Health professionals are expected to be familiar with common and clinically significant complementary medicine interactions or at least know where to look them up. Knowing the dynamic and kinetic interactions associated with commonly used complementary medicines helps to identify the risk of drug interactions. Although information on complementary medicine interactions is not readily provided by the manufacturers, evidence is available by way of case reports, independent research and web-based resources, which have increased in recent years. Collectively, these data make interactions with complementary medicines largely predictable and therefore preventable.
Key words: drug interactions, St John\'s wort.
Aust Prescr 2010;33:177-80
The Therapeutic Goods Administration refers to complementary medicines as \'medicinal products containing herbs, vitamins, minerals, nutritional supplements, homoeopathic medicines, traditional medicines and certain aromatherapy products\'.1 In Australia, complementary medicines are largely regulated as unscheduled medicines, and are usually self-selected.
Complementary medicines are very popular among Australians, with surveys indicating that up to 60% of people use at least one complementary medicine on a regular basis. However, about 50% of consumers also report using a conventional medicine on the same day as their complementary medicine.23 It is not surprising, therefore, that healthcare professionals and consumers alike are concerned about the potential for drug interactions between these medicines.
As so many Australians use complementary medicines, including children, the elderly, patients with chronic disease, mental health disorders and cancer, it is important that prescribers always ask what complementary products their patients are taking in addition to any conventional medicines. Knowing this, and extrapolating reported pharmacodynamic and pharmacokinetic outcomes, can help predict potential drug interactions.
Complementary medicines are frequently used in the context of polypharmacy. A study of 3070 elderly people found that 74.2% took at least one prescription drug and one complementary medicine, with 32.5% of them using three or more prescription medicines with three or more complementary medicines.4This translates to an increased risk of drug interactions. In a study of 458 US Veterans\' Administration patients, 197 of them reported taking complementary medicines combined with prescription medicines. Of these patients, 45% had potential for interactions, which was rated as serious in 6% of patients.5 In another study which interviewed 3000 people (aged 57−85) about prescription, over-the-counter and complementary medicine use, 4% of them were potentially at risk of a major drug–drug interaction.6 It has been suggested that once a patient is on eight or more medicines, regardless of origin, there is a 100% chance of a drug interaction occurring.7
As with other drugs, complementary medicine interactions can be broadly classified by their mechanism, that is, pharmacodynamic and pharmacokinetic. The former are due to overlap of pharmacological actions, while the latter result from changes in absorption, distribution, metabolism or excretion.
Risk factors for significant complementary medicine interactions are the same as for conventional medicines. These include patient characteristics (such as extremes of age, frailty, female gender, cognition, comorbities and genetic disposition) and medication factors (such as high medication burden, recent changes in medicines, drugs with a low therapeutic index and limited elimination pathways).
Due to their complex chemical structure, herbal medicines are prone to interactions via the oxidative cytochrome P450 system or the efflux drug transporter P-glycoprotein.89 In vitro assays, using human tissue or cell lines, are frequently used to determine whether a herb affects these enzymes.10 However, in vitro findings do not necessarily correlate with what happens in the human body. As several herbal medicines and many prescription drugs are substrates, inducers or inhibitors of CYP isoenzymes or P-glycoprotein, interactions can ensue when they are used concomitantly.9 A classic example is St John\'s wort, which has kinetic interactions with a wide range of drugs via the induction of CYP1A2, CYP3A4, CYP2C9 and P-glycoprotein.11 This lowers the concentration of the concomitant drug.
- the most frequently used complementary medicines in Australia, from survey and sales data12
- interactions with serious or clinically significant outcomes.
Table 1 8111314 categorises interactions by their possible outcome, severity, supporting evidence and proposed mechanism. Generic guidance on interaction management is given in the key, within the definitions of severity (major, moderate, minor). Certain therapeutic drug classes appear repeatedly in the table such as antiplatelet drugs, anticoagulants, antidepressants, antihypertensives, hypoglycaemics, immunosuppressants, antiretrovirals and hormones. Health professionals should monitor patients closely when a complementary medicine is taken concomitantly with these drugs.
Finding information about complementary medicine interactions
Most complementary medicines are listed (AUST L) medicines, which are not subjected to the same rigorous premarketing safety and efficacy trials as registered (AUST R) medicines. Thus evidence of their interaction potential is often not available. In addition, manufacturers are not obliged to provide a consumer medicine information leaflet with advice or warnings regarding complementary medicine interactions.
