Rawlins–Thompson classification

The Rawlins–Thompson system of classification divides ADRs into two main groups: Type A and Type B (Rawlins, 1981). Type A reactions are the normal, but quantitatively exaggerated, pharmacological effects of a drug. They include the primary pharmacological effect of the drug, as well as any secondary pharmacological effects of the drug, for example, ADRs caused by the antimuscarinic activity of tricyclic anti-depressants. Type A reactions are most common, accounting for 80% of reactions.

Type B reactions are qualitatively abnormal effects, which appear unrelated to the drug’s normal pharmacology, such as hepatoxicity from isoniazid. They are more serious in nature, more likely to cause deaths, and are often not discovered until after a drug has been marketed. The Rawlins–Thompson classification has undergone further elaboration over the years (Table 5.1) to take account of ADRs that do not fit within the existing classifications (Edwards and Aronson, 2000).

Table 5.1 Extended Rawlins–Thompson classification of adverse drug reactions

The DoTS system

The DoTS classification is based on Dose relatedness, Timing and patient Susceptibility (Aronson and Ferner, 2003). In contrast to the Rawlins–Thompson classification, which is defined only by the properties of the drug and the reaction, the DoTS classification provides a useful template to examine the various factors that both describe a reaction and influence an individual patient’s susceptibility.

DoTS first considers the dose of the drug, as many adverse effects are clearly related to the dose of the drug used. For example, increasing the dose of a cardiac glycoside will increase the risk of digitalis toxicity. In DoTS, reactions are divided into toxic effects (effects related to the use of drugs outside of their usual therapeutic dosage), collateral effects (effects occurring within the normal therapeutic use of the drug) and hyper-susceptibility reactions (reactions occurring in sub-therapeutic doses in susceptible patients). Collateral effects include reactions not related to the expected pharmacological effect of the drug or off-target reactions of the expected therapeutic effect in other body systems. It is worth noting that approximately 20% of newly marketed drugs have their dosage recommendations reduced after marketing, often due to drug toxicity.

The time course of a drug’s presence at the site of action can influence the likelihood of an ADR occurring. For example, rapid infusion of furosemide is associated with transient hearing loss and tinnitus, and a constant low dose of methotrexate is more toxic than equivalent intermittent bolus doses. DoTS categorises ADRs as either time-independent reactions or time-dependent reactions. Time-independent reactions occur at any time within the treatment period, regardless of the length of course. Time-dependent reactions range from rapid and immediate reactions, to those reactions which can be delayed.

The final aspect of the DoTS classification system is susceptibility, which includes factors such as genetic predisposition, age, sex, altered physiology, disease and exogenous factors such as drug interactions (Table 5.2)

Table 5.2 DoTS system of ADR classification

Age

Elderly patients may be more prone to ADRs, with age-related decline in both the metabolism and elimination of drugs from the body. They also have multiple co-morbidities and are, therefore, exposed to more prescribed drugs. Chronological age is, therefore, arguably a marker for altered physiological responses to drugs and for the presence of co-morbidities and associated drug use rather than a risk per se. As the population ages, the mitigation of preventable ADRs in the elderly will become increasingly important.

Children differ from adults in their response to drugs. Neonatal differences in body composition, metabolism and other physiological parameters can increase the risk of specific adverse reactions. Higher body water content can increase the volume of distribution for water-soluble drugs, reduced albumin and total protein may result in higher concentrations of highly protein bound drugs, while an immature blood–brain barrier can increase sensitivity to drugs such as morphine. Differences in drug metabolism and elimination and end-organ responses can also increase the risk. Chloramphenicol, digoxin, and ototoxic antibiotics such as streptomycin are examples of drugs that have a higher risk of toxicity in the first weeks of life.

Older children and young adults may also be more susceptible to ADRs, a classic example being the increased risk of extrapyramidal effects associated with metoclopramide. The use of aspirin was restricted in those under the age of 12, after an association with Reye’s syndrome was found in epidemiological studies. Additionally, children can be exposed to more adverse effects due to the heightened probability of dosing errors and the relative lack of evidence for both safety and efficacy.

Gender

Women may be more susceptible to ADRs. In addition, there are particular adverse reactions that appear to be more common in women than men. For example, impairment of concentration and psychiatric adverse events associated with the anti-malarial mefloquine are more common in females.

