Which medications used in paediatric practice have demonstrated natural health product-drug interactions?

Herbal therapies and other forms of complementary and alternative medicine (CAM) are used by many Canadian children encountered in the ambulatory paediatric setting (1). Parents often administer natural health products (NHPs) and conventional medicines to their children simultaneously, but are usually unaware of potentially adverse pharmacological interactions (2). Physicians have a responsibility to be wary of these interactions, but does this mean that the conscientious paediatrician is at risk of being overwhelmed by yet another large arena of new health knowledge? Current approaches to evidence-based medicine acknowledge that the ever-growing body of medical information is too vast for any individual physician to internalize (3). The physician’s role as information manager is to know how to access current and relevant information that guides the response to clinical questions in a patient-centred manner. This is the principle that paediatricians should apply in their evidence-based approach to NHP-drug interactions. The clinician’s first step is to become comfortable seeking information about CAM use from patients and their parents. Most parents using CAM on their child want to talk about it with their paediatrician, but only a minority may do so (4). It is important that the paediatrician routinely screens for CAM use in a nonjudgmental manner that is most likely to render the desired information without compromising patient-physician rapport. Open-ended questions, such as “what do you do for your child when he or she has an earache or fever?”, are suggested to initiate the discussion of CAM (5). If more specific questions are required, normalizing the use of CAM is suggested, for example, “some families pursue other therapies, such as natural health products (eg, echinacea and chamomile) or see other health care providers (eg, a chiropractor or naturopath) – does your child receive any of these products or therapies?” The second step is to formulate an evidence-based response to the specific clinical question prompted by a patient’s use of CAM or NHPs. For example, a postrenal transplantation adolescent is on tacrolimus for immunosuppression: are there any potentially adverse interactions if she starts to take St John’s wort for depression? The systematic review discussed in Part A summarized the available evidence and illustrated that some of the most commonly used NHPs (St John’s wort, garlic, American ginseng, ginkgo biloba and echinacea) have known interactions with conventional drugs used in paediatric practice. Although there are currently no pharmacokinetic trials reporting NHP-drug interactions in children, pharmacokinetic and drug interaction data in children are often similarly lacking for conventional drugs (6). Whether considering use of an NHP or a conventional drug, paediatricians should always be cautious about applying adult pharmacokinetic data to children. Although the pharmacokinetics of some drugs, such as omeprazole, are similar in both adults and children (7), pharmacokinetic parameters are often developmentally dependent due to physiological differences that include children’s relatively increased total body water composition, decreased adipose tissue and decreased skeletal muscle mass, and differences in glomerular filtration rates compared with those of adolescents and adults (8). Therefore, the absence of adverse effects in adults does not guarantee safety in children. In regard to the case of the depressed adolescent mentioned above, the systematic review discussed in Part A cited a recent pharmacokinetic study (9) in which renal transplantation patients on tacrolimus who were coadministered St John’s wort had significantly reduced peak and trough blood concentrations of tacrolimus, thereby increasing the risk of transplant rejection. The study did not include children or adolescents and was not a randomized, controlled trial. However, in the absence of more relevant or higher quality evidence, these findings suggest that the clinician should advise the patient to seek a different treatment for her mood disorder. In addition to the pharmacokinetic interactions addressed in Part A, paediatricians should also consider possible pharmacodynamic interactions between conventional drugs and NHPs. Pharmacodynamics involves the biochemical and physiological processes underlying drug actions, such as cellular binding, uptake and intercellular metabolism. For example, in a young child taking phenobarbital for a seizure disorder, coadministration of valerian (a central nervous system depressant used as a sleep aid) could theoretically potentiate the sedating effects of a barbiturate or benzodiazepine. Where can the busy paediatrician find information on NHP-drug interactions to guide patient counselling and monitoring? As information managers, paediatricians need on-line resources that provide updated information about herbal pharmacology in an easy-to-access format. Recent reviews (10,11) of herbal medicines in the mainstream paediatric literature suggest several Internet resources. Evidence-based sources of NHP-related information that require a paid subscription are Natural Standard ( ) and Natural Medicines Comprehensive Database ( ). Two recommended Web sites for information regarding NHP-drug interactions that can be accessed without a subscription are The Longwood Herbal Task Force ( ) and HerbMed ( ). The Longwood Herbal Task Force provides a ‘monograph’ for each herb, which identifies the author and his affiliation, indicates the date of the latest revision and cites all references. For example, the monograph for valerian states that although animal studies suggest that valerian may potentiate the effects of barbiturates, no such effects have been reported in humans (12). It is important to recognize that in the absence of pharmacokinetic studies in human subjects, potential NHP-drug interactions are often inferred on theoretical grounds from laboratory studies, or based on individual case reports in which adverse events cannot always reliably be attributed to a specific NHP-drug interaction (13). Clinicians need to be aware of both conventional and complementary therapies used by their patients, and advise families when they have concerns. Monitoring for potential NHP-drug interactions requires clinical vigilance because routine laboratory tests to measure drug serum concentrations are unavailable for most agents used in paediatric practice. All suspected adverse events should be reported to Health Canada ( ). In addition, the Canadian Paediatric Surveillance Program is planning a surveillance study to monitor adverse events related to CAM, including potential NHP-drug interactions. Data from the study will help to guide future studies of NHP-drug interactions that are likely to be most relevant to Canadian paediatric practice.

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