Over the counter medication
June 2005
Risk of adverse events
All pharmacologically active substances will have a main ‘intended’ effect and other effects known as ‘side effects’. Side effects may be beneficial in their own right, cause a minor inconvenience, or pose a serious threat to health. OTC drugs are no exception.
Adverse events associated with a drug can either be potentially predictable based on pharmacological principles, or idiosyncratic and therefore unexpected. There might also be an increase in a common event, which may not immediately be linked to drug use. The unexpected are almost always rare events, may arise as a direct result of the action of the drug per se, or its interaction with other drugs. In retrospect they might have been predictable as with the COX-2 selective NSAIDs [go to reference 4]. By virtue of their rarity, they are increasingly likely to be identified as volume of usage increases. Some adverse events can be fatal.
When a new medicine is proposed for deregulation its current safety profile, as a prescription-only medicine, is one of the key data sources used to inform decision making. At that point, however, the above noted rare events may not be apparent and continued systematic pharmacovigilance is important to monitor events as usage increases as a result of OTC availability. Reassessment of status as an OTC may also be necessary as is illustrated by the example below.
One of the first medicines to be deregulated was the second-generation non-sedating antihistamine terfenadine. It is a good example of a well-used drug which caused an idiosyncratic adverse event, which was only identified after widespread use. It was deregulated in 1984, and in 1992 was formally linked to serious and sometimes fatal cardiac arrhythmias. This occurred when terfenadine was taken by patients with cardiac or hepatic disease, in overdose, or with drugs with which it interacted (eg ketoconazole), or certain food stuffs (eg grapefruit juice) (Anonymous 1997, Committee for Safety of Medicines and Medicines Control Agency 1992). The product was first restored to prescription-only use (1997), but soon removed completely from UK availability.
Perhaps more unexpected have been the serious interactions between the herbal preparation St John’s Wort (hypericum perforatum) and some commonly prescribed drugs, including warfarin, ciclosporin, oral contraceptives, digoxin, theophylline, and selective serotonin reuptake inhibitors. Reduced blood concentrations of these drugs result from the enzyme inducing properties of St John’s Wort. Although theoretically predictable, the herbal classification of the product means that there are limited regulatory mechanisms in the UK to control its distribution and use. Awareness of the specific problem with St John’s Wort has been raised through official letters from the Committee on Safety of Medicines to pharmacists and doctors (Committee on Safety of Medicines 2000). In Ireland certain herbal remedies such as St John’s Wort have relatively recently been reclassified as POM, although this is reported to have been an unpopular move with the public. A further example of a safety issue with a herbal product is kava-kava [go to reference 5] (Breckenridge 2002). Of general concern is the fact that the ‘herbal’ label seems to be associated by the public with safety due to its ‘natural’ content, resulting in a lack of recognition from both the public and professionals of the potential potency of the products.
Some side effects may be predictable such as the increased risk of gastro-intestinal bleeding from the use of NSAIDs. Although there is some evidence that ibuprofen is as safe as paracetamol when used at OTC doses, and for short duration (Moore et al 1999) it cannot always be assumed that OTC drug users will adhere to the licensing restrictions. In a small Scottish study (Sinclair et al 2001, Sinclair et al 2000), purchasers of ibuprofen were followed up over six months. Subjects reported that they were using OTC ibuprofen for long-term conditions, and over extended periods of time (for example more than 13 weeks). More significantly, just under 10 per cent took doses above those recommended for OTC use, and some even above the recommended prescribed dose. Small numbers also took ibuprofen when they had an active or past history of peptic ulcer, or asthma, both of which are contra-indicated co-morbidities. Patient follow up indicated an increased incidence of GI events. However, the key finding is that it cannot be assumed that all OTC medicine users will adhere to the recommended dosage regimes on which predicted safety is based. Improved labelling, patient education and support might be ways to overcome these problems while maintaining the advantages of OTC availability.
The examples given above illustrate the need to be alert to the potential for ‘safe’ OTC drugs to cause unexpected problems, either when used on their own or in combination with other prescribed products. Formal mechanisms should be in place to support this and are discussed further in section 5, Information and communication.
Footnotes
[4] COX-2 selective NSAIDs are associated with increased risk of cardiovascular events and several have now been withdrawn or are subject to ‘caution in use’ advice (Committee on Safety of Medicines 2004). These selective NSAIDs were associated with reduced gastro intestinal effects compared to non- selective NSAIDs because of the limited inhibition of COX-1 which has a gastro protective effect. However inhibition of COX-1I is also related to reduced to blood clot formation. This is the rationale for people to take daily low dose aspirin, and one explanation for the increased cardiovascular risk of the COX-2 drugs (Davies and Jamali 2004).
[5] ‘On the basis of the data available, the Committee on Safety of Medicines (CSM) has reached the provisional view that the possible therapeutic benefits of medicinal products containing the herbal ingredient kava-kava (piper methysticum) can not be considered to outweigh the safety risks. Kava-kava is considered to have the potential to cause hepatotoxicity which may be serious. The level of risk is not known but is likely to be rare at normal doses. The mechanism of toxicity is not understood and there are no clear predictors of toxicity’ CEM/CMO/2002/10.