Females are more susceptible to drug-induced torsade de pointes, a ventricular arrhythmia linked to ventricular fibrillation and death. Women are also over-represented in reports of torsades de pointes associated with cardiovascular drugs (such as sotalol) and erythromycin. This increased susceptibility in women is thought to be due to their longer QTc interval compared to men.

Co-morbidities and concomitant medicines use

Reductions in hepatic and renal function substantially increase the risk of ADRs. A recent study examining factors that predicted repeat admissions to hospital with ADRs in older patients showed that co-morbidities such as congestive cardiac failure, diabetes, and peripheral vascular, chronic pulmonary, rheumatological, hepatic, renal, and malignant diseases were strong predictors of readmissions for ADRs, while advancing age was not. Reasons for this could be pharmacokinetic and pharmacodynamic changes associated with pulmonary, cardiovascular, renal and hepatic insufficiency, or drug interactions because of multiple drug therapy (Zhang et al., 2009).

Ethnicity

Ethnicity has also been linked to susceptibility to ADRs, due to inherited traits of metabolism. It is known, for example, that the cytochrome P450 genotype, involved in drug metabolism, has varied distribution among people of differing ethnicity. For example, CYP2C9 alleles associated with poor metabolism can affect warfarin metabolism and increase the risk of toxicity. This occurs more frequently in white individuals compared to black individuals.

Examples of ADRs linked to ethnicity include the increased risk of angioedema with the use of ACE inhibitors in black patients (McDowell et al., 2006), the increased propensity of white and black patients to experience central nervous system ADRs associated with mefloquine compared to patients of Chinese or Japanese origin, and differences in the pharmacokinetics of rosuvastatin in Asian patients which may expose them to an increased risk of myopathy. However, susceptibility based on ethnicity could be associated with genetic or cultural factors and ethnicity can be argued to be a poor marker for a patient’s genotype.

Pharmacogenetics

Pharmacogenetics is the study of genetic variations that influence an individual’s response to drugs, and examines polymorphisms that code for drug transporters, drug-metabolising enzymes and drug receptors. A greater understanding of the genetic basis of variations that affect an individual’s response to drug therapy has promised to lead to a new era of personalised medicine. Arguably, pharmacogenetics has yet to deliver on an appreciable scale, the reduction in ADRs that was predicted. However, there are some important examples of severe ADRs that may be avoided with knowledge of a patient’s genetic susceptibility.

As already noted, major genetic variation is found in the cytochrome CYP450 group of isoenzymes. This can result in either inadequate responses to drugs, or increased risk of ADRs. Clinically relevant genetic variation has been seen in CYP2D6, CYP2C9, CYP2C19 and CYP3A5. A large effect on the metabolism of drugs can occur with CYP2C9, which accounts for 20% of total hepatic CYP450 content.

The narrow therapeutic index of warfarin, its high inter-individual variability in dosing and the serious consequences of toxicity have made it a major target of pharmacogenomic research. Studies of genetic polymorphisms influencing the toxicity of warfarin have focused on CYP2C9, which metabolises warfarin and vitamin K epoxide reductase (VKOR), the target of warfarin anticoagulant activity. Genetic variation in the VKORC1 gene, which encodes VKOR, influences warfarin dosing by a threefold greater extent than CYP2C9 variants. In 2007, the U.S. Food and Drug Administration (FDA) changed the labelling requirement for warfarin, advising that a lower initial dose should be considered in people with certain genetic variations. However, concerns remain because genetic variation only accounts for a proportion of the variability in drug response and clinicians may obtain a false sense of reassurance from genetic testing leading to complacency in monitoring of therapy. In addition, there appears to be little evidence of additional benefit (Laurence, 2009), in terms of preventing major bleeding events, compared to careful monitoring of the INR (see chapter 23)

