10th edition march 2019 - blackmores institute

10TH EDITION MARCH 2019

Pg.2 Pg.3

NOTE: Blackmores has made every effort to ensure that the information in this guide is accurate and up-to-date but this does not guarantee that every possible interaction is included. Blackmores cannot be held responsible for any future changes that may occur in this constantly expanding area of study. The information in this guide is for informational purposes only and is not intended as a substitute for professional advice. Healthcare professionals who consult this document are cautioned that any medical or product-related decision is the sole responsibility of the healthcare professional. Blackmores advises that healthcare professionals should ask patients about both complementary medicine and drug use. Should an adverse event occur, send a ‘blue card’ adverse reaction reporting form to the TGA or go online to www.tga.gov. au/reporting-problems-0#medicine and inform the manufacturer of both the complementary medicine and the medication.

About this guide

This Complementary Medicine Interactions Guide is a concise and comprehensive reference resource designed to give healthcare professionals clinically relevant, evidence-based information about potential interactions between complementary medicines and pharmaceutical medications.

For the most part, complementary medicines can be used alongside conventional pharmaceutical drug treatments. However, some complementary medicines may interact with certain medications to reduce, or sometimes increase, their effect, or to cause potential adverse effects. In addition, some complementary medicines may have the ability to reduce drug side effects and also some common medications may adversely affect the nutritional status of individuals over time. Severity, likelihood and level of evidence is provided in this guide to assist in assessment of risk and to support appropriate recommendations.

Blackmores Institute is grateful to the University of Sydney School of Pharmacy for their role in reviewing the evidence and contribution to this updated guide.

Blackmores Institute

Blackmores Institute is the academic and professional arm of Blackmores Limited, established to support and drive an evidence-based approach to natural medicine. With a focus on research and education, our primary purpose is to improve the quality use of natural medicine by contributing to the evidence base and translating this knowledge into practical healthcare education and clinical resources. We partner with leading academic institutions and research bodies to investigate novel ingredient development, discovery and innovation, and legacy projects. We also proudly support the development of future leaders through academic and practice grants. Our team includes researchers, academics, healthcare professionals, educators and communicators, working together to evaluate natural health literacy through

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10th Edition

K E YTheoretical

in vitro and/or animal evidence with unclear implications, However, it cannot exclude the

possibility of occurring in humans

Possible Evidence suggests this

interaction might occur in some patients

Likely Evidence suggests this interaction is likely to occur in most patients

Variable Nature of interaction

may vary

Low Healthcare professional intervention unlikely to

be required

Moderate Intervention by a

healthcare professional may be required

High Clinical evaluation by a

healthcare professional is recommended to assess

the degree of intervention required

A - At least 1 good quality randomised,

placebo-controlled trial or meta-analysis or systematic review

B - Lower quality human study

D - in vitro or animal studies

C - Case reports

Severity of

interaction

Likelihood of

interaction

Level of evidence

• Research funding• Education programs• Healthcare professional advisory services• Research symposia and conferences• Interactions guidelines• News and research updates• Systematic reviews• Academic projects

Printed on FSC paper

Unlikely Evidence suggests this

interaction can occur, but is not likely to occur in

many patients

Pg.4 Pg.5

INGREDIENT MECHANISM LIKELIHOOD RECOMMENDATIONSDRUG/CLASS/ENZYME/TRANSPORTER

EVIDENCENATURE of INTERACTION

SEVERITY of

OUTCOME

AndrographisAndrographis

paniculata

Alpha-lipoic acid

AstragalusAstragalus

membranaceus

Anticoagulants and antiplatelet agents

May increase drug effect

May increase or decrease drug effect

May have additive effect to drug

Antioxidants may decrease the activity of chemotherapy or make

chemotherapy more effective

Level DAnimal and in vitro study

Level DAnimal study

Level AClinical trials

Theoretical

Theoretical

Variable

Moderate

Moderate

Moderate

Use with caution under supervision of a healthcare professional and monitor

Avoid concomitant use

No significant adverse effect or reduction in the effectiveness of chemotherapy

identified in studies. Supplementation may reduce side effects

Herb effect on drug (May decrease drug

side effect)

Chemotherapeutic agents (Cisplatin and vinorelbine)

Chemotherapeutic agents

No direct interaction

Acidophilus See ‘Probiotics’

INGREDIENTLIKELIHOOD

of INTERACTION

RECOMMENDATIONSEVERITY

of OUTCOME

MECHANISM of INTERACTION

DRUG, DRUG CLASS, ENZYME or TRANSPORTER


May have additive hypoglycaemic effect

Level AClinical trials suggest ALA may affect glucose-lowering effect of

these medications


Hypoglycaemic drugs

May decrease drug effect

Co-administration of levothyroxine with ALA

may decrease conversion to active T3 form

Level DPreliminary animal studies Theoretical


Levothyroxine

CYP450 enzyme substrates (CYP1A1, CYP1A2 and

CYP2B)


May increase or decrease blood levels of substrates

via inhibition of these enzyme activities

Level DAnimal and in vitro study Theoretical

Variable (depending

on drug and disease

state)


Immunosuppressants May decrease drug effect

May have opposing effect to drug

Level CCase report


AshwagandhaWithania somnifera

Benzodiazepines (Diazepam)


May have additive effect to drug due to GABAergic

activity

Level DAnimal study (Co-administration of extract of withania somnifera (50 mg/kg) and diazepam (0.5 mg/kg) increased the seizure threshold)

Theoretical Use with caution under supervision of a healthcare professional and monitor

Chemotherapeutic agents (Doxorubicin, cyclophospha-mide, epirubicin, fluorouracil)

Herb effect on drug (May improve che-motherapy-induced

fatigue)

Unknown mechanism of the interaction

Level BHuman study (Withania somnifera

6 g/d throughout 6 months chemotherapy in breast cancer

patients)

Low Use with caution under supervision of a healthcare professional and monitor

Psychotropic drugs (Olan-zapine, typical antipsychot-ics, antidepressants, mood

stabilisers, antianxiety, hypnotic)

Herb effect on drug (May improve nega-

tive, general and total symptoms and stress)

May improve neurotrans-mitter dysfunctions due

to GABAergic and NMDA potentiating activity of

withania

Level AClinical trials (Adjunctive treat-ment with extract of Withania somnifera 1000 mg/d improved

negative symptoms and stress in patients with recent exacerbation of schizophrenia. Another clinical

trial showed extract of Witha-nia somnifera 500 mg/d improved cognitive abilities without serious

adverse effects.)

Low

Use with caution under supervision of a healthcare professional and monitor. Mild

to moderate and transient side effects were reported such as somnolence, epigastric discomfort or loose stools

Low

Possible

Possible

Possible

Possible

Possible

Moderate - High

Moderate - High

Moderate - High

Moderate

Moderate - High

Moderate - High

Pg.6 Pg.7



SEVERITY of

OUTCOME

Bacopa See “Brahmi”

Black cohoshCimicifuga racemosa

Level BHuman study


May increase or decrease drug effectCYP2D6 substrates

May increase or decrease blood levels of drug via

inhibition of this enzyme activity

Level Din vitro study on mouse breast

cancer cell lineTheoretical Avoid concomitant use


depending on chemotherapeutic

agents

Chemotherapeutic agents (Docetaxel, doxorubicin,

cisplatin)

May increase cytotoxicity of docetaxel and

doxorubicin or may decrease cytotoxicity

of cisplatin


Avoid concomitant useMay decrease drug effect

Immunosuppressants Astragalus may have immunostimulant activity Theoretical Moderate

- High

AstragalusAstragalus

membranaceus

Possible

Moderate -High

Variable (depending on drug and

disease state)

Betacarotene Level AClinical trials

Interaction may be minimised by separating dose of medication and betacarotene by at least 2 hours. Supplementation recommended

Drug effect on nutrient (May

decrease nutrient effect)

Orlistat, plant sterolsBetacarotene absorption

may be decreased by these drugs

LowLikely

Bilberry Vaccinium myrtillus

Level C Case report (Rectal bleeding after

taking warfarin with bilberry)


May increase risk of bleeding



Moderate - High

Possible

Level AClinical trial (Drug-herb

interaction was not directly studied. The ingestion of bilberry

extract significantly decreased the incremental AUC for both

glucose and insulin compared to placebo)


May increase drug effectHypoglycaemic drugs


Theoretical

Variable (depending

on drug and disease

state)

TheoreticalLevel D

in vitro study Use with caution under supervision of a

healthcare professional and monitor

Herb effect on drug (The combination

may have an immunostimulatory

effect)

Antibiotics (Doxycycline and cephalosporins)

May improve the viability of thymocytes Moderate

Level Din vitro study (Drug-herb

interaction was not directly studied. A significant dose-de-

pendent inhibition of ACE activity was seen after incubation with

bilberry extract)

Use with caution under supervision of a healthcare professional and monitorMay increase drug

effect

Antihypertensive drugs (ACE inhibitors)


Theoretical Moderate - High


interaction was not directly studied. Bilberry extract in-

creased IC50 values of erlotinib)

Avoid concomitant useMay decrease drug effect

Anticancer agent (Erlotinib)Bilberry anthocyanins

may modulate the growth-inhibitory effect of

erlotinib



of INTERACTION


of OUTCOME



Pg.8 Pg.9



SEVERITY of

OUTCOME

BromelainLevel A

Clinical trials (160 mg bromelain appreared to increase intra-

operative amoxicillin levels in tissue, serum and skin samples.

