from tobacco-related diseases than from alcohol, cocaine, heroin, suicide, murder, car accidents, fires and AIDS combined. 1.1 billion people still use tobacco products globally. 46% of men and 26% of women aged 15 and over in Europe smoke – that’s more than 214 million people in total. Zyban makes a difference half of all long-term smokers will die from a smoking- 31 million people worldwide are estimated to have used related illness. bupropion in all its indications – 9 million of them as an aid an estimated 70% of smokers want to quit – only 20-30% to stop smoking. try quitting each year and just 3-5% of them actually over 2 million people globally are estimated to have succeed with will power alone. Many of these start stopped smoking using Zyban. smoking again in the future[8,9]. in Europe, it is estimated that more than 1.7 million people global purchases of anti-smoking drugs (including nicotine have used Zyban as an aid to stop smoking and around replacement therapy products) are estimated to be 425,000 are estimated to have remained smoke-free after $1.3 billion. 12 months. smoking related diseases reduce quality of life and place a an extensive programme of clinical trials has included over significant burden on healthcare resources[5, 39-41]. eight large, double-blind, placebo controlled studies demonstrating the efficacy and tolerability of Zyban in more than 7,000 smokers. studies show that smokers using Zyban to help them quit are twice as likely to stay free of tobacco for up to a year as they are with placebo[13-15,19,24,33]. Safety profile confirmed Zyban is effective at reducing cravings and alleviating bupropion, the active ingredient in Zyban, is well withdrawal symptoms[13,14,19]. tolerated, with experience in over 31 million patients. Zyban offers the best chance of success when quitting and GSK has conducted a thorough analysis of the spontaneous is the most effective smoking cessation product reports of death received for bupropion and has identified available[14,18]. no new safety issues than when the product was first Zyban is among the most cost-effective health launched in 1989. interventions available. all available evidence indicates that treatment with Zyban for smoking cessation is not associated with an increased risk of death when compared to the smoking population. all evidence available indicates that treatment with bupropion in all indications is not associated with an increased risk of death when compared to the general Zyban is safe when used appropriately[13,22]. It should not, population. however, be prescribed to anyone who has: Zyban is associated with low discontinuation rates due to adverse events – the most common side effects are • hypersensitivity to active ingredient (bupropion insomnia, dry mouth, headache and nausea; these are hydrochloride) or other ingredients generally mild to moderate and often disappear within a • current seizure disorder or history of seizure disorder few weeks of treatment. • CNS tumour Zyban has a favourable cardiovascular profile. In a study of • abrupt withdrawal from alcohol or any medicine smokers with cardiovascular disease, the adverse event associated with seizure risk on withdrawal (in particular profile with Zyban was similar to that seen in studies benzodiazepines or benzodiazepine-like agents) conducted in a general population. • current or previous eating disorder the risk of seizure associated with Zyban, when used in • severe hepatic cirrhosis accordance with product information, is rare (0.1%) and • recent or current use of MAOIs (monoamine oxidase similar to or less than other commonly used drugs such as inhibitors) anti-depressants. • history of bipolar disorder GlaxoSmithKline Zyban THE FACTS Review reveals no increased risk of death with bupropion GlaxoSmithKline develops and manufactures medicines that not only work, but also do not put the people taking them at any unacceptable risk of serious side effects. With all of its products, GSK regularly monitors reports of adverse events from all over the world, to ensure they remain safe to use. Prescribing information is regularly reviewed by GSK in close collaboration with regulatory bodies and, whenever necessary, modified. After an apparent increase in spontaneous adverse event reports involving deaths, particularly sudden deaths, among patients taking Zyban, the company initiated a cumulative review of all reported deaths associated with bupropion, to determine whether there were any increased risks involved. Data from three different areas were investigated: • a comprehensive evaluation of reports of death • the pattern of reporting of deaths between countries • an epidemiological