Despite the lack of hard data, health professionals still need to make reasonable recommendations to patients about potential interactions. With a view to helping Australians make more informed decisions about using complementary medicines, an independent consortium from Mater Health Services Brisbane, Bond University and University of Queensland, with funding from the National Prescribing Service, evaluated complementary medicines information resources in 2008.12 Specific criteria were used to identify 52 resources – 26 of these were shortlisted and assessed for technical quality, content and clinical utility. The quality of drug interaction information was also assessed in the review, specifically whether mechanisms were outlined, degree of severity was stated, and whether the absence of known drug interactions was disclosed. While many resources (free or subscription) had technical strengths, few had comprehensive interaction coverage. Those with some detail are included for further reading. Two of the highest ranked resources were online subscription databases, both of which contained reasonably comprehensive complementary medicine–drug interaction checkers. These were:
- Natural Standard ( www.naturalstandard.com, ) which provides detailed monographs and brief summaries (\'bottom line\')
- Natural Medicines Comprehensive Database ( www.naturaldatabase.com. )
Consumers frequently use complementary medicines in combination with conventional medicines. For this reason, health professionals should always consider the potential for pharmacodynamic and pharmacokinetic interactions between them. High quality evidence is increasingly available for identification and prevention of these interactions.
- Therapeutic Goods Administration. The regulation of complementary medicines in Australia – an overview. 2006 Apr, updated 2007 Apr 24.
www.tga.gov.au/cm/cmreg-aust.htm [cited 2010 Jul 27]
- Kotsirilos V. GPs\' attitudes toward complementary medicine. Aust Fam Phys 2007;36:270-1.
- Australian Bureau of Statistics. Complementary therapies. Australian Social Trends, 2008. Paper 4102.0.
www.abs.gov.au/AUSSTATS/abs@.nsf/Lookup/4102.0Chapter5202008 [cited 2010 Jul 27]
- Nahin RL, Pecha M, Welmerink DB, Sink K, DeKosky ST, Fitzpatrick AL. Concomitant use of prescription drugs and dietary supplements in ambulatory elderly people. J Am Geriatr Soc 2009;57:1197-205.
- Peng CC, Glassman PA, Trilli LE, Hayes-Hunter J, Good CB. Incidence and severity of potential drug-dietary supplement interactions in primary care patients: an exploratory study of 2 outpatient practices. Arch Intern Med 2004;164:630-6.
- Qato DM, Alexander GC, Conti RM, Johnson M, Schumm P, Lindau ST. Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States. JAMA 2008;300:2867-78.
- Cadieux RJ. Drug interactions in the elderly. Postgrad Med 1989;86:179-86.
- Boullata J. Natural health product interactions with medication. Nutr Clin Pract 2005;20:33-51.
- Interactions. In: Dietary supplements – a framework for evaluating safety. Institute of Medicine. Washington, DC: The National Academies Press;
2005. p. 235-46.
www.nap.edu/books/0309091101/html [cited 2010 Jul 27]
- MacGregor JT , Collins JM, Sugiyama Y, Tyson CA, Dean J, Smith L, et al. In vitro human tissue models in risk assessment: report of a consensus-building workshop. Toxicol Sci 2001;59:17-36.
- Jellin JM, editor. Natural medicines comprehensive database. www.naturaldatabase.com. [cited 2010 Jul 27]
- McGuire TM, Walters JA, Dean AJ, Van Driel M, Del Mar C, Kotsirilos V, et al. Review of the quality of complementary medicines information
resources: summary report. Sydney: National Prescribing Service; 2009.
www.nps.org.au/__data/assets/pdf_file/0005/69656/CMsInfoSummary.pdf [cited 2010 Jul 27]
- Bjerrum L, Lopez-Valcarcel B, Petersen G. Risk factors for potential drug interactions in general practice. Eur J Gen Pract 2008;14:23-9.
- Barnes J, Anderson LA, Phillipson JD. Herbal interactions. Pharm J 2003; 270:118-21.
Barnes J, Anderson LA, Phillipson JD. Herbal medicines. 3rd ed. London: Pharmaceutical Press; 2007. (also part of MedicinesComplete, www.medicinescomplete.com)
Stockley\'s Drug Interactions. Baxter K, editor. 9th ed. London: Pharmaceutical Press; 2010. (also part of MedicinesComplete, www.medicinescomplete.com)
Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 3rd ed. Sydney: Elsevier Australia; 2010.
The review of natural products. Facts & Comparisons.
Natural & alternative treatments. EBSCO.
Kuhn MA, Winston D. Winston and Kuhn\'s herbal therapy and supplements: a scientific and traditional approach. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 2008.
Therapeutic Goods Administration. New labelling requirements and consumer information for medicines containing Black cohosh. Update 29 May 2007.
www.tga.gov.au/cm/0705blkcohosh.htm [cited 2010 Jul 27]
Therapeutic Goods Administration. Kava – safety alerts & advisory statements.
www.tga.gov.au/alerts/kava.htm [cited 2010 Jul 27]
Conflict of interest: none declared