A success story for pharmacogenetics is the story of the nucleoside analogue reverse transcriptase inhibitor (NRTI) abacavir. Hypersensitivity skin reactions to abacavir are a particular problem in the treatment of human immunodeficiency virus (HIV) infection. Approximately 5–8% of patients taking abacavir develop a severe hypersensitivity reaction, including symptoms such as fever, rash, arthralgia, headache, vomiting and other gastro-intestinal and respiratory disturbances. Early reports that only a subset of patients was affected, a suspected familial predisposition, the short onset time (within 6 weeks of starting therapy), and an apparent lower incidence in African patients led to suspicion of a genetic cause. Subsequent research revealed a strong predictive association with the human leukocyte antigen HLA-B*5701 allele in Caucasian and Hispanic patients. The presence of the allele can be used to stratify the predicted risk of hypersensitivity as high risk (>70%) for carriers of HLA-B*5701 and low risk (<1%) for non-carriers of HLA-B*5701. Evidence from the practical use of HLA-B*5701 screening has shown substantial falls in the incidence of hypersensitivity reactions, as well as a more general improved compliance with the medication (Lucas et al., 2007).

Another example of a success story for pharmacogenetics involves the cutaneous ADRs Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Both are serious reactions associated with substantial morbidity and mortality in which up to 40% of patients with TEN may die. SJS and TEN have been associated with numerous drugs, although the incidence of these reactions is extremely rare. Anti-epileptic drugs, such as carbamazepine and phenytoin, are known causes of SJS and TEN. The reactions are more common in South East Asian populations, including those from China, Thailand, Malaysia, Indonesia, the Philippines and Taiwan and, to a lesser extent, India and Japan. The presence of HLA allele, HLA-B*1502, for which genetic testing is available, indicates an increased risk of skin reactions for carbamazepine, phenytoin, oxcarbamazepine and lamotrigine. The FDA has recommended HLA-B*1502 screening before using carbamazepine and phenytoin in South East Asian individuals.

Erythrocyte glucose-6-phophatase dehydrogenase (G6PD) deficiency

G6PD deficiency is present in over 400 million people world-wide. It is a sex-linked inherited enzyme deficiency, leading to susceptibility to haemolytic anaemia. Patients with low levels of G6PD are predisposed to haemolysis with oxidant drugs such as primaquine, sulphonamides and nitrofurantoin. There are many variants of the genotype, leading to varied susceptibilities in individuals.

Porphyrias

The porphyrias are a heterogeneous group of inherited disorders of haem biosynthesis. The disorders are transmitted as autosomal dominants, with the exception of the rare congenital porphyria, which is recessive. The effects of drugs are of most importance in patients with acute porphyrias, in which certain commonly prescribed agents may precipitate life-threatening attacks. Other trigger factors include alcohol and changes in sex hormone balance. In the acute porphyrias, patients develop abdominal and neuropsychiatric disturbances, and they excrete in their urine excessive amounts of the porphyrin precursors 5-aminolaevulinic acid (ALA) and porphobilinogen.

A number of drugs may induce excess porphyrin synthesis. However, it is extremely difficult to predict whether or not a drug may cause problems in patients with porphyria and the only factors shown to be clearly linked with porphyrinogenicity are lipid solubility and membrane fluidisation, that is, the ability to disrupt the phospholipid bilayer of the cell membrane. A number of commonly used drugs induce ALA synthase in the liver, but there is wide variation between porphyric patients in their sensitivity to drugs which may trigger attacks. Thus, whereas a single dose of a drug may be sufficient to trigger an acute attack in one patient, another may require a number of relatively large doses of the same drug to produce any clinically significant effect. Lists of drugs which are known to be unsafe and drugs which are thought to be safe for use in acute porphyria are available in the British National Formulary.

Spontaneous reporting

Pharmacovigilance uses multiple methods, but the following will focus on spontaneous reporting systems. Spontaneous reporting systems collect data about suspected ADRs in a central database. Cases are not collected in a systematic manner, but accumulate through reports submitted spontaneously by people who make a connection between a drug and a suspected drug-induced event. In the UK, the spontaneous reporting scheme is the Yellow Card scheme. In some countries reporting is a voluntary activity, in others reporting is a legal requirement. There is no evidence that such a requirement increases reporting rates.

Spontaneous reporting has a number of advantages. It is relatively cheap to administer, can follow a product throughout its life and can also accept reports to over-the-counter medication and herbal treatments. Such schemes are, however, passive surveillance systems, which rely on the ability of health professionals to recognise possible ADRs and to distinguish these from symptoms related to underlying disease. It is important to emphasise that only a suspicion of a causal link between a drug and an adverse event is required, not confirmation of the association. One disadvantage of spontaneous reporting systems is their inability to quantify the risk. Such systems supply a numerator (the number of reports), but estimates of the incidence of reactions cannot be made because the population exposed to the drug cannot be ascertained accurately. Furthermore, only a minority of reactions are reported. Spontaneous reports are, however, an important form of evidence leading to drug withdrawals and are crucial for hypothesis generation.

Yellow Card Scheme

The UK’s Yellow Card Scheme was established in 1964 following the thalidomide tragedy. The Scheme is operated by the Medicines and Health care Products Regulatory Authority (MHRA). Health care professionals and coroners can submit reports of suspected ADRs using a Yellow Card (found in the British National Formulary) or using an on-line form (http://www.yellowcard.gov.uk). An association between the medicine and the event does not have to be confirmed. A suspicion is sufficient for a report to be submitted. The MHRA request that all serious suspected ADRs are reported by health care professionals concerning established medicines (drugs and vaccines). For newer drugs and vaccines, all suspected ADRs should be reported, even if minor events. Newer medicines under intensive surveillance are identified with an inverted black triangle symbol in product information and standard prescribing texts. Black triangle status is generally maintained for at least 2 years, but the period varies, depending on how much information is obtained about a product’s continued safety. All suspected ADRs occurring in children should be reported even if the medicine has been used off-label.

Information from Yellow Card reports is entered into a database, suspected reactions are categorised using the internationally accepted Medical Dictionary for Regulatory Affairs (MedDRA) and the resultant signals generated by the combined reports are then assessed for causality. Where there is a valid signal which may be an ADR, further work may be required to assess the association further. This could involve requesting further details from reporters, contacting manufacturers, reviewing the literature or conducting pharmacoepidemiological studies. The MHRA estimates that about 40% of the safety signals investigated by the Agency are generated from spontaneous reports.

When new ADRs are identified and an association confirmed, the MHRA may take action in the form of changes to the Summary of Product Characteristics (SmPC) and/or the patient information leaflet (PIL), restricting usage or withdrawing marketing authorisation for the medicine. Withdrawal of marketing authorisation or change in use requires that prescribers and suppliers be informed immediately, but such information is also usually publicised in the media; hence, patients are often aware of these actions and may present with requests for information and advice.

Unfortunately, spontaneous reporting systems, including the Yellow Card Scheme, suffer from severe under-reporting. A systematic review estimated this to be between 82% and 98% (Hazell and Shakir, 2006). There are a variety of reasons for this, including lack of certainty that the medicine caused the symptom, but it is important to emphasise that such certainty is not required. There is also no requirement to provide the patient name or contact details, only those of the actual reporter; hence, confidentiality, also cited as a reason for under-reporting, is no longer an issue. Furthermore, the MHRA have systems in place to check for duplicate reports covering the same incident, thereby eliminating concern about two people submitting reports about the same event in a given patient.

Published case reports

The first suspicions of a less common or unpredictable reaction may often be seen in a case report from a practitioner. As seen by the cases of thalidomide and practolol, astute and vigilant clinicians submitting case reports to the medical press has been of importance in drug safety. Case reports have been described as a form of non-systematic voluntary reporting. However, reports are not solicited and their appearance in the medical literature is in the gift of medical editors. Editors may demand a causal link, or a case series, requiring higher standards of investigation than regulatory agencies demand from a spontaneous report. These high standards can prevent case histories from reaching publication and deter many clinicians. Furthermore, the time it takes for a case report about a suspected ADR to be published could be several months, during which time more patients may be exposed to the potential risk.

Cohort studies

Cohort studies are prospective pharmacoepidemiological studies that monitor a large group of patients taking a particular drug over a period of time. Ideally such studies compare the incidence of a particular adverse event in two groups of patients, those taking the drug of interest and, another group, matched for all important characteristics except the use of the drug. These studies can indicate the relative risks associated with the adverse event in people exposed to the drug being studied.

Case–control studies

Case–control studies compare the extent of drug usage in a group of patients who have experienced the adverse event with the extent of usage among a matched control group who are similar in potentially confounding factors, but have not experienced the event. By comparing the prevalence of drug taking between the groups, it may be possible to identify whether significantly more people who experienced the event also took a particular drug. Examples of associations which have been established by case–control studies are Reye’s syndrome and aspirin and the relationship between maternal diethylstilboestrol ingestion and vaginal adenocarcinoma in female offspring. Case–control studies are an effective method of confirming whether or not a drug causes a given reaction once a suspicion has been raised. Being retrospective, they rely on good record-keeping about drug use and are not capable of detecting previously unsuspected adverse reactions.

Identifying and assessing ADRs in clinical practice

Outside the pharmacovigilance environment of companies and regulatory agencies, the identification of potential ADRs is an essential component of clinical practice. Although assessments in practice may lack the formality of expert or algorithmic assessment, they are likely to take into account similar factors, such as whether the clinical event is commonly drug related, the temporal relationship with drug use, a dose relationship and exclusion of other possible causes. A list of such factors is set out in Box 5.1.

There are many triggers which can lead to the suspicion of an ADR. For example, changes in medicines, dose reduction, prescription of medicines used to treat allergic reactions or those frequently used to counteract the effects of other drugs. Simple questioning of patients could easily be incorporated into many aspects of routine care to increase the chances of detecting potential ADRs.

The process of identifying an ADR then involves making a judgement about whether or not a particular event such as a symptom, condition or abnormal test result could be related to a drug used in the patient experiencing the event. The prior experiences of the patient with other medicines should also be taken into consideration.

Every opportunity should be taken to question patients about their experience, to determine whether they perceive any adverse events which could be due to medicines. While routinely asking simple questions is important, it is of equal value to develop a positive attitude towards the patients’ perception of suspected ADRs. There is some evidence that health professionals may dismiss patients who report that they have experienced an ADR, but many patients identify such problems appropriately, using factors such as onset, effect of dose change, effect of de-challenge or even re-challenge, as well as the information sources freely accessible to them (Krska et al., 2011). To ascertain whether a symptom reported by a patient can be reasonably suspected of being an ADR requires careful questioning.

As stated above, the MHRA encourage reporting of all serious suspected ADRs to established drugs and all suspected ADRs to new drugs or vaccines. If not reporting themselves, health professionals should consider encouraging others to report. For example, a community pharmacist may have insufficient information to complete a Yellow Card as fully as possible, so may encourage a general practitioner to report. Alternatively, a hospital pharmacist may report on behalf of a consultant clinician. Encouraging others to report also extends to providing information about reporting and educating others, including patients, to report. Community pharmacies and general medical practices should all have a supply of Yellow Cards for patients, but patients may require advice and support in completing these. Pharmacists in particular, because of their role in dispensing prescriptions, may also be involved in educating and supporting others in preventing ADRs and in developing methods to detect ADRs through prescription monitoring.

Preventing ADRs

The majority of ADRs are thought to be preventable; hence, there is potential to dramatically reduce the costs associated with ADRs and possibly also deaths. Assessing preventability is a difficult area, since it involves judgements and many different methods have been developed for making these judgements. The approach of Hallas et al. (1990) is widely used, providing definitions of avoidability which range from definite (due to a procedure inconsistent with present-day knowledge or good medical practice) to unevaluable (poor data or conflicting evidence). Recent estimates suggest that between 53% and 72% of hospital admissions due to ADEs are preventable, while a meta-analysis (Beijer and de Blaey, 2002) showed that 88% of ADRs causing hospital admission in the elderly were preventable. However, not all ADRs are absolutely preventable and assessments using hindsight are unlikely to replicate clinical decision making at the point of prescribing. Preventability also varies from those with clear solutions, such as the prescribing of a teratogenic drug to a female of child bearing age, to those where the drug increases the risk of an event that occurs within the population.

ADRs can be prevented by checking previous ADR history, minimising the use of drugs known to carry a high risk of ADRs and tailoring drug selection to individuals based on the factors which predispose them to ADRs. Strategies are still required to minimise the burden of ADRs, but many recent initiatives have the potential to do so. For example, electronic decision support, increasing regular review of medicines, improved sharing of information about patients between health care providers and the increasing availability of guidance on drug selection and appropriate use should all increase rational prescribing, which may have an effect on the incidence of ADRs.

Monitoring therapy

Monitoring the effects of drugs either by direct measurement of serum concentration or by measurement of physiological markers is another potential mechanism to reduce the risk of ADRs. For example, it has been estimated that one in four of preventable drug-related hospital admissions are caused by failure to monitor renal function and electrolytes (Howard et al., 2003).

Clozapine, used for the management of treatment resistant schizophrenia and psychosis, is associated with significant risk of agranulocytosis. Mandatory monitoring of white blood cell counts has effectively eliminated the risk of fatal agranulocytosis.

Ideally, advice on monitoring should be clear, provide an evidence-based frequency of monitoring and acceptable values. However, robust evidence for the optimal monitoring frequency is limited, hampering specific guidance on monitoring. Guidelines vary between various expert bodies and drug information sources. An examination of the adequacy of manufacturers’ advice on monitoring for haematological ADRs found that advice was too vague to be useful to prescribers (Ferner et al., 2005).

Currently, monitoring is often neglected, although practitioners may take greater care when treating the elderly and those with more co-morbidities (McDowell., 2010). Warfarin remains one of the top 10 drugs involved in drug-induced admissions, despite a clearly defined monitoring requirement.

Explaining risks to patients

Numerous studies have shown that patients want to receive information about side effects, although one study comparing patients’ views to those of health professionals found that the latter viewed providing side effect information as of much less importance than patients did in receiving it. One of the main sources of information about ADRs is the PIL, which must be provided every time a medicine is prescribed or supplied. Ultimately, patients then have to make a decision about whether or not to use the medicine. Therefore, they have a right to receive understandable information about the potential for harm that a medicine may cause, to enable them to make an informed decision. While there may still be debate about whether the provision of information on side effects encourages reduced adherence to taking medicines or spurious reporting of adverse effects, it is clear that this information is useful to patients and its availability will increase. Patients do use the PIL when suspected adverse events are experienced, to assist in ascribing the cause of the problem; therefore, as outlined above, side effect information should be understandable and there is now a requirement to test information leaflets with patients prior to granting a marketing authorisation for a medicine.

Patients increasingly access a wide range of information sources about medicines and ADRs themselves; indeed, they are actively encouraged to do so. Hence, they may question judgements about the selection of individual products they have been prescribed or sold. In this situation, the health professional must be able to interpret the information accessed by the patient to ensure it is unbiased and accurate.

The EU recommends using verbal terms to describe the risk of experiencing an ADR, ranging from ‘very common’ (for rates of more than 1 in 10) to ‘very rare’ (for rates of less than 1 in 10,000). The MHRA advocates combining words with frequencies, for example, ‘Common (affects more than 1 in 100 persons)’. Studies show that patients tend to over-estimate the risk when these are described using words only and that patients differ in their understanding of what the terms mean. Percentages, particularly those below 1%, are also not understood by everybody. This lack of understanding of the risks of experiencing an ADR can potentially reduce willingness to use the medicine.

Another approach is the use of pictures, such as faces, graphs or charts. One example is the ‘Paling palette’, which is a grid of 1000 stick figures to convey information on the chances of experiencing a particular outcome. A similar method is a ‘Cates plot’ which is a grid of 100 faces or 1000 faces for rarer events, coloured differently and either smiling or downcast depending on the outcome. An example of a Cates plot is provided in Fig. 5.1. These types of icon grids are mainly used to convey the potential benefits and risks of a particular action, but can also be used to explain the risks of getting a side effect. Cates plots have been used to good effect by the UK’s National Prescribing Centre. However, there are people who do not find these easy to understand (Ancker et al., 2006).

Fig. 5.1 Acute coronary syndrome (ACS) patient decision aid: aspirin plus clopidogrel versus aspirin alone.

Copyright National Prescribing Centre, reproduced by permission.

Much work has been undertaken on risk communication. It is important to appreciate that, when communicating information about potential ADRs, how risks are perceived will be affected by the relationship between the health professional and the patient, the patient’s prior experience and beliefs, how information is framed and the context in which it is given. Patients may also have views on the acceptability of ADRs, which should be taken into account when selecting a product for an individual. An ADR which is viewed as minor by health professionals may be considered to reduce quality of life by one patient, while another patient may be happy to accept this for the potential benefit the medicine offers. Even when drugs are withdrawn from the market for safety reasons, significant numbers of patients will feel they were willing to accept the harm–benefit of the drug. Communicating the harms and benefits of medicines is, therefore, an important role of health professionals.