The effect persisted 3 hours after surgery)

Use with caution under supervision of a healthcare professional and monitorMay increase drug

effectAmoxicillin

May increase levels of amoxicillin in tissue and blood by increasing the

absorption and enhancing its penetration into tissues

Level DAnimal and in vitro study (Oral bromelain retained substantial

proteolytic activity throughout the gastrointestinal tract when in com-

bination with antacids)

No evidence from human studies to support clinical recommendations


increase nutrient effect)

Antacids

May increase retention of proteolytic effect

of bromelain when in combination with antacids

Theoretical Low

Brahmi Bacopa monnieri Level A

Clinical trialsUse with caution under supervision of a


May increase effect of AChE inhibitor and

cholinergic drug. May decrease

effectiveness of anticholinergic drug

Acetylcholinesterase (AChE) inhibitor, anticholinergic drug, cholinergic drug

May increase acetylcholine levels due to inhibition of

acetylcholinesterase Moderate

Level D in vitro study



CYP450 enzyme substrates (CYP1A2, CYP2C19, CYP2C9, CYP3A4)


inhibition of these enzyme activities

Theoretical

Level DAnimal study



Thyroid hormone May have additive effect to drug

Theoretical Moderate

Boswellia Boswellia serrata

Level Din vitro study



CYP450 enzyme substrates (CYP1A2, CYP2C9,

CYP2C19, CYP2D6 and CYP3A4)

May increase or decrease substrate blood levels via inhibition of these enzyme

activities

Theoretical

Level D in vitro study Avoid concomitant useMay decrease drug

effectImmunosuppressants


Theoretical


disease state)


disease state)

Likely

Moderate

Level Din vitro study (Bromelain 25-50mg/

mL decreased IC50 value of cisplatin in malignant peritoneal

mesothelioma cells)


May increase drug effect Cisplatin Bromelain may increase

apoptosis and autophagy Theoretical

Moderate - High

Level CCase report (Ecchymosis devel-oped on forearms after taking

naproxen with bromelain)


May increase drug side effectNSAIDs (Naproxen) Mechanism unclear Possible

Moderate - High

Level B Human study (Drug-herb interaction was not directly studied. Bromelain

showed antiplatelet and anticoagulant effect)






Moderate -High


of INTERACTION


of OUTCOME



Possible

Pg.10 Pg.11



SEVERITY of

OUTCOME

Chromium

Multiple mechanisms pro-posed (addressing dietary

intake, skeletal muscle fat oxidation, and insulin signalling) with studies

ongoing

Level A Clinical trials (Evidence based

on sulfonylureas. Combination of glipizide and chromium improved

glycaemic control, increased insulin sensitivity and significantly

attenuated body weight gain induced by glipizide)


Nutrient effect on drug (May increase

drug effect but decrease associated

side effects)

Hypoglycaemic drugs Low

Chondroitin sulfate Level C

Case report (warfarin)

Possible Avoid concomitant useMay increase drug effect

Anticoagulant and antiplatelet agents

May have additive effect to drug. Chondroitin is a small component of a heparinoid and might

have weak anticoagulant activity

Moderate - High

Chaste Tree See “Vitex”

CeleryApium

graveolens

Level CCase report


Level C Case reports

Theoretical

Possible

Possible Moderate - High




Thyroid hormone




CYP1A2 substrates

Venlafaxine



Celery may increase blood levels of venlafaxine by

inhibition of CYP2D6

May decrease blood levels of drug

Moderate


disease state)

Calcium

Level BSmall human study. Calcium-rich food considered to be the major reason for reduced absorption

PossibleInteraction may be minimised by

separating dose of medication and calcium by at least 2 hours


ModerateBeta Blockers (Atenolol,

sotolol)

Calcium may decrease absorption of atenolol

sotalol

Level B Study in arrhythmic patients

using IV calcium and case report


Calcium channel blockers (verapamil)


Calcium may decrease the hypotensive effect of

verapamilModeratePossible

Level CCase reports


May increase drug side effect

Thiazide diureticsCalcium may increase the

risk of hypercalcaemia with these drugs

ModeratePossible

Level A (quinolones)Level B (bisphosphonates)

Level C (tetracyclines, thyroid hormones)

Interaction may be minimised by separating dose of medication and

calcium by at least 2 hours

May decrease drug effect Moderate

Bisphosphonates, tetracycline or quinolone

antibiotics, thyroid hormones

Calcium may decrease the absorption and efficacy of

these drugsPossible

Level CCase reports

Avoid concomitant useMay increase drug side effect

Ceftriaxone

IV calcium and IV ceftriaxone may result

in precipitation of a ceftriaxone-calcium salt in

the lungs and kidneys

Possible High


Avoid concomitant use. If indicated, interaction may be minimised by taking

2 hours before or 6 hours after taking calcium


Antiretrovirals (Integrase inhibitors - dolutegravir, elvitegravir, raltegravir)

Calcium may reduce blood levels of dolutegravir,

elvitegravir and raltegravir through chelation



of INTERACTION


of OUTCOME



May decrease absorption of chromium by forming insoluble complex when pH is raised in gastroin-testinal tract by antacids

Level DAnimal study (Chromium levels

in blood were lower when in combination with antacids)



decrease blood levels of nutrient)

Antacids (Aluminium hydroxide and magnesium

hydroxide)Theoretical Moderate

Possible

Pg.12 Pg.13



SEVERITY of

OUTCOME

Level AClinical trial in leukemia and

lymphoma patients

Level Din vitro studies found beta blockers

inhibited mitochondrial CoQ10 enzymes

Theoretical Low Assess nutrient status and supplement if indicated




Nutrient effect on drug (May decreases

drug side effect)


Chemotherapeutic agents (Anthracyclines such as

daunorubcin, doxorubicin)

Beta-blocker adrenergic agents


CoQ10 levels may be decreased by these drugs

Despite the potential benefits of CoQ10 in

preventing cardiotoxicity, it is unknown if

CoQ10 diminishes the antineoplastic effect of

doxorubicin therapy

CoQ10 may have procoagulant or

anticoagulant effect

Co-enzyme Q10 (CoQ10)

Low

ColeusColeus forskohlii


Level DAnimal studies

TheoreticalModerate -

HighUse with caution under supervision of a

healthcare professional and monitorMay increase drug

effect



Level BHuman and animal studies using

IV extractsRelevance to oral doses unknown

TheoreticalNo significant adverse effect expected. Use with caution uder supervision of a health care professional and monitor


Antihypertensive drugs Moderate - High

CoQ10 does not elicit its protective effect against doxorubicin-induced cardiotoxicity by reducing the drug levels in the blood or by inhibiting

the formation of doxorubicinol

Moderate - High

May have additive hypotensive effect

Level AMeta-analyses in patients taking

anti-hypertensive drugs

Moderate - High


May increase drug effectAntihypertensive drugs Likely

Possible

Level ASeveral studies in hyperlipidaemic patients; statins decreased plasma CoQ10 levels (effect on tissue levels

not established)

