Australian Prescriber
VOLUME 33 : NUMBER 6 : December 2010

Drug interactions with complementary medicines

Geraldine M Moses, Senior Clinical Pharmacist, Mater Health Services, Brisbane, and Treasure M McGuire, Assistant Director of Pharmacy, Mater Health Services, and Conjoint Senior Lecturer, School of Pharmacy, University of Queensland, Brisbane, and Associate Professor of Pharmacology, Faculty of Health Sciences and Medicine, Bond University, Queensland

Summary

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

Introduction

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'.1In 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.2,3It 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.

Polypharmacy

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.5In 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.6It 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

Drug interactions

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.8,9In vitroassays, using human tissue or cell lines, are frequently used to determine whether a herb affects these enzymes.10However,in vitrofindings 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.9A 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.11This lowers the concentration of the concomitant drug.

Table 18,11,13,14shows selected documented interactions which have been chosen based on a composite of:

  • the most frequently used complementary medicines in Australia, from survey and sales data12
  • interactions with serious or clinically significant outcomes.

Table 1 8,11,13,14categorises 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.

Table 18,11,13,14

Table 1

Evidence-based complementary medicine interactions8,11,13,14
This table shows complementary medicines with at least one 'major' interaction.

Complementary medicineInteracting drugPossible outcomeSeverity and level of evidence*Proposed mechanisms/comment
Black cohoshCisplatin↓ cytotoxic effectModerate, level DAnimal data only
Hepatotoxic drugs e.g. high-dose paracetamol, alcohol↑ risk of hepatotoxicityModerate, level DPharmacodynamic additive risk
CYP2D6 substrates e.g. amitriptyline↑ substrate levels and drug effectModerate, level BModerate inhibitor of CYP2D6
CalciumQuinolone antibiotics, sotalol, tetracycline, thyroxine↓ drug effectModerate, level BFormation of insoluble salts and decreased absorption
Celery seedThyroxine↓ drug level and effectModerate, level DMechanism unknown but two case reports
Chamomile (German)CYP1A2 and CYP3A4 substrates↑ drug levelsModerate, level DTheoretical
CNS depressants↑ drug effectModerate, level DAdditive sedative effects
Coenzyme Q10Chemotherapy (e.g. alkylating drugs)↓ cytotoxic effectModerate, level BMay counteract cytotoxic oxidative stress
Antihypertensives↑ drug effectModerate, level BCoenzyme Q10 has an antihypertensive effect
Warfarin↓ drug effectModerate, level DCoenzyme Q10 may have vitamin K-like effects
CranberryWarfarin↑ drug effectModerate, level BCranberry has variable effects on CYP3A4, CYP2C9, CYP1A2
EchinaceaCYP1A2 and CYP3A4 substrates e.g. clopidogrel (prodrug), olanzapine, warfarin↑ substrate levelsModerate, levels B and D respectivelyInhibition of CYP1A2 and CYP3A4
Evening primrose oilAntiplatelet drugs, warfarin↑ drug effectMajor, level BContains gamma-linolenic acid, probable anticoagulant
FenugreekHypoglycaemic drugs↑ drug effectModerate, level BAdditive hypoglycaemic effect
Antiplatelet drugs, warfarin↑ bleeding riskModerate, level DAntiplatelet activity
Fish oilAntihypertensive drugsAdditive blood pressure loweringModerate, level BAdditive blood pressure-lowering effect found with some antihypertensives.
Antiplatelet drugs, warfarin↑ bleeding riskMinor, level BAntiplatelet activity in high dose
Contraceptives, oral↓ fish oil effectsModerate, level BMay decrease triglyceride-lowering effects
GarlicContraceptives, oral↓ drug effectModerate, level DInduces CYP3A4
Saquinavir/non-nucleoside reverse transcriptase inhibitors↓ drug levels and effectMajor, level BInduces CYP3A4
Antiplatelet drugs, warfarin↑ bleeding riskModerate, level DTheoretical antiplatelet activity
GingerAntiplatelet drugs, warfarin↑ bleeding riskModerate, level BAntiplatelet activity
Ginseng (Panax)Hypoglycaemic drugs↓ blood glucoseModerate, level BHypoglycaemic effect. Conflicting evidence.
Immunosuppressants e.g. azathioprine↓ drug effectModerate level BLargely theoretical
CYP2D6 substrates↑ substrate levelsModerate, level BCYP2D6 inhibitor but conflicting evidence
Stimulants e.g. caffeine↑ drug effectsModerate, level BAdditive pharmacodynamic effect
GinkgoAnticonvulsants↑ seizure riskModerate, level DLarge amounts of ginkgotoxin can cause neurotoxicity
Warfarin, antiplatelet drugs↑ bleeding riskMajor, level DAntiplatelet activity after several weeks
CYP2C9 substrates e.g. glipizide, warfarin, celecoxib↑ substrate levelsModerate, level DInhibits CYP2C9 activity
CYP1A2, CYP2C19, CYP2D6 and CYP3A4 substrates↑ substrate levelsModerate, level BPotentially inhibits these enzymes
Hypoglycaemic drugs↑ ↓ drug effectModerate, level BVariably affects blood glucose concentrations
GlucosamineWarfarin↑ bleeding riskMajor, level DSeveral case reports of increased INR
HawthornCalcium channel blockers, nitrates, phosphodiesterase inhibitors↑ drug effectMajor, level DAdditive vasodilator effects
Digoxin, beta blockers↑ drug effectMajor, level DAdditive effects on heart rate and/or blood pressure. Hawthorn has cardiotonic effects.
KavaCNS depressants↑ drug effectMajor, level AAdditive somnolence
CYP1A2, CYP2D6, CYP2C9, CYP2E1, CYP3A4 substrates↑ substrate levelsModerate, level BKava potentially inhibits these enzymes
P-glycoprotein substrates↑ substrate levelsModerate, level D
Lactobacillus acidophilusImmunosuppressants↑ risk of infectionModerate, level D
Antibiotics↓ drug effectModerate, level D
Milk thistleCYP2C9 substrates e.g. amitriptyline, phenytoin, warfarin↑ drug effectModerate, level BInhibits CYP2C9, glucuronidase and organic anion transporting polypeptide 1B1. Conflicting evidence.
Noni juiceWarfarin↓ drug effectModerate, level DContains vitamin K
Olive leafAntihypertensive drugs↑ drug effectModerate, level BAdditive antihypertensive effects
Hypoglycaemic drugs↑ drug effectModerate, level BAdditive hypoglycaemic effects
PsylliumCarbamazepine, lithium↓ drug effectModerate, level DDecreases gastrointestinal absorption of other drugs
Hypoglycaemic drugs↑ drug effectModerate, level BAdditive hypoglycaemic effects
SeleniumAntiplatelet drugs, warfarin↑ drug effectModerate, level DSelenium dose of 10 microgram/kg/day can increase bleeding time
Statins, niacin↓ drug effectModerate, level ASelenium plus beta carotene, vitamins C and E decreased the lipid-lowering effect
SennaDigoxin, diuretics↑ drug effectModerate, level DAdditive potassium loss with long-term use or high doses of senna
St John's wortAlprazolam↓ drug levels & effectMajor, level BIncreased clearance; half-life reduced by 50%
Amitriptyline↑ drug effectMajor, level BIncreased risk of serotonin syndrome
Antidepressants, tramadol↑ drug effectMajor, level D
Pethidine↑ drug effectMajor, level D
Triptans↑ drug effectModerate, level D
Clopidogrel↑ bleeding riskModerate, level BIncreased conversion to active metabolite
CYP1A2, CYP2C9, CYP3A4 substrates e.g. imatinib, indinavir, tacrolimus, carbamazepine, phenytoin↓ drug levels & effectCYP3A4 =Major, level B CYP1A2, CYP2C9 = Moderate, level BInduces CYP enzymes
Non-nucleoside reverse transcriptase inhibitors, protease inhibitors↓ drug levels & effectMajor, level BInduces CYP3A4
Oral contraceptives↓ drug levelsMajor, level BRisk of breakthrough bleeding/contraceptive failure
P-glycoprotein substrates e.g. digoxin, fexofenadine, irinotecan↓ drug levels & effectMajor, level BInduces intestinal P-glycoprotein
Simvastatin↓ drug levelsModerate, level BStatin levels reduced by up to 28%
Warfarin↓ drug effectMajor, level BInduces CYP1A2, CYP2C9 and CYP3A4
ValerianAlprazolam↑ drug levelsMajor, level BCYP3A4 inhibitor. Alprazolam increased by 19% in one study.
CNS depressants↑ drug effectMajor, level DPharmacodynamic effect
CYP3A4 substrates↑ substrate effectModerate, level D
Vitamin EAntiplatelet ,warfarin↑ bleeding riskModerate, level BAntiplatelet activity
Chemotherapy↓ drug effectModerate, level DPossible antagonism of oxidative stress