analysis of the number of reports of death in the UK and US, in comparison to the number of deaths expected in both the general population and the more ‘at risk’ smoking WE KNOW FOR A FACT population. THAT ONE OUT OF TWO SMOKERS WILL DIE FROM The work was done over several months, so that the most recent SMOKING. THAT SAME follow-up information could be included. The findings relate to cases URGENCY DOESN’T APPEAR initially received up to 31 December 2001, as it takes several months IN THE MEDIA AT ALL to obtain adequate data for evaluation. AND YOU HAVE TO ASK, WHY IS THAT?Dr Fenton Howell ASH Ireland A medicine that saves lives | CONTINUED FROM FRONT COVER helping smokers quit and keeping them The risk of dying from smoking is far smoke-free over the long term. It believes greater than the risk involved with Zyban. Zyban offers the best chance of success And it would be wrong for a few press when quitting and is the most effective reports, which do not detail the risks of smoking cessation product available[14,19]. smoking or the effectiveness and safety of Zyban, to put some patients off what is potentially a life-saving medicine. Benefits of stopping smoking Time after stopping: 20 minutes 8 hours 24 hours 48 hours BP, HR and peripheral Nicotine and CO levels fall All Nicotine eliminated. CO normal, mucociliary circulation improve. by 50%. PaO2 – N. Taste and smell improved. clearance, risk of MI falls. GlaxoSmithKline Zyban THE FACTS BUPROPION IS, FOR THE TIME BEING, THE MOST EFFECTIVE (REGISTERED) METHOD OF STOPPING SMOKING…IT IS REGRETTABLE IF BIASED REPORTING IN THE PRESS SHOULD UNDERMINE THESE FAVOURABLE DEVELOPMENTS. Wagena/De Graaf/Chavannes/Van Grootheest/Van Schayck Nederlands Tijdschrjft voor Geneeskunde, 4 August 2001 Evaluation of reports of deaths leading to death took place after the related diseases (120,000 deaths each patient had stopped taking bupropion. year in the UK alone). A full From the launch of bupropion to treat epidemiology review showed there was depression in 1989 to 31 December Other reports of death involved no increase in the risk of death in 2001 (nearly 13 years’ post marketing chronic smoking related respiratory patients treated with bupropion. experience), an estimated 31 million diseases, cancer and other conditions. people have used the medicine in all There were isolated reports where the The safety profile for bupropion is well- its indications. Nine million have cause of death was related to seizures, established and the most commonly used it as an aid to stop smoking. but only with patients who had reported reactions are consistent with existing risk factors for seizure. experience from clinical trials. What’s In that period, there have been more, assessment of the UK population spontaneous reports of deaths in The number of deaths reported for based on the Health and Economic patients prescribed bupropion which patients who have taken bupropion is Consequences of Smoking Model has have been reviewed and documented very small[42,23,4] compared with the demonstrated that, for smokers who by both external regulatory agencies mortality associated with smoking are motivated to quit and are treated and GSK[42,23,4]. with bupropion SR, 15,933 lives can be A smoker’s best chance to quit saved and 48,537 cases of smoking- In the majority of the reports attributable morbidity can be avoided received, there is an alternative Since its first launch in 1989 in the USA for over a five-year period. explanation for the patient's death, the treatment of depression, it is estimated such as the patient’s underlying that a total of 31 million people have used Pattern of reporting condition[42,23]. In the UK, bupropion worldwide. More than nine cardiovascular disorders such as million have now taken Zyban as an aid to The pattern of reporting of deaths for myocardial infarction, and quit smoking and it is estimated that over the UK appeared to be different from cerebrovascular disorders such as two million of them have successfully kicked the older North American markets, so stroke, were the cause of death in 80 their addiction to tobacco. this was an area examined in the per cent of reports. These diseases review. The pattern was looked at for are common in smokers. In addition, Tobacco addiction is serious. Tobacco is more the UK, Canada and the US, from the a number of patients were not taking addictive than heroin or cocaine[6,25]. And launch of Zyban in each country and bupropion at the time of death. Zyban is a unique, non-nicotine tablet compared to the number of patients therapy that is believed to act directly on two using it on a monthly basis. With patients who died suddenly, the of the brain’s chemicals that are involved in GSK review showed that several that addiction – firstly dopamine, which is Reporting in Canada and the US was patients had a history of associated with craving, and secondly fairly consistent over time, but it was cardiovascular disease or risk factors norepinephrine, which is thought to be highly variable in the UK. It is not for sudden death, or that the event responsible for symptoms associated with unusual to receive a high number of smoking cessation attempts and tobacco withdrawal, such as agitation, anxiety, loss of Bupropion HCI SR acts on the concentration, increased appetite, sweating neurotransmitters involved in nicotine and depressed mood. addiction Modifies Alters Although most smokers want to quit, less dopamine noradrenergic than half actually attempt to stop each year release in activity in and only a fraction of them actually succeed. ‘reward’ ‘withdrawal’ pathway pathway (locus One of the reasons is that most smokers quit (mesolimbic coeruleus) just with their own willpower – a virtually system) ineffective method that has only a three to five per cent success rate. Quitting smoking is difficult and many people start smoking again at some point, too, so repeated attempts to quit are often needed. With Zyban, however, real life data have confirmed the clinical trial findings that up to one in two people treated will quit smoking and up to one in three will still be smoke- free a year later[27,28,33]. That makes it the most 72 hours 2-12 weeks Breathing easier, bronchospasm effective smoking cessation product available. Circulation improves. relaxes. Energy improves. GlaxoSmithKline Zyban THE FACTS Balancing benefit over risk All medicines that treat conditions connected with the central nervous system (CNS) have varying degrees of side effects. And, since adverse event reports with any new expected number in the smoking serious CNS illnesses such as addiction medicine, because they are more likely population. necessarily require serious medications, to attract attention and, in some Zyban is no exception. countries, they are monitored more In the US, both the total number of closely. But the increased awareness of reports of deaths and the number of Dry mouth, insomnia, headache and nausea Zyban in the UK created by the reports of deaths due to specific causes are the most common side effects significant coverage in the lay media is received for all indications of bupropion experienced by people taking the medicine, believed to have generated a was considerably lower than the all of which are usually well-tolerated. But, corresponding increase in the number expected number for the general on rare occasions, it has also been linked to of reports of adverse events. population, so a comparison with the more serious reactions such as seizure and smoking population was not carried out. severe hypersensitivity. Epidemiological analysis The evidence available, therefore, The risk of seizure associated with the The number of reports of death indicates that Zyban is not associated correct use of Zyban, however, is rare and is received in the UK and US for Zyban – with an increased risk of death similar to or lower than that associated with both the total number of deaths and compared to the general population. other commonly used drugs, such as anti- deaths due to specific causes – was depressants. compared to the expected number of Key Points deaths in the general population and Patients should always consult their physician the more ‘at risk’ smoking population. • bupropion is well tolerated and has a well about their health status and other established safety profile. Total exposure is medications they are taking before using Given the high death rate of smokers, approximately 31 million patient including Zyban, to make sure it is appropriate. The it was expected that deaths reported 9 million who have been treated for Zyban labelling clearly points out its non- among bupropion users would be smoking cessation. suitability for certain patients (see panel on page 5). higher than in the general population, • all available evidence indicates that but similar to that observed in the treatment with Zyban for smoking Smoking cessation attempts normally lead to a smoking population. cessation is not associated with an variety of withdrawal symptoms, such as increased risk of death compared to the anxiety, depression, restlessness, poor In the UK, however, the total number smoking population. concentration and irritability/aggression, which of reports of death, as well as the • the evidence available indicates that might be interpreted as side effects of Zyban. number of reports for most causes of bupropion treatment (taking all death, was substantially lower than indications) is not associated with an In clinical studies with smokers, no significant expected in the general population. increased risk of death compared to the product-related side effects have been The number of reports of sudden death general population. reported in those that have a pre-existing was higher than expected in the • no new safety issues associated with Zyban. cardiovascular disease or chronic general population but below the • favourable benefit/risk with Zyban. obstructive pulmonary disease (COPD). And studies show that there were no significant average changes in blood pressure with Zyban in the general smoker population or in smokers with existing I HAD TRIED TO QUIT SMOKING FOR MANY YEARS, cardiovascular disease. BUT ONLY WITH ZYBAN DID I SUCCEED. NOW I HAVEN’T SMOKED FOR MORE THAN A YEAR. The overall benefit/risk balance of Zyban IT IS FANTASTIC.Bjarne, 52 hasn’t changed since the product was first The Netherlands licensed in the US in 1997, with the drug’s effectiveness and the health and economic benefits of quitting smoking in general, clearly outweighing any known risk. This view was recently endorsed by an independent third party. 3-9 months 1 year 10 years 15 years Cough and wheeze improve. Risk of MI reduced by 50%. Risk of lung cancer reduced by 50%. Risk of stroke back to normal. Risk of MI back to normal. GlaxoSmithKline References  GSK data on file.  Balfour DJK. The pharmacology underlying pharmacotherapy for tobacco dependence: A focus on bupropion. 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Treating tobacco use and dependence. Clinical Practice Guideline. Rockville (MD): US Department of Health and tobacco-related diseases kill more people Human Services. Public Health Service. June 2000. each year than alcohol, cocaine, heroin,  IMS Database 2000.  GSK data on file. suicide, murder, car accidents, fires and  GSK data on file.  Zyban (bupropion hydrochloride) Sustained-Release Tablets. Product AIDS in total. Information. GlaxoSmithKline, 2001. Available at URL: …RISK OF http://zyban.ibreathe.com  Jorenby DE, Leischow SJ, Nides MA, et al. A controlled trial of sustained- For every 1,000 20-year-olds that smoke, DYING FROM release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999;340:685-691. one will be murdered and six will die in SMOKING IS  Hurt RD, Sachs DP, Glover ED, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med motor vehicle accidents. But 250 will die in middle age because of tobacco and a TENS OF 1997;227:1195-1202.  Holm KJ, Spencer CM. Bupropion: A review of its use in the management further 250 will die in old age for the same THOUSANDS OF of smoking cessation. Drugs 2000;59:1007-1024.  Tashkin D, Kanner R, Bailey W, et al. Smoking cessation in patients with chronic obstructive pulmonary disease: A double-blind, placebo- reason. In other words, half of all long-term TIMES GREATER controlled, randomised trial. Lancet 2001;357:1571-1575.  Tonstad S, Aaserud E, Hjalmarson A, et al. Zyban is an effective and smokers will die from one of more than 25 THAN THE RISK well-tolerated aid to smoking cessation in a general smoking population – an international study. Abstract presented at the Fourth Annual identified smoking related illnesses. FROM USING Conference of the European Society for Research on Tobacco and Nicotine, September 2001 Paris, France. ZYBAN  Hughes JR, Stead LF, Lancaster T. Anti-depressants for smoking cessation (Cochran Review). http://www.cochrane.org. WHO also estimates, however, that ASH  Tonstad S, Farsang C, Manolis AJ, Astbury C, Hider A, Sweet R. (2001). Zyban is an effective and well-tolerated aid to smoking cessation in 1.1 billion people still use tobacco products smokers with cardiovascular disease [abstract]. Eur Heart J:256.  Dunner DL, Zisook S, Billow AA et al. A prospective safety surveillance globally – that’s one-third of the planet’s Zyban is recognised by study for bupropion sustained-release in the treatment of depression. J entire population. Nearly four million anti-smoking groups as a Clin Psychiatry 1998;59:366-373.  Zyban European Summary of Product Characteristics, 2001. people die each year due to smoking proven and essential aid to  Medicines Control Agency. Zyban (bupropion HCl SR) Safety Update, 8 April 2002. (http://www.mca.gov.uk ) related disease, equivalent to more than help people stop smoking.  National Institute for Clinical Excellence. Technology Appraisal Guidance – No.39. Guidance on the use of Nicotine Replacement Therapy (NRT) 10,000 every day, with over 33 per cent of and Bupropion for smoking cessation. March 2002.  Henningfield JE et al.Psychopharmacology of nicotine. In: Nicotine all deaths among people aged 40-69 and The UK-based Action on addiction. Principles and management. Orleans CT, Slade J. (ed.) Oxford University Press, 1994:24-45. 30 per cent of all cancer deaths caused Smoking and Health (ASH),  Ascher JA, Cole JO, Colin J-N, et al. Bupropion: a review of its mechanism directly by smoking. for example, points to the of antidepressant activity. J Clin Psychiatry 1995;56:395-401.  Van der Molen T, Raaijmakers JAM. Afkicken Met Bupropion. Medisch fact that, since users of the Contact 2001;56(37):1333-1336.  Holmes S, Browning D, Powell S et al. Real-World smoking cessation Every ten seconds, someone in the world medicine are smokers, there rates with bupropion SR in general practice in the UK. Presented at the 3rd European Conference on Tobacco or Health. 20-22 June, 2002. dies because of tobacco use. will always be sudden Warsaw, Poland.  Gonzales DH, Nides MA, Ferry LH, et al. Bupropion SR as an aid to deaths from heart disease smoking cessation in smokers treated previously with bupropion: a The direct and indirect costs of treating or stroke reported, but that radnomized placebo-controlled study. Clin Pharmacol Ther 2001;69:438- 444. people with tobacco related diseases also they may be due to  Fiore MC et al. Tobacco dependence and the nicotine patch. Clinical guidelines for effective use. JAMA 1992;268:2687-2694. places huge burdens on healthcare budgets smoking or causes other  Peto R, Chen ZM, Boreham J. Tobacco, the growing epidemic. Nature Medicine 1999;5(1):15-17. around the world[5,24]. And the situation is than Zyban.  Tashkin D, Kanner R, Bailey W, et al. Smoking cessation in patients with chronic obstructive pulmonary disease: a double-blind, placebo- worsening: if the current rates of increasing controlled, randomised trial. Lancet 2001;357:1571-1575. tobacco use continue, the annual number “The risk of dying from  Jarvis MJ, Powell S, Marsh H, et al. A meta-analysis of clinical studies confirms the effectiveness of bupropion SR (Zyban) in smoking of deaths caused by smoking globally will smoking is tens of cessation. Abstract presented at the Seventh Annual Conference of the Society for Research on Tobacco and Nicotine, 2001 23-25 March, reach 10 million by the late 2020s[5,31]. thousands of times greater Seattle, Washington, USA.  The Lewin Group. Health and Economic Consequences of Smoking than the risk from using (HECOS) model. (Available at URL: http://www.ea3.lewin.com/hecos)  Jamerson BD, Nides M, Jorenby DE, et al. Late-term smoking cessation Estimates suggest that 70 per cent of Zyban,” says ASH director, despite initial failure: An evaluation of bupropion sustained release, nicotine patch, combination therapy, and placebo. Clin Ther 2001;23:744- smokers want to quit, but only 20 to Clive Bates. “This drug has 752. 40 per cent actually attempt to stop each a minimal risk when used  Hays JT, Hurt RD, Rigotti NA, et al. Sustained-release bupropion for pharmacologic relapse prevention after smoking cessation. A year and just three to five per cent of properly and its safety is randomized, controlled trial. Ann Intern Med 2001;135:423-433.  Anonymous. Bupropion to aid smoking cessation. Drug Ther Bull them actually succeed. comparable to the very 2000;38:73-75.  http://www.ash.org.uk/ widely used anti-depressant  Raw M, McNeill A, West R. Smoking cessation guidelines for health professionals. A guide to effective smoking cessation intervention for the The good news is that quitting smoking drugs. health care system. Thoraxo 1998;53 (Suppl 5) Parts 1 and 2. has substantial and immediate health  American Thoracic Society. Cigarette smoking & health. Am J Respir Crit. Med. 1996;153;861-865. benefits for smokers of all ages. One year “No-one should be put off  McKenzie TD, Bartecchi CE, Schrier RW. The human costs of tobacco use (second part of 2 parts) N. Eng J Med. 1994;330:975-980. after someone stops smoking, their excess using Zyban to help them  ADRAC 2001. (http:www.%20ADRAC.com) risk of heart disease is half that of a stop smoking. Not only is it smoker’s. Within five years, the risk is the effective in helping people same as that of a non-smoker. The risk of quit, but it also helps lung cancer is reduced by about 50 per prevent the heart disease, cent after ten years. And the overall risk of cancer and respiratory death approaches that of someone who illnesses that are so often has never smoked after ten to 15 years. the fate of smokers.” This is an information document and education aid produced by GSK Pharmaceuticals Europe, 980 Great West Road, Brentford, TW8 9GS, UK.