Recognizing idiosyncratic adverse drug reactions in children: A practice imperative

In North America, adverse drug reactions (ADRs) continue to be a major cause of morbidity, hospital admission and death (1). The above statement runs counter to the common assumption of health care professionals and the general public that, when drugs are approved for marketing, their safety has been clearly determined by the Federal Drug Administration in the United States and the Therapeutic Products Programme in Canada. There are some limitations to the drug approval process. With most drugs, approval for marketing is granted following phase III clinical trials. However, these trials are typically short in duration, are conducted in relatively small numbers of patients (usually involving hundreds, not thousands of patients) under conditions that are not clinically routine, and often exclude patients with co-morbidities and co-medications (2). Usually, early regulatory trials exclude children (3). Under the above investigative conditions, the most common ADRs will be observed (2) usually in adult populations exclusively; less common ADRs may be missed altogether.

WHAT IS AN IDIOSYNCRATIC ADR?

Idiosyncratic ADRs are unpredictable and difficult to prevent, if risk factors for occurrence are unknown. Idiosyncratic ADRs do not occur in most patients, may be unrelated to both the dose and the pharmacology of the drug, and can be potentially life-threatening. They include the most serious and dangerous ADRs known: lupus, bone marrow toxicity (aplastic anemia), hepatitis and Stevens-Johnson syndrome (4,5). Clinically, idiosyncratic ADRs may occur immediately or become evident a few days or weeks after therapy. Patients may recover following discontinuation of the offending medication or show a continued, even fatal, reaction.

Little is known about the mechanisms of most idiosyncratic ADRs; however, in some cases, they may be mediated by the immune system (6). Lack of knowledge about the causes of idiosyncratic ADRs prevents the ready identification of individual paediatric patients who may be at risk (7,8).

PHARMACOGENETICS

Many factors may influence a child’s response to a drug (eg, age, diet, concomitant medications, general health); however, one key factor is the child’s genetic inheritance. The study of the interaction between drug response and genetic makeup is called pharmacogenetics. A major objective of pharmacogenetics is to determine the causes of ADRs or to predict recurrence. Achieving this objective will involve acquiring knowledge of which genes are responsible for the polymorphisms that lead to different drug response phenotypes. The targets of this inquiry are many, including but not limited to genes coding for proteins that are involved in the following:

• drug absorption;

• metabolism;

• transport to the site of activity;

• receptor binding;

• across-membrane transport;

• intracellular signal transduction;

• secretion and elimination; and

• the overall regulation of responses.

The above mechanisms are being investigated by using a variety of approaches from basic pharmacology to high resolution techniques of molecular genetics, but the discipline of pharmacogenetics is still in its infancy (9). In time, pharmacogenetics may provide a library of data regarding genomic sequences and sequence variants. Through the use of such a library, mapping genetic polymorphisms may identify paediatric patients at risk for idiosyncratic ADRs before an offending drug is administered (10,11).

However, neither a library of genomic information nor a set of clinically useful guidelines exists. Indeed, there is no test to predict beforehand (or to prove afterwards) that a particular drug causes (or caused) an idiosyncratic ADR in any individual patient (9), much less a child. Thus, there is little genetic testing that the practising clinician can use to anticipate an idiosyncratic ADR in his or her patient.

HOW CAN IDIOSYNCRATIC ADRs BE MINIMIZED?

If the promise of pharmacogenetics is still just a promise, what practical alternatives are available for paediatric populations? It has been suggested that many cases of idiosyncratic ADRs may be prevented or minimized by making only minor changes to the health care system (12). Suggested changes include the following:

• providing continuing education to prescribers so that they are better prepared to recognize early the onset of an idiosyncratic ADR;

• restricting the prescription of drugs that commonly cause serious idiosyncratic ADRs;

• providing patients and parents with written instructions that identify the early symptoms of idiosyncratic ADRs; and

• instituting periodic pharmacodynamic monitoring (eg, hematological assessments for possible bone marrow toxicity or hepatic assessments for possible liver toxicity).

The authors of this paper agree with the first three recommendations. However, there is a lack of substantive evidence to suggest that periodic pharmacodynamic monitoring is useful in preventing or minimizing idiosyncratic ADRs. Given that the definition of an idiosyncratic ADR means that these reactions are unpredictable, ‘periodic’ monitoring is subject to wide interpretation as to when and how often a patient should be monitored. The cost of such an intervention would almost certainly outweigh the benefits in most situations at this time.

The changes noted above would be a good first step to minimizing rare but, often, serious reactions. Furthermore, a process for the collection of ADR data (from both adult and paediatric populations), a commitment to interpret these data and a specific feedback process for the dissemination of this information is needed because the current system of voluntary reporting of ADRs is clearly inadequate. Dissemination of information is the most important, yet most conspicuously lacking, component of the current system.

Idiosyncratic reactions will continue to occur. Routine monitoring is unlikely to aid in avoiding ADRs. In the absence of a proactive surveillance system that regularly polls paediatricians and pharmacists regarding the occurrence of ADRs in their practices, what is a busy paediatrician to do?

RECOMMENDATIONS FOR PAEDIATRICIANS

• Have a high index of suspicion when untoward effects are seen with recently initiated or changed drug therapy.

• Be aware of potential reactions by continuous review of the medical literature.

• Inform patients about likely initial symptoms of idiosyncratic ADRs.

• Report suspected ADRs to local experts in clinical pharmacology, toxicology, pharmacy, or allergy and immunology, and to ADR monitoring programs (Table 1).

TABLE 1:

To whom should paediatricians report a suspected adverse drug reaction (ADR)?

Paediatricians should report suspected ADRs to the following authorities: – local experts in clinical pharmacology; – the manufacturer; – a participating Health Canada regional ADR centre (the addresses of ADR centres are listed on the Web sites of Health Canada’s Therapeutic Products Programme <http://www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english/forms/adverse_e.pdf> and <http://www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/french/forms/adverse_f.pdf>); or – the Health Canada national ADR centre at Canadian Adverse Reaction Monitoring Program (CADRMP), Bureau of Licensed Product Assessment, Therapeutic Products Programme, Health Canada, Address Locator 0201C2, Ottawa, Ontario K1A 1B9. Telephone 613-957-0337, fax 613-957-0335. The ADR Reporting Form can be found in the Canadian Compendium of Pharmaceuticals and Specialties (13) or on the Web sites of the Therapeutic Products Programme listed above. The Canadian Adverse Drug Reaction Monitoring Program Guidelines for the Voluntary ADR Reporting by Health Professionals can be found at <http://www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english/guides/adr/adr_guideline_e.pdf> and <http://www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/french/guides/adr/adr_guideline_f.pdf>.