Low Assess nutrient status and supplement if indicated



HMG-CoA reductase inhibitors (statins) Likely

CoQ10 levels may be depleted by these drugs

Level AConflicting data

Clinical trial found no interaction.Multiple case reports of changes

to INR

Possible

Level AConflicting data

Clinical trials show conflicting results. Systematic review

found inadequate evidence to recommend routine use with

statins

LowInadequate evidence to support

supplementation in all patients taking statins

HMG-CoA reductase inhibitors (statins)

CoQ10 may decrease myalgia associated with

statin use

Nutrient effect on drug (May decrease

drug side effect)

PossibleLevel A

Conflicting dataClinical trials


Hypoglycaemic drugs May have additive hypoglycaemic effect


Moderate - High

Possible

Chromium May decrease blood

levels of drug by reducing absorption

Level BHuman study (Chromium picolinate significantly decreased the AUC of

serum thyroxine)

ModerateAvoid concomitant use. If chromium is

indicated, interaction may be minimized by separating the dose by 2 hours


Levothyroxine Possible


of INTERACTION


of OUTCOME



May increase the absorp-tion of chromium

Level DAnimal studies (Chromium levels in blood, urine and tissues were

higher when in combination with aspirin or indomethacin)

ModerateUse with caution under supervision of a



increase blood levels of nutrient)

NSAIDs (Aspirin and indomethacin) Theoretical

Pg.14 Pg.15



SEVERITY of

OUTCOME

EchinaceaEchinacea

angustifolia Echinacea purpurea

Evening primrose oil

Dong quaiAngelica

polymorpha

CranberryVaccinium

macrocarpon

Level BConflicting data

Human study found no interactionCase reports of seizures in

schizophrenic patients exist

High Use with caution under supervision of a healthcare professional and monitor


Phenothiazine May lower seizure threshold

Unlikely

Level CCase report in patient using

lopinavir/ritonavir with evening primrose experiencing an increase

in blood levels of drugs

Moderate - High

Avoid concomitant useMay increase drug effect

Antiretrovirals (Lopinavir/ritonavir)

May increase blood levels of drug

Possible

Level BHuman studies


disease state)



CYP3A4 substratesMay increase or decrease blood levels of drug via

induction of this enzyme activity

Possible

Level BAnimal studies, in vitro and in vivo

evidence of immunomodulatory effect.

No case report evidence

Moderate-High Avoid concomitant use

May increase drug side effectImmunosuppressants May have opposing effect

to drugPossible



disease state)



CYP1A2 and CYP2D6 substrates

May increase or decrease blood levels of drug

via inhibition of these enzyme activities

Possible

Level CCase report involving concurrent use of etoposide, cisplatin, and echinacea. Patient developed profound thrombocytopenia

Moderate - High Avoid concomitant useMay increase drug

effectChemotherapeutic agent

(Etoposide)

May increase blood levels of drug via inhibition of CYP1A2, CYP2C19,

CYP2C9, CYP3A4

Possible

Level CSeveral case reports and animal

studies

Moderate - High Avoid concomitant useMay increase drug

effect


May have additive effect to drug Possible




Aspirin May have additive effect to drug Unlikely

Level CCase report

High Avoid concomitant useMay decrease drug effect

Tacrolimus May decrease blood levels of drug Possible

Level AConflicting data.

Clinical trials suggest no evidence of increasing drug affects with

cranberry juice. Case reports exist.in vitro studies suggest cranberry

effect warfarin metabolism (CYP3A4 minor metaboliser)

Moderate - High





Unlikely

Level CCase report

Variable (depending

on drug and disease

state)



CYP3A4 substrates



Possible


of INTERACTION


of OUTCOME



Pg.16 Pg.17



SEVERITY of

OUTCOME

Flaxseed oil

Fish Oil

FeverfewTanacetum parthenium

FenugreekTrigonella

foenum-graecum

Likely Moderate - High


Hypoglycaemic drugs May have additive effect to drug

Level AHuman studies and meta-analyses

confirm blood glucose-lowering effect in patients with type-2

diabetes


Theoretical ModerateUse with caution under supervision of a

healthcare professional and monitorTheophylline May decrease blood levels

of drug

Level DAnimal study (oral administration

of theophylline 200 mg after fenugreek in male beagle dog)



Avoid concomitant useAnticoagulant and antiplatelet agents


Level CCase report in patients with arrhythmia using fenugreek

capsule and warfarin



of INTERACTION


of OUTCOME



Folic acid

Level CCase report

Moderate - High

Avoid concomitant useMay cause compound resistance


Chemotherapeutic agents (Cisplatin, oxaliplatin,

irinotecan)

Possible


Multiple clinical trials have found no increase in risk of bleeding

with antiplatelet or anticoagulant drugs, however there are

some studies that suggest an interaction, particularly at higher

doses

Moderate - High


High doses of fish oil (>3 g/d omega-3 fatty acids) may increase the risk of

bleeding with these drugs

May increase drug effect depending on

fish oil dose


Possible (depending on fish oil

dose)

Level AConflicting dataHuman studies

Moderate - High

Interaction unlikely at normal doses. Use with caution under supervision of a


High doses (30-40 g/d) of flaxseed oil may increase the risk of bleeding with

these drugs



Unlikely (possible with high

doses)

Level BConflicting data.

in vitro and in vivo studies found feverfew inhibits platelet

aggregation.Human study found no such effect






Level Din vitro study found low inhibitory

activity

No significant adverse effect expected. Use with caution under supervision of a





CYP450 enzyme substrates (CYP1A2,

CYP2C8, CYP2C9, CYP2C19 and CYP3A4)

Theoretical


disease state)

Level AMeta-analyses in patients taking

anti-hypertensive drugs

Blood pressure should be monitored when patient is on high dose of fish oil


depending on fish oil dose


Antihypertensive drugs Likely Moderate

Level A Clinical trials

Moderate - High

Blood pressure should be monitored when patient is on high dose of flaxseed

oil

May have additive hypotensive effect. Dose

dependent

May increase drug effect. Dose dependent

Antihypertensive drugs Likely

Level CMultiple case reports

Moderate - High

Assess and monitor nutrient status and supplement if indicated

May decrease folic acid levels

Drug effect on nutrient (May decrease blood

levels of nutrient)

Co-trimoxazole, sulphazalazine,

phenytoin, phenobarbital, primidone and methotrexate

Possible

Pg.18 Pg.19



SEVERITY of

OUTCOME

Folic acid

GarlicAllium sativum

Level CCase reports

Moderate - High

Avoid concomitant useFolic acid may increase the toxicity of fluorouracil and

capecitabine


Fluorouracil and capecitabine Possible


Moderate - High

Follow Australian Medicines Handbook’s recommendations for concurrent use of

folic acid and methotrexate

Folic acid may decrease the efficacy of

methotrexate for children with lymphoblastic

leukaemiaFolic acid may decrease

drug side effect in rheumatoid arthritis


Methotrexate Likely

Level A Conflicting data

Human studies show conflicting results. Interaction more likely at higher doses (>7 g). Case reports

Moderate - High


May increase the risk of bleeding with these

medications

May increase drug effect depending on

formulation and dose

Anticoagulants and antiplatelet agents Possible

Level AClinical trials indicate

antihypertensive activity with aged garlic extract (480-960 mg/d)

Moderate - High


May have additive hypotensive effect to drug.

