PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, VOL 1: 15 1-1 54 (1992)

REVIEW

Aspirin and Reye’s Syndrome - an over-the-counter Adverse Reaction

SHEILA KELLY The Proprietary Association of Great Britain, Vernon House, Sicilian Avenue, London, W C l A 2QH

KEY WORDS - Adverse drug reaction, non-prescription medicines, aspirin, Reye’s Syndrome

The Proprietary Association of Great Britain (PAGB) is the trade association representing the manufacturers of non-prescription or over-the counter (OTC) medicines. We are a regulatory body for the industry because we control all the advertising that is directed to the public through our code of practice. The system is based on pre- publication vetting so it brings us into daily contact with our 75 companies and we hold copies of their product licences. We are also the association con- sulted by the Government on all relevant issues and we have close involvement with companies and the Medicines Control Agency (MCA) on every- thing to do with the regulations governing this seg- ment of the pharmaceutical market.

Most of thedata about the usage ofnon-prescrip- tion medicines are generated by the companies who sell them. They obviously have the sales data, and they are constantly carrying out market research to find out how people are using their products. To gain some information on the whole market, PAGB asked the British Market Research Bureau to carry out a study in 1200 volunteers over a whole year. They conducted face-to-face interviews and asked about minor illnesses and attitudes to medi- cines.

The study showed that on average people in the United Kingdom (UK) suffer from five episodes of ill health in any 2-week period. This shows that the symptom pool is enormous: five episodes each fortnight in a population of 56 million people. This means that there are 280 million symptoms a fort- night; about 2 million symptoms a day.

The conditions concerned are ailments such as headaches, coughs, colds, aches and pains, skin problems and digestive disorders. Most people do not take anything for these conditions. But about

24% use a non-prescription medicine, which they choose and use entirely on their own without medi- cal advice for conditions that they have diagnosed for themselves.

They buy their medicines from a variety of out- lets. About three-quarters are bought in pharma- cies. The rest come from supermarkets, corner shops, service stations and other outlets. In most cases, they are family medicines bought along with the household shopping for use by several members of the family.

The main difference between prescription and non-prescription medicines is that non-prescription medicines are chosen by the consumers themselves, not by doctors. The potential for adverse effects may seem to be high but, in fact, there are consider- able safeguards.

The first of these is that users of non-prescription medicines are very cautious and conservative. They tend to choose one product and to stick to it. The study described earlier showed that over 80% of people were satisfied with the way their medicines worked and that they would choose the same medi- cine again. This means that they know which prod- ucts suit them and that they do not keep changing.

Obviously, the medicines that are available for use in self-medication are carefully evaluated by the MCA with this use in mind. New drugs are never immediately available for self-medication. They are restricted to prescription-only supply until the adverse drug reaction (ADR) profile is well established. The Medicines Act allows the MCA to enforce prescription-only (POM) status for at least 5 years. In practice, most medicines remain in this category for much longer. Most of the ingredients used in non-prescription medicines

1053-8569192/030151-04$05.00 0 1992 by John Wiley & Sons, Ltd.

Received 10 February 1992 Accepted 15 April I992

152 SHEILA KELLY

have been known for decades and new ADRs are not expected.

In recent years, the ingredients of these medicines have been moving from prescription control. Seven major ingredients have moved in this way since the process began in 1983. A consultation letter, which has just been issued, proposes that the imidazoles should be released for the treatment of vaginal can- didosis. These moves do not happen without a full review of the ADR data, including a reassessment of the potential for risk if the product is used with- out medical advice. When ibuprofen moved from prescription control, its non-prescription indica- tion for headache was different from the established indication for arthritis and new clinical work had to be carried out before the change was agreed.

To help people decide whether the product is the right one for them and to make sure that they use it correctly considerable information is given. For example, the non-prescription version of hyd- rocortisone can be sold (without prescription) only for irritant and contact dermatitis and insect bites and stings. The front of the pack of these products helps people to realize what conditions the medi- cine can be used for by giving examples of the agents that may have caused the reaction - and the rest of the pack gives instructions about usage, duration of use and warnings about not using the product on the face or other areas of the body where absorption may be high.

The industry has always given much information with non-prescription medicines. This is because the products are chosen by lay people and generally are used only intermittently and by families: if the information is on the pack itself then it is still there 6 months or a year later when the product is used again.

New adverse reactions with non-prescription medicines are rare but they do occur. When they happen they are reported by doctors through the yellow card system, which is used for prescription medicines. They also tend to be reported in medical journals and, in the past few years, a sprinkling of warnings have appeared in the warning letters sent by the Committee on Safety of Medicines (CSM) to pharmacists and doctors. But, given the amount of usage, these reports are few.

In 1986, just such a major ADR event occurred with one of the oldest non-prescription ingredi- ents-aspirin.

Aspirin was first marketed in 1899, and it might be expected that in nearly 100 years everything would be known about it. This is not the case and

new indications are still being investigated, such as its use in heart disease.

Reye’s syndrome was first reported in 1963. It is a very severe disorder that is almost entirely limited to children. The usual situation is that of a child recovering from a feverish condition who suddenly becomes ill again. There is protracted vomiting then signs of brain dysfunction, such as lethargy, staring, stupor, delirium, screaming, rapid respiration, spasms and coma, leading to death or survival with severe brain damage.

No single cause of the condition is known and it is believed to have a multifactorial aetiology. A genetic or metabolic factor is thought to be one cause; pesticides have been investigated as another trigger.

Aspirin began to be considered as one factor in the aetiology of Reye’s syndrome in the late seven- ties in the United States (US). Studies, small scale, and not particularly well controlled, were carried out in Arizona, Michigan and Ohio. These involved about 200 cases of Reye’s syndrome and seemed to show that salicylates were more likely to have been taken in the Reye’s syndrome cases compared with the controls.

The Centre of Disease Control in the US reviewed all the data with the help of external con- sultants and concluded that there was no causative link. All the studies had methodological problems and so the Public Health Service carried out a further better controlled study that eliminated these problems. The pilot phase of the study was avail- able in 1984. There were 30 cases of Reye’s syn- drome and 28 (or 93%) had received salicylates. The pre-disposing viral conditions were often influenza or chickenpox.

These US data led to requirements for manufac- turers to put warnings on their packs of aspirin, and the Food and Drugs Administration (FDA) instituted an educational programme aimed at the general public and doctors to warn against the use of aspirin in children with the two pre-disposing conditions. It also triggered the need for the UK to consider whether action should be taken here.

A study of Reye’s syndrome began in the UK in 198 1, and in 1986 the UK data became available from the Reye’s Syndrome Surveillance Scheme; these data added to the evidence that there was some link between aspirin and the condition.

The UK study showed that the disease pattern seemed to be different. In the US, the previous viral condition was often influenza or chickenpox. In the UK, there was no such link with influenza and

0 1992 by John Wiley & Sons, Ltd. PHARMACOEPIDEMIOLDGY AND DRUG SAFETY, VOL. 1: 15 1-1 54 (1992)

ASPIRIN A N D REYE’S SYNDROME 153

the viral conditions seemed to be more diverse. There was no winter peak in the UK, and the chil- dren were much younger. While the American chil- dren were generally teenagers, the median age in the UK was 14 months and 93% ofcases were under 12 years of age.

With this weight of evidence, the CSM thought that action was necessary and brought PAGB into the picture. The CSM recommendation was that aspirin may be a contributory factor in the aetio- logy of Reye’s syndrome in some children and. therefore, that it should not be used in feverish conditions without medical advice, and that pae- diatric products containing aspirin should no longer be on general sale.

If aspirin had been a prescription product, the saga might have ended there, with doctors receiving the usual letter from the CSM; there would have been amendments to the data sheet and little publi- city. With an ingredient such as aspirin this was not an option.

Table 1 summarizes the problem and was the basis of our discussions with the licensing auth- ority. ADRs usually involve prescription products and often just one company holds the licence. Even if the product is out of patent, there is usually one company with the full database. Discussion with one company can be conducted quickly and easily and action agreed. For aspirin, there were 180 licences and numerous ‘own-label’ variations sold by supermarket chains such as Safeway or Tesco.

With prescription products there are only 11000 retail outlets, while a general sale product such as aspirin is sold from about 123000 outlets.

The major aspirin companies were members of PAGB and the Aspirin Foundation, which spon- sors research into aspirin. We called our companies together and told them in confidence about the CSM recommendation.

The first decision made by the industry was that they would not just remove the paediatric products from general sale but that they would take them ofT the market completely. The industry thought that all illnesses experienced by young children were feverish in nature and that if the product was not to be used for such conditions then it should not be on the market.

We then looked at the adult aspirin packs. The magnitude of the problem was realized when the number of packs in circulation was considered. In each pharmacy, some prescription products will have one or two packs ~ perhaps 30000 packs in all. We estimated that there were around 25 million

aspirin packs in the distribution chain, and that if there was an average of one pack per household then a further 21 million packs were in people’s homes.

These packs had label instructions, which included children’s doses, and they would be in the home for a long period of time. If the average household purchases an aspirin pack once or twice a year, then it would be a long time before the new packs filtered through and, as we were dealing with such an old ingredient, it was likely that people were not reading the packs.

We decided that label warnings alone would not work. We needed to tell the public directly about this change in product usage. We needed to do this in co-operation with the Department of‘Health. We found that the department was planning its own information campaign directed to doctors and pharmacists in the usual way, so ours could dovetail into it.

The campaign to tell people about the change in use was developed by J. Walter Thompson. They were asked to develop a campaign that would get attention without alarming people unnecessarily. They recommended press advertising, as the story was a complicated one and print would give time to read it and take it in.

The target audience was housewives with chil- dren. There are around 7 million such persons in the UK. The advertisements appeared in the natio- nal daily and Sunday press, with some targeting to the ethnic press in relevant areas. We expected that we would achieve 73% coverage of the target audience. Newspaper readership in this country is high, and an issue like this involving child safety was bound to attract attention in editorial as well as in the advertising itself. The campaign was launched with a press conference held jointly with the Department of Health. The Chief Medical OR- cer explained the problem and the industry con- firmed the response. Such a story of course generated an enormous amount of coverage - and this added to the impact of the campaign.

The visual used a child’s hand with a tablet in it. Companies never portray such images in medi- cines advertising and it was thought that this would work best. The headline explained what the adver- tisement was about and the body copy explained the problem while emphasizing its extreme rarity.

The press campaign was supplemented by broad- cast coverage. The Department of Health activated its red alert system, which guarantees that all the major television news stations give the announce-

0 1992 by John Wiley & Sons, Ltd. PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, VOL. 1: 15 1-154 (1992)

154 SHEILA KELLY

ment priority; in the broadcast media the advertise- ment was covered by national and regional tele- vision and radio. A total of 109 ‘spots’ were tracked over the week following the announcement.

The aim was to get parents to stop buying junior aspirin (the 75 mg dosage form), to stop them giving adult aspirin to children and to inform people with- out making them think that aspirin was dangerous for everyone. We wanted to avoid the usual press reaction and we wanted to reassure parents who had given aspirin to their children in the recent past.

Did we achieve our aims? Well, taking the chil- dren‘s products off the shelves was easy to achieve. Products flooded back into the manufacturers within days. The advertising campaign was tested with follow-up market research and it showed that people were aware that there was a problem of aspirin and children and that their first reaction was not to give their children anything but to take them to the doctor for advice.

At PAGB, vast numbers of telephone calls were expected on the day the news broke. We had a few from journalists wanting to know which prod- ucts contained aspirin, our biggest problem was that of complaints from people who had been tak- ing the 75 mg tablets to prevent secondary myocar- dial infarction. We received complaints from users and doctors on this point and, in due course, the products were made available for this indication under medical supervision.

This UK action led to reviews of aspirin and Reye’s syndrome in the European Economic Com- munity and throughout the world. Most countries required manufacturers to put warnings on the leaf- lets for the products and most of the warnings fol- low the US pattern, rather than that of the UK. Ireland made the children’s product prescription

only, and France is still insisting that Reye’s syn- drome does not exist.

No other industry groups went as far as we did in the UK and now, 6 years later, some observers say that we did not need to do this. We went too far responding to a very weak case and destroyed a market, which had some very successful products.

We thought that the action was right, that the campaign had worked and that the industry had acted in a responsible way.

The market for non-prescription medicines is vitally dependent on a very high level of safety, the provision of good information with the prod- uct, and the existence of trust between the user and supplier. In this case we maintained that trust and

Table I-Composition of pharmaceutics data for aspirin and prescription-only medicine

Prescription- Aspirin only

production

Licences involved Usually 1 180 and own labels

Retail outlets 11000 123000

Packs 30000 46 million

Labels Pharmacist Company

Implementation Doctors and Public Dharmacists

users of OTC medicines know that if a new problem arose that the industry would respond properly, and that they would not be put unnecessarily at risk. If such a situation ever arose again, I am sure that we would take the same steps.

0 1992 by John Wiley & Sons, Ltd. PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, VOL. 1: 151-154 (1992)