CYP
INR
CNS

cytochrome P450
international normalised ratio
central nervous system

* Interaction rating adapted from Natural Medicines Comprehensive Database.11 The level of severity (major, moderate, minor) has been calculated using the evidence and probability of harm. This rating is linked with a generic recommendation for management.
MajorStrongly discourage patients from using this combination as a serious adverse outcome could occur. If used, patient should be monitored closely for potential adverse outcomes.
ModerateUse cautiously or avoid combination as a significant adverse outcome could occur. If used, monitor for potentialadverse outcomes.
MinorBe aware that there is a chance of an interaction. Advise patients of symptoms that may occur and an action planto follow.

Level of evidence ratings:
AHigh-quality randomised controlled trial or meta-analysis
BNon-randomised clinical trial, literature review, clinical cohort or case-control study, historical control or epidemiologic study
CConsensus or expert opinion
DAnecdotal evidence; in vitro or animal study or theoretical based on pharmacology

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 2008.12Specific 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:

Conclusion

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.

References

  1. 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]
  2. Kotsirilos V. GPs' attitudes toward complementary medicine. Aust Fam Phys 2007;36:270-1.
  3. 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]
  4. 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.
  5. 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.
  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.
  7. Cadieux RJ. Drug interactions in the elderly. Postgrad Med 1989;86:179-86.
  8. Boullata J. Natural health product interactions with medication. Nutr Clin Pract 2005;20:33-51.
  9. 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]
  10. 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.
  11. Jellin JM, editor. Natural medicines comprehensive database.www.naturaldatabase.com. [cited 2010 Jul 27]
  12. 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]
  13. Bjerrum L, Lopez-Valcarcel B, Petersen G. Risk factors for potential drug interactions in general practice. Eur J Gen Pract 2008;14:23-9.
  14. Barnes J, Anderson LA, Phillipson JD. Herbal interactions. Pharm J 2003; 270:118-21.

Further reading

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.

https://healthlibrary.epnet.com/GetContent.aspx?token=af362d97-4f80-4453-a175-02cc6220a387&chunkiid=120459[cited 2010 Jul 27]

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



First published online 1st of December 2010