Dose dependent


Antihypertensive drugs Likely

Level Bin vitro and open studies using

chlorzoxazone


disease state)


May increase blood levels of substrates via inhibition

of this enzyme activity


CYP2E1 substrates Possible

Level CCase report


disease state)



inhibition of hepatic CYP3A4 enzyme activity


Hepatic CYP3A4 substrates

Possible

Level BHuman study


disease state)


May decrease blood levels of drug via induction of

intestinal CYP3A4 enzyme activity


Intestinal CYP3A4 substrates (Saquinavir)

Possible

Level Bin vitro and human studies found

garlic decreased levels of the protease inhibitors saquinivir and

ritonavir


disease state)


May decrease blood levels of substrates via

upregulation of intestinal ABCB1 or ABCC2 activity


Intestinal P-glycoprotein substrates Possible

Level BHuman study

Modeate - High

(depending on dose)


May have additive hypoglycemic effect


Metformin Possible


of INTERACTION


of OUTCOME



Level BUncontrolled studies in epileptic

patients

HighUse only under supervision of healthcare

professional and monitor phenytoin blood concentration

Folic acid may decrease the efficacy of phenytoin


Phenytoin Likely

Pg.20 Pg.21



SEVERITY of

OUTCOME

GingerZingiber officinale


Clinical trials indicate normal doses ≤4 g/d are unlikely to cause

platelet dysfunction.Human study with high dose

ginger (10 g) and in vitro studies showed inhibition of platelet

aggregation

Moderate - High

Do not use high doses (≥4 g/d) in patients with bleeding disorders or

those taking antiocagulant medication. Use with caution under supervision of a


May increase the risk of bleeding with these

medications


Anticoagulants and antiplatelet agents Unlikely

Level DAnimal study

Moderate - High


May decrease blood level of drug


Ciclosporin Theoretical

Level DAnimal study


healthcare professional and monitor May increase absorption

and plasma half lifeMay increase drug

effectMetronidazole Theoretical

Level DAnimal study

High Avoid concomitant useMay increase blood levels of drug via unknown

mechanism


Tacrolimus Theoretical

GinkgoGinkgo biloba

Level CCase reports

Moderate - High


May increase risk of seizure


Anticonvulsants (Phenylbarbitone, sodium

valproate, phenytoin)Possible

Level AMeta-analysis and studies

Low No significant adverse effect expected

Ginkgo may add to the beneficial

effect of haloperidol, chlorpromazine and

olanzapine in the treatment of schizophrenia

Herb effect on drug (May increase drug

efficacy)

Chlorpromazine and haloperidol

Likely



May increase or decrease blood levels of drug via weak inhibition of these

enzyme activities


CYP450 enzyme substrates (CYP 1A2,

CYP2C9, CYP3A)Theoretical


Human studies found ginkgo decreased levels of omeprazole,

but had no effect on voriconazole





CYP2C19 substrates Possible

Level CCase report

Moderate - High


May increase blood levels of drug due to possible

induction of CYP3A4 and P-glycoprotein


Efavirenz Possible

Level B Conflicting data.

Clinical trials and human studies found ginkgo had a variable effect

on drug activity. Animal and in vitro studies suggest ginkgo may

reduce insulin resistance

Moderate - High


Ginkgo may increase or decrease blood glucose

levels


Hypoglycaemic drugsPossible


Moderate - High


May increase blood level of drug


Nifedipine Possible


disease state)


disease state)

LIKELIHOOD of

INTERACTIONRECOMMENDATION

SEVERITY of

OUTCOMEINGREDIENT MECHANISM of

INTERACTIONDRUG, DRUG CLASS,

ENZYME or TRANSPORTER

Pg.22 Pg.23



SEVERITY of

OUTCOME

Ginseng (Korean) Panax ginseng

GinkgoGinkgo biloba


Moderate - High

Avoid concomitant useMay increase blood level of drug


Raltegravir Possible

LIKELIHOOD of


SEVERITY of




Level CCase report

Moderate - High


May have an effect on neurochemical system


Amitriptyline Possible

Level Bin vitro, animal and human ex vivo

studiesAvoid concomitant use

Korean ginseng may falsely elevate or decrease assays for blood digoxin

levels

May interfere with the accuracy of a range of tests measuring serum

digoxin

DigoxinPossible High


Clinical trials find ginkgo does not have a significant effect on platelet function and does not interact with

warfarin, aspirin or clopidogrel.Case reports suggest an interaction is possible

Moderate - High


Ginkgo may increase risk of bleeding with these

medications


Anticoagulants and antiplatelet agents Unlikely

Level AClinical trials in NIDDM patients

and healthy subjects




Hypoglycaemic drugs Moderate - HighLikely

Level CCase reports (ginseng type not

specified)


Korean ginseng may increase the side effect of

phenelzine or other MAOIs


Monoamine Oxidase Inhibitors (MAOI)

(Phenelzine)

ModerateUnlikely


Clinical trial results suggest no interaction.

Case reports existin vitro studies suggest possible

interaction

Moderate - High


Possible CYP450 enzymes interaction and Vitamin K

effect on ginseng


Anticoagulant and antiplatelet agents Possible



May increase or decrease blood level of drugs via



CYP2D6 substrates PossibleVariable

(depending on drug and

disease state)

Level Din vitro study Low No evidence from human studies to

support clinical recommendations

May enhance susceptibility of colon cancer cells to

docetaxel

Herb effect on drug (May increase drug

efficacy)

Docetaxel Theoretical

Level DAnimal study

Low No evidence from human studies to support clinical recommendations

May have a protective effect on doxorubicin-

induced toxicity


side effect)

Doxorubicin Theoretical



Korean ginseng may cause a phytoestrogenic effect

May increase or decrease drug effect Oestrogen

Theoretical Low - Moderate


Moderate - High


May decrease blood levels of drugs possibly due to

induction of CYP3A4


Midazolam Possible

Level CCase report High Avoid concomitant use

May increase blood levels of drugs possibly due to

inhibition of CYP3A4


Imatinib Possible

Pg.24 Pg.25



SEVERITY of

OUTCOME

Glucosamine

LIKELIHOOD of


SEVERITY of




Ginseng (Siberian)

Elutherococcus senticosus

Level B in vivo study found anticoagulant

activity for an isolated constituent.Human study in athletes

adminstered a preparation of Siberian ginseng and andrographis

found reduced coagulation

Avoid concomitant useSiberian ginseng may

increase risk of bleeding with this medication



Level AHuman trials in women with

breast and ovarian cancer undergoing chemotherapy

treatment


Siberian ginseng may increase tolerance for

chemotherapy and improve immune response

Nutrient effect on drug (May decrease drug

side effect)

Chemotherapeutic agents

Level B Human studies





CYP3A4 and CYP2D6 substrates

Level Bin vitro, animal and human ex vivo

studies

Avoid concomitant useSiberian ginseng may

falsely elevate or decrease assays for blood digoxin

levels

May interfere with the accuracy of a range of tests measuring serum

digoxin levels

Digoxin



May have additive hypoglycaemic effect to

drug


Hypoglycaemic drugs

Level CTwo case reports (ginseng type

not specified)


Siberian ginseng may increase side effect of

phenelzine or other MAOIs


Monoamine Oxidase Inhibitors (MAOI)

(Phenelzine)



May increase blood level of drug via inhibition of P-gp

May increase drug effectP-glycoprotein substrates

Moderate - High

High

Moderate - High

Moderate - High

Grape seedVitis vinifera

Level Din vitro studies


May decrease platelet adhesion to fibrinogen





disease state)


disease state)

Moderate

LowLikely

Likely

Possible

Possible

Possible

Unlikely

Possible

Level CCase reports Avoid concomitant use

Glucosamine may increase risk of bleeding with this

medication



Moderate - High

Possible

Level AClinical trials indicate no

interaction.Lower-level studies reports

changes to glucose and insulin levels

Interaction unlikely but use with caution under supervision of a healthcare

professional and monitor

Glucosamine may affect blood glucose levels in people with diabetes

May decrease drug effectHypoglycaemic drugs Unlikely

Level A Clinical trial (6 weeks treatment with both vitamin C 500 mg and grape seed polyphenol 1000 mg

daily increased blood pressure in hypertensive patients)

Avoid combination of vitamin C and grape seed in hypertensive pateintsUnknown mechanismMay have opposing

effect to drug Antihypertensive drugs +

vitamin CModerate -

HighPossible

Pg.26 Pg.27



SEVERITY of

OUTCOME

Grape seedVitis vinifera

HawthornCrataegus monogyna

Level Din vitro study (100 mg of grape seed extract inhibited CYP2C9

and intestinal CYP3A4 activity) in vitro and animal study (Wild grape

seed procyanidins diminished CYP2E1 expression in vitro

and downregulated the protein expression level of liver CYP2E1

in rats)


May increase or decrease blood levels of drug via inhibition

of these enzyme activities


CYP450 enzyme substrates (CYP2C9, CYP2E1, Intestinal

CYP3A4)

Theoretical


disease state)

Level DAnimal study (1 week treatment

of grape seed extract (80 mg/kg) with the administration of

intravenous midazolam (10mg/kg) increased the effect of midazolam) Midazolam is bio-transformed to the active metabolite via hepatic

CYP3A4 enzyme



induction of hepatic CYP3A4 enzyme activity


Hepatic CYP3A4 substrates

Theoretical


disease state)

Level DAnimal study (400 mg/kg of grape

seed extract showed protective effects on the testicular toxicity induced by cisplatin (10 mg/kg)

in rats)


Unclear mechanism. May suppress free radicals and rescue the down-regulated expression of testosterone

synthesis induced by cisplatin

Herb effect on drug (May reduce cisplatin-

induced oxidative/nitrative stress)

Cisplatin Theoretical Low

Level DAnimal study (100 mg/kg grape

seed extract showed cardio-protective effect without affecting

antitumor effects of 2mg/kg doxorubicin)


Unclear mechanism. May protect DNA from oxidative

damage

Herb effect on drug (May attenuate

doxorubicin-induced toxicity)

Doxorubicin Theoretical Low

Level BHuman study (300 mg of grape

seed did not significantly change metabolic rates of

dextromethorphan (CYP2D6 substrate) in healthy volunteers)

Level DIn vitro study (100 mg of grape seed extract inhibited CYP2D6

activity)


May increase or decrease blood levels of drug via inhibition of this

enzyme activity


CYP2D6 substrates


disease state)

Unlikely

Level CCase report

Moderate - High





Possible

Green-lipped mussel


Several case reports of raised INR.Small human study found no

effect on platelet aggregation, prothrombin time, APTT, fibrinogen or factor VII


Green-lipped mussel may increase the risk of bleeding with this

medication




LIKELIHOOD of


SEVERITY of




Pg.28 Pg.29



SEVERITY of

OUTCOME

LIKELIHOOD of


SEVERITY of




HawthornCrataegus monogyna

Level DAnimal study


May have additive vasodilation effect


Phosphodiesterase-5-Inhibitors

Theoretical

Holy basilOcimum

tenuiflorum

Level DAnimal study

Moderate - High


May inhibit platelet aggregation



Theoretical

Level AClinical trial in NIDDM patients found holy basil may decrease

blood glucose levels

Moderate - High




Hypoglycaemic drugs

Level DAnimal study High Use with caution under supervision of a


May potentiate phenobarbitone - induced

sleeping time


Phenobarbital Theoretical

HopsHumulus lupulus Level D

in vitro studiesUse with caution under supervision of a






CYP1A2, CYP1B1, CYP2C8, CYP2C9,

CYP2C19, CYP3A4)

Theoretical



May bind to estrogen receptor site

May decrease drug effectOestrogen Theoretical

HorsetailEquisetum

arvense

Level CCase reports (2 patients had

detectable viral loads)High Avoid concomitant use

May decrease blood levels of drug by increasing renal excretion of drug due to its diuretic properties or via flavonoids and phenols in horsetail that could induce

CYP450 enzyme activity


Antiretrovirals (Lamivudine, zidovudine, emtricitabine, efavirenz,

tenofovir)

Level Din vitro study (Horsetail extract

from 800 mg of horsetail)






CYP2D6)Theoretical

Iodine Level CCase reports


healthcare professional and monitorMay increase blood levels

of iodine

May increase adverse effect on thyroid

function Amiodarone


Moderate Use with caution under supervision of a healthcare professional and monitor

Iodine may precipitate hypothyroidism


Antithyroid drugs Theoretical

Level CCase reports and open study in

patients taking lithiumModerate Use with caution under supervision of a


Iodine at high doses may increase the hypothyroid

activity of lithium carbonate

May increase drug side effectLithium

Level BStudies in euthyroid subjects -

thyroid function inhibited Moderate


Iodine (at very high doses) may precipitate or exacerbate hyper or

hypothyroidism


Thyroid hormone


disease state)


disease state)

Low - Moderate



May have additive vasodilation effect


Nitrate Possible

Possible

Possible

Possible

Possible

Possible

Level AClinical trials suggest hypotensive

effect



May increase drug effect Antihypertensive drugs Moderate -

HighLikely

Moderate - High

Pg.30 Pg.31



SEVERITY of

OUTCOME

LIKELIHOOD of


SEVERITY of




Iron Level BHuman studies

Avoid concomitant use. If indicated, interaction may be minimised by taking

2 hours before or 6 hours after drug

May decrease the absorption of drug

May decrease drug effect Bisphosphonates


Use with caution under supervision of a healthcare professional and

monitor. Avoid concomitant use. If iron is indicated, interaction may be reduced by taking 4-6 hour before or 2 hours after

drug



Captopril


Avoid concomitant use. If iron is indicated, interaction may be minimised by taking 2 hours before or 6 hours after

drug


May decrease drug effect Dolutegravir

Level BStudies in patients (carbidopa,

levodopa, methyldopa) and healthy subjects (penicillamine)


drug



Methyldopa, levadopa, carbidopa and penicillamine



drug



Mycophenolate



drug



Tetracycline and quinolone



drug



Thyroid hormone

KelpFucus vesiculosus

Level CCase reports


May increase or decrease blood level of drug

May increase or decrease drug effectLithium

Level AClinical trial found T3 decreased

and TSH increased.Case reports of hyperthyroidism

and hypothyroidism


Taking kelp may precipitate or exacerbate hyper or hypothyroidism


Thyroid hormone

LiquoriceGlycyrrhiza glabra Level A

in vitro and in vivo studies and systematic review


Additive effect to drug classes, however may induce CYP3A4 and

CYP2C9 (metabolisers of warfarin) which may decrease blood levels of

warfarin



Level BOpen studies and case report


May have hypertensive effect (at high doses 50-

200 g/d)


Antihypertensive drugs

Level D Animal study




Cisplatin Theoretical

High

Moderate - High

High

Moderate - High

Moderate - High

Moderate - High

Moderate - High

Moderate - High

Moderate

Moderate

Moderate

Moderate

Possible

Possible

Possible

Possible

Possible

Likely

Likely

Likely

Likely

Possible

Possible

Pg.32 Pg.33



SEVERITY of

OUTCOME

LiquoriceGlycyrrhiza glabra

Level BOpen human studies




Corticosteroids (Prednisolone)

LIKELIHOOD of


SEVERITY of







inhibition or induction of this enzyme activity

May increase or decrease drug effectCYP3A4 substrates






CYP450 enzyme substrates (CYP2C9, CYP2C19, CYP2B6,

CYP2C8)

Theoretical

Level CCase report, in vitro study and

animal studyAvoid concomitant use

Liquorice may increase the risk of digoxin toxicity (possibly via hypokalaemia and/or inhibition of P-gp)

May increase drug side effectDigoxin

Level BOpen human studies (dosage 100-

200 g/d) and case reportsUse with caution under supervision of a


Liquorice (at high doses - over 100 g/d) may increase

the risk of electrolyte disturbances, especially

hypokalaemia, with these medications


Potassium-depleting diuretics, laxatives

LuteinLevel D

Animal study (Co-administration of Lutein 0.5 mg/kg and cisplatin

5mg/kg in rats)


May have antioxidant and anti-inflammatory effects

Nutrient effect on drug (May prevent cisplatin-

induced retinal damage)

Cisplatin Theoretical

Level Din vitro studies showed dose-dependent effects. (Lutein (5-

100mg/L) had inhibitory effects on CYP3A4. Lutein (2.8 mg/L) did not

inhibit CYP3A4 activity)





CYP3A4 substrates Theoretical

Level Din vitro study study showed enhanced cytotoxic effect in

breast cancer cells. Another in vitro and animal study showed

that the combination of lutein and doxorubicin reduced sarcoma cell proliferation and tumour growth.


May have additive effect to drug on reactive

oxygen species-mediated apoptosis. May reduce doxorubicin-induced

inflammatory response via inhibition of NF-kB

expression

Nutrient effect on drug (May enhance

cytotoxicity and reduce cancer

resistance)

Doxorubicin Theoretical

Level DAnimal study (Co-administration of lutein 0.5 mg/kg, ethambutol

50 mg/kg and isoniazid 50 mg/kg in rats)


May have antioxidant and anti-inflammatory effects

Nutrient effect on drug (May prevent

isoniazid-induced toxic optic neuropathy)

Ethambutol + isoniazid Theoretical

High

Moderate - High


disease state)


disease state)

Moderate

Moderate


disease state)

Low

Low

Possible

Possible

Possible

Possible

MagnesiumLevel C

Case reportAvoid concomitant use

May have additive inhibitory effects on

presynaptic acetylcholine release

May increase drug side effect such as muscle weakness

Aminoglycosides Moderate - HighPossible

Pg.34 Pg.35



SEVERITY of

OUTCOME

LIKELIHOOD of


SEVERITY of




Level BHuman studies Avoid concomitant use

Proguanil may form complexes with

magnesium

May decrease drug effect Proguanil HighPossible

Level Bin vitro study and human

study based on IV route of administration

Avoid concomitant useMagnesium may reduce the efficacy of warfarin



Moderate - High

Possible

Magnesium

Level BHuman studies and case reports

Assess nutrient status and supplement if indicated

Electrolyte disturbances, including low serum

magnesium levels, may occur with this medication. This has been association with nephrotoxicity, and

may necessitate stopping the drug and giving

intravenous electrolyte replacement


levels of nutrient)Amphotericin-B Possible Moderate

Level AClinical trial using high dose of

magnium (3204 mg/d magnesium chloride)


Magnesium may have additive antiarrythmic

effect

Nutrient effect on drug (May increase drug

efficacy)

Antiarrythmic drugs LowPossible

Level AMeta-analysis


Magnesium may have additive hypotensive effect


Antihypertensive drugs (calcium channel blockers)

Moderate - HighPossible

Level AClinical trial using IV

administration


May have additive inhibitory effects on acetylcholine release


Rocuronium ModeratePossible

Level BMultiple case reports, case series,

reviews Assess nutrient status and supplement

if indicated

Proton pump inhibitors may cause

hypomagnesaemia if taken long-term (usually >1 year)


levels of nutrient)Proton pump inhibitors Moderate

Likely (with long term use)

Level AClinical trials Avoid concomitant use

Bisphosphonates may form complexes with

multivalent cations such as magnesium

May decrease drug effect Bisphosphonates ModerateLikely

Level A (tetracycline and quinolone antibiotics)

Level B (chlorpromazine)Level B (penicillamine)

Level D (digoxin)Level D (nitrofurantoin)

Interaction may be minimised by separating the administration of

medication and magnesium by at least 2 hours

Magnesium may decrease the absorption and efficacy

of these drugsMay decrease drug

effect

Digoxin, chlorpromazine, penicillamine, tetracycline,

nitrofurantoin and quinolone antibiotics

LowPossible



May decrease drug effect Gabapentin

Level BMultiple studies and case reports Assess nutrient status and supplement

if indicated

Loop diuretics and, to a lesser extent, thiazide

diuretics, interfere with magnesium reabsorption

in the kidneys, which increase urinary losses and may reduce serum

magnesium levels


levels of nutrient)

Loop and thiazide diuretics

Moderate - High

Moderate

Possible

Likely (with long term use)

Pg.36 Pg.37



SEVERITY of

OUTCOME

LIKELIHOOD of


SEVERITY of




Milk thistle/St Mary’s thistle

Silybum marianum


No significant adverse effect expected. Use with caution uder supervision of a health care professional and monitor

Milk thistle may have cardioprotective activity against doxorubicin and nephroprotective activity

against cisplatin


side effect)

Chemotherapeutic agents(Cisplatin, doxorubicin)



May increase or decrease blood levels of substrate

via inhibition or induction of this enzyme activity


CYP3A4 substrates



May inhibit or induce P-gp activity


P-glycoprotein substrates Theoretical



May increase blood levels of drug by inhibiting

glucuronidation of drug


Raloxifene Theoretical


Avoid concomitant useMay decrease drug hepatic clearance


Sirolimus


Avoid concomitant use depending on severity of disease state

May increase blood level of drug via inhibition of

CYP2CP, CYP3A4 and P-gp activity


Tamoxifen

Nicotinic acidLevel C

Case reports (Warfarin)Avoid concomitant useMay have additive effect

to drug May increase drug

effectAnticoagulant and antiplatelet agents



May reduce the clearance of niacin by competing for

glycine conjugation

Drug effect on nutrient (May increase or

decrease niacin side effect)

Aspirin

Oats (Avena sativa)

Level AClinical trials find oats decrease blood pressure. In one trial, 73% of patients were able to stop or

reduce their medication




Antihypertensive drugs

High

High

Moderate - High

Moderate - High


disease state)


disease state)

Moderate

Low

Unlikely

Possible

Possible

Possible

Possible

Possible

Level C Case report


Mechanism unknownMay increase drug side effect

Bile acid sequestrants

Level C Case report


May increase risk of myopathy


Gemfibrozil

Level C Case report


High dose nicotinic acid (1500 mg/d) may increase the risk of rhabdomyolysis and myopathy with statins


HMG-CoA reductase inhibitors (statins)

Moderate

Moderate

Low - Moderate

Possible

Possible

Possible




May decrease drug effect Thyroid hormone

Level CCase reports


May have additive effect to nutrient

Drug effect on nutrient (May increase nutrient

side effect)Transdermal nicotine

Moderate

Low - Moderate

Possible

Possible

Likely

L-methionineLevel B

Open study in patients with Parkinson’s disease


Methionine may decrease the efficacy of levodopa in

Parkinson’s disease


Levodopa LowPossible

Moderate - High

Pg.38 Pg.39



SEVERITY of

OUTCOME

Oats (Avena sativa)



May reduce intestinal absorption of atorvastatin


Atorvastatin Theoretical

LIKELIHOOD of


SEVERITY of




Level BHuman study


May decrease metabolism of cortisone


Intramuscular cortisonePara-aminobenzoic acid (PABA)

Level Bin vitro studies and human study Avoid concomitant useMay inhibit antimicrobial

activities of drugMay decrease drug

effect

Sulphonamides and sulphones (Dapsone)

Level BOne uncontrolled study found very high dose of isolated constitutent

prolonged prothrombin time


May have additive anticoagulant effect (at

very high doses)


Anticoagulants and antiplatelet agents Theoretical

Pau d’Arco

Pelargonium Pelargonium

sidoides

PeppermintMentha x piperita

Level AClinical trials and systematic

reviews

No significant adverse effect expected. Use with caution uder supervision of a health care professional and monitor

May have additive LDL-c lowering effect


Lipid-lowering agents (Statins and ezetimibe)

Phytosterols / Plant sterols

Level CMultiple case reports

Avoid concomitant usePotassium may increase

the risk of hyperkalaemiaMay increase drug

side effect

ACE inhibitors, angiotensin receptor

blockers and potassium-sparing diuretics

Potassium

Level A Multiple trials in adults and children taking antibiotics

No significant adverse effects expected. Supplementation may be beneficial

May restore gut flora and reduce diarrhoea

secondary to antibiotic therapy


drug side effect)Antibiotics

Probiotics

Level AClinical trial in women with

vulvovaginal candidiasis

No significant adverse effects expected. Supplementation may be beneficial

Combination therapy may improve clinical outcome


efficacy)Fluconazole

Lactobacillus species including:

L. acidophilusL. reuteri

Level CCase report

Avoid concomitant use in critically ill and immunocompromised patients

May predispose opportunistic infection due

to immunosuppression

May predispose opportunistic infection

ImmunosuppressantsL.Rhamnosus

GR-1L. Reuteri RC-14

Moderate - High

Level Din vitro studies find pelargonium has immune modulatory activity

Avoid concomitant useMay have opposing effect to drug

May decrease drug effectImmunosuppressants


Level DAnimal study suggests interaction

unlikely


Pelargonium contains coumarin which

may reduce platelet aggregation, additive

effect to drug




High

Level D Animal study Avoid concomitant use



Ciclosporin Theoretical High

Moderate - High

Moderate - High

Moderate

Moderate

Low - Moderate

Low - Moderate

Low

Low

Possible

Possible

Level BOpen study using felodipine,

simvastatin (CYP3A4 substrates) Level D

Animal study (CYP1A2, CYP2C0 and CYP2C19 substrates)


May increase or decrease blood levels of drug via inhibition of CYP1A2, CYP2C9 and CYP2C19 enzyme activities and induction of intestinal

CYP3A4 enzyme activity



CYP1A2, CYP2C9, CYP2C19)


disease state)

Possible

Likely

Likely (dose-

dependant)

Likely

Likely

Possible (depending on disease

state)

Pg.40 Pg.41



SEVERITY of

OUTCOME

Level AClinical trial


Psyllium may decrease post-prandial blood

glucose levels


Hypoglycaemic drugsPsyllium husk

LIKELIHOOD of


SEVERITY of





Interaction may be minimised by separating dose of medication and

psyllium by at least 2 hours

Psyllium may decrease the absorption of oral

drugs if doses are taken comcommitantly


Oral drugs and nutritional supplements

Quercetin

Level D Animal study and in vitro study




Anticoagulant and antiplatelet agents Theoretical Red clover/

IsoflavonesTrifolium pratense






CYP450 enzyme substrates (CYP1A2, CYP2C9,CYP2C19,

CYP3A4)

Theoretical



May decrease drug metabolism due to

decrease in glutathione cellular concentration

May increase drug side effect Daunorubicin Theoretical

Level D in vitro study Avoid concomitant use

May increase blood levels of drug via inhibition of

P-gp expression

May increase drug effectDigoxin Theoretical

Moderate - High

Moderate - High

Moderate - High

Moderate - High

Variable (depending

on drug and disease

state)

Variable (depending

on drug and disease

state)

Possible

Possible

Level AClinical trial found quercetin

supplementation reduced systolic, diastolic and mean arterial

pressure in stage 1 hypertensive subjectsLevel D

in vivo study found increased bioavailability for diltiazem but

mechanism is unknown




Antihypertensive drugs (Calcium channel

blockers)

Moderate - High Possible

Level BHuman, animal and in vitro

studies


May increase or decrease blood levels of enzyme

substrates via inhibition of these enzyme activities



CYP1A2, CYP2C8, CYP3A4, CYP2C9,

CYP2D6)



Quercetin may inhibit OATP1B1-mediated

transport


Organic anion transporting polypeptide

(OATP) substrates (OATP1B1)



Quercetin may inhibit P-gp pump efflux


P-glycoprotein substrates

Variable (depending

on drug and disease

state)

Variable (depending

on drug and disease

state)

Variable (depending

on drug and disease

state)



May increase blood level of drug by displacing warfarin from human

serum albumin binding site and CYP2C9 inhibition


Anticoagulant and antiplatelet agents Theoretical

Moderate - High

Possible

Possible

Possible

Pg.42 Pg.43



SEVERITY of

OUTCOME



Red clover binds to estrogen receptors and is capable of acting as both agonists and antagonists


Oestrogen Theoretical

Red clover/ Isoflavones

Trifolium pratense

LIKELIHOOD of


SEVERITY of






May have additive hypoglycaemic effect to

drug


Hypoglycaemic drugs Theoretical



May have additive lipid-lowering effect to drug


Lipid-lowering drugs

Level CCase report Avoid concomitant useMechanism unknownMay increase drug

side effect Methotrexate


Red clover may have oestrogenic activity and

may theoretically interfere with tamoxifen efficacy


Tamoxifen


Avoid concomitant useMay increase blood levels of drug via inhibition of

P-gp expression


Vinblastine Theoretical

Saw palmetto Serenoa repens

Level BHuman study (Study with 12

volunteers showed interaction with CYP1A2, 3A4, 2E1, 2D6 is

unlikely) Level D

in vitro study (Saw palmetto extract showed potent inhibition of CY3A4, CYP2D6 and CYP2C9)


May increase or decrease blood level of drugs via



CYP450 enzyme substrates

(CYP1A2,3A4,2E1,2D6)



May have additive hypotensive effect to drug

May increase drug effectAntihypertensive drugs

Soy/isoflavonesGlycine max

Moderate - High

Moderate - High

High

Moderate - High

Moderate - High

Variable (depending

on drug and disease

state)

Variable (depending

on drug and disease

state)

Low - Moderate


interaction was not directly studied. Saw palmetto extract showed an inhibitory effect on

5-alpha reductase activity)


May have additive effect to drug due to inhibitory

effect on 5-alpha reductase


5-alpha reductase inhibitors

Theoretical


interaction was not directly studied. Saw palmetto decreased

the androgen-sensitive LNCaP human prostate cancer cell number in the presence of testosterone or

dihydrotestosterone)


May have inhibtory effect on 5-alpha reductase


Androgen (Testosterone and dihydrotestosterone) Theoretical

Moderate

Moderate

Possible

Possible

Possible

Possible

Unlikely

Level CCase report (Drug-herb interaction

was not directly studied. Saw palmetto can lead to prolonged

bleeding time)






Pg.44 Pg.45



SEVERITY of

OUTCOME

Soy/isoflavonesGlycine max

LIKELIHOOD of


SEVERITY of




Level BHuman studies (CYP2C9 and 3A4)

Level Din vitro studies (CYP1A2) and

animal study (CYP2E1)



inhibition of CYP1A2 and CYP2E1 enzyme activities and induction of CYP2C9

and CYP3A4 enzyme activities


CYP450 enzyme substrates (CYP2C9,

CYP2E1, CYP3A4)



May have additive diuretic effect to drug


Diuretic drugs Theoretical





Gemfibrozil Theoretical



May have additive hypoglycemic effect to

drug


Hypoglycaemic drugs

Level D Animal study Avoid concomitant use

Soy may have estrogenic activity and may

theoretically interfere with tamoxifen activity

May decrease drug effectTamoxifen

Level B Human study and case report


Soy may decrease blood levels of drug


Thyroid hormone

Level AMultiple studies with oral

contraceptives, warfarin, protease inhibitors, reverse transcriptase

inhibitors, simvastatin, atorvastatin, verapamil, irinotecan, imatinib, methadone, cyclosporin,

tacrolimus, fexofenadine, nifedipine, midazolam,

omeprazole, voriconazole

Avoid or consult with healthcare professional before concomitant us


induction of these enzyme activities


CYP450 enzyme substrates (CYP2C19,

CYP3A4)

St John’s wortHypericum perforatum


Avoid High doses (>7 g) prior to surgery. Use with caution under supervision of a

healthcare professional and monitorMechanism unknownMay increase drug

effect Chemotherapeutic agents Theoretical

Moderate - High

Moderate - High

Variable (depending

on drug and disease

state)

Variable (depending

on drug and disease

state)

Moderate

Moderate

Possible

Possible

Possible

Level Din vitro studies (fermented soy

products contain tyramine)


Tyramine in fermented soy products may cause additive blood pressure

effect


Monoamine Oxidase Inhibitors (MAOI) Theoretical



May increase blood level of drug via inhibition of P-gp


P-glycoprotein substrates (daunorubicin)

Theoretical




May increase drug side effect Progesterone

Variable (depending

on drug and disease

state)

Moderate Possible

Likely

Level BHuman study and case report

(Warfarin)Avoid concomitant use

Soy protein may decrease the anticoagulant effect of

warfarin



Moderate - High Possible

Moderate - High

Moderate - High

Moderate

Possible





HMG-CoA reductase inhibitors

(Atorvastatin, simvastatin)

Low - ModeratePossible

Pg.46 Pg.47



SEVERITY of

OUTCOME

LIKELIHOOD of


SEVERITY of




Level B Human study of the various CYP

enzymes

Avoid or consult with healthcare professional before concomitant use


induction of these enzyme activities


CYP450 enzyme substrates (CYP2B6,

CYP2C9, CYP2E1 and CYP 1A2)

St John’s wortHypericum perforatum

Level AClinical trials Avoid concomitant use

St John’s wort may decrease blood levels of

this medication

May decrease drug effectDigoxin

Level Din vitro and animal studies Avoid concomitant use

May have additive serotonergic effect


Pethidine and dextromethorphan

Theoretical

Level AClinical trials - interaction seen at

doses over 2 g/d (dried herb)

Avoid or consult with healthcare professional before concomitant use

St John’s wort may decrease blood levels of these medications via induction of P-gp

expression

May decrease drug effectP-glycoprotein substrates

Level CCase study of aminolevulinic acid.

in vitro study


Hypericin content of St John’s wort may

increase the possibility of photosensitivity reactions


Photosensitising drugs

Level BMultiple case reports of

serotonergic syndrome. Human study in patients taking

amitriptyline. Case report of monoxidase activity


St John’s wort has additive serotonergic effects that

can lead to serotonin toxicity when taking the

respective antidepressants concomitantly


Prescription antidepressants -

tricyclics, SSRIs and SNRIs, MAOIs

Level C Case report

Avoid concomitant useMay have additive serotonergic effect


Triptans

Level Din vitro and animal studies (Drug-herb interaction was not directly studied. 10 mg/kg of lyophilized aqueous extract of tribulus fruit decreased ACE activity in rats)




Antihypertensive drugs (ACE inhibitors)

Theoretical

Tribulus Tribulus terrestris

Moderate - High

Moderate - High

Moderate - High

Variable (depending

on drug and disease

state)

Variable (depending

on drug and disease

state)

Moderate

Moderate

Moderate

Level DAnimal study (Tribulus dry extract ameliorated the damage induced

by cyclophosphamide in mice testes)


May have antioxidative effect

Herb effect on drug (May improve

reproductive damage induced by cyclophosphamide)

Cyclophosphamide Theoretical Low

Level DAnimal study (Tribulus fruit

extract at dose 100, 300 and 500 mg/kg body weight provided

protection against the cisplatin induced renal toxicity in mice)


May decrease cisplatin accumulation in kidney via diuretic effect of tribulus

Herb effect on drug (May decrease renal

side effects induced by cisplatin)

Cisplatin Theoretical Low

Possible

Possible

Possible

Possible

Likely

Possible

Level AClinical trials (Drug-herb

interaction was not directly studied. Tribulus terrestris showed a significant blood

glucose-lowering effect in diabetic women compared to placebo.)




Hypoglycaemic drugs Theoretical Moderate - High

Pg.48 Pg.49



SEVERITY of

OUTCOME

LIKELIHOOD of


SEVERITY of




Level DConflicting data in vitro study Avoid concomitant use

Antioxidant effect of curcumin may inhibit

apoptosis


Chemotherapeutic agents Theoretical

TurmericCurcuma longa

Level Din vitro and animal studies


May increase or decrease substrate blood levels via inhibition of this enzyme

activity






activity




May increase or decrease substrate blood levels via induction of this enzyme

activity


CYP2A6 substrates

Level CCase report on tacrolimus



activity




May compete with estrogen binding sites

(dose dependent)

May increase or decrease drug effectOestrogen Theoretical

Level BHuman study (for glibenclamide)




Hypoglycaemic drugs





Norfloxacin Theoretical



May increase drug blood levels via inhibition of P-gp


P-glycoprotein substrates Theoretical



May increase drug blood levels due to increased

bioavailability


Paclitaxel Theoretical


Avoid concomitant useMay increase drug blood levels


Sulfasalazine

Level CCase report (Case of patient

self-medicating with valerian and passion flower while on 2 mg

lorazepam)

Avoid concomitant useMay have additive effect to drug by binding to the

GABA receptors

May increase inhibitory activitiy of drug and drug side

effect

Benzodiazepines (Lorazepam, alprazolam)

ValerianValeriana officinalis

Moderate - High

Moderate - High

Moderate - High

Moderate - High

Level Din vitro studies find antiplatelet

effect


May have additive effect to drug (antiplatelet effect) at high doses (o ver 15 g/d)




High

Moderate - High

Variable (depending

on drug and disease

state)

Variable (depending

on drug and disease

state)

Variable (depending

on drug and disease

state)

Variable (depending

on drug and disease

state)

Variable (depending

on drug and disease

state)

Moderate

Variable (depending

on drug and disease

state)

Possible

Possible

Possible

Possible

Possible

Possible

Pg.50 Pg.51



SEVERITY of

OUTCOME

Level AClinical trial (1000 mg of valerian tablet daily did not significantly

change CYP3A4 and CYP2D6 activities)Level D

in vitro studies showed moderate to potent CYP3A4 inhibitory

effects by valerian. Another in vitro study showed an induction of CYP3A4 and CYP2D6 activities

by valerian



inhibition or induction of these enzyme activities



CYP2D6)

ValerianValeriana officinalis

LIKELIHOOD of


SEVERITY of




Level AClinical trial (4 weeks treatment

of valerian 530 mg at night 1 hour before sleep improved

neuropsychiatric adverse effects of efavirenz such as anxiety and

insomnia)


May act on GABA-A receptor and boost melatonin release

Herb effect on drug (May prevent efavirenz-induced neuropsychiatric adverse effects)

Efavirenz

Level Din vitro study (Inhibitory effects

of valerian on the glucuronidation of paracetamol, estradiol and

morphine)


May have inhibitory effects on glucuronidation

May decrease excretion of drug

UGT substrates (UGT1A1, UGT2B7) (Paracetamol,

estradiol, morphine)Theoretical


Assess nutrient status and supplement if indicated. Interaction may be minimised

by separating dose of medication and vitamin A by at least 2 hours

Vitamin A absorption may be decreased by orlistat

Drug effect on nutrient (May decrease nutrient

effect)

OrlistatVitamin A

Level A Systematic review

Avoid concomitant useMay have additive effect to drug

May increase drug side effectRetinoids

Level DVitamin A and tetracycline are in the list of medications that may

produce intracranial hypertension

Avoid concomitant useMay have additive effect to drug

May increase risk of benign intracranial

hypertensionTetracycline


Supplementation may be beneficial

Vitamin B2 found to have migraine preventive

activity. No additive effect with antimigraine drugs

investigated


effect)

Migraine drugs Theoretical

Vitamin B2

Level BCase reports and human study

Avoid concomitant useVitamin C chelates

alumium and may increase aluminium absorption

May increase drug side effect (especially

in renal failure patients)

Aluminium-containing antacids

Vitamin C

Level AClinical trial (6 weeks treatment with both vitamin C 500 mg and grape seed polyphenol 1000 mg

daily increased blood pressure in hypertensive patients)

Avoid combination of vitamin C and grape seed in hypertensive patients

Unknown mechanism of the interaction


Antihypertensive drugs + Grape seed

High

High

Moderate - High

Moderate - High

Variable (depending

on drug and disease

state)

Variable (depending

on drug and disease

state)

Low

Low

Low

Unlikely

Possible

Likely

Likely

Possible

Possible

Possible

Pg.52 Pg.53



SEVERITY of

OUTCOME

LIKELIHOOD of


SEVERITY of




Vitamin C

Level CCase reports


Vitamin C may cause transient deterioration of cardiac function with

desferrioxamine


Desferrioxamine





Oestrogen



High doses of vitamin C (>3 g) may decrease the elimination rate of

paracetamol


Paracetamol

Level BOpen study Avoid concomitant use



Protease inhibitors (Indinavir)



May increase drug absorption

May increase drug effect Aluminium TheoreticalVitamin D3

No significant adverse effect expected. Assess nutrient status and supplement

if indicated

Vitamin D3 improves bone mineral density and

decreases the risk of bone-related side effect


drug side effect)

Anticonvulsants Level A Clinical trials

No significant adverse effect expected in humans. Assess nutrient status and

supplement if indicated

Vitamin D3 decreases the risk of bone mineral

density loss with the initiation of antiviral

agents


drug side effect)

Antiretrovirals (Efavirenz, emtricitabine

and tenofovir) Level A

Clinical trials


May decrease blood level of drugs via induction of

CYP3A4 Nutrient effect on drugAtorvastatin


No significant adverse effect expected in humans. Use with caution under

supervision of a healthcare professional and monitor

Combination therapy may improve clinical outcome


efficacy)Budesonide (oral) Level A

Clinical trials


May have opposing effect to drug. Decrease drug effect by causing

hypercalcemia with high doses of vitamin D3

May decrease drug effect (Dose

dependent)

Calcium channel blockers (Diltiazem and verapamil)

Level C Case report


Mechanism unknownDrug effect on nutrient

(May decrease nutrient effect)

Chemotherapeutic agentsLevel B

Human study



Antioxidants like vitamin C may reduce the activity of chemotherapeutic drugs or may make chemotherapy

more effective by reducing oxidative stress


Chemotherapeutic agents TheoreticalModerate -

High



Calcium channel blockers may inhibit uptake of

vitamin C by intestinal cells

Drug effect on nutrient (May decrease nutrient effect)

Calcium channel blockers (Nifedipine) Theoretical Moderate -

High

High

Moderate - High

Moderate - High

Moderate - High

Moderate - High

Moderate

Moderate

Low

Low

Low

Low - Moderate

Possible

Possible

Possible

Possible

Possible

Possible

Possible

Possible

Possible

Possible

Pg.54 Pg.55



SEVERITY of

OUTCOME

LIKELIHOOD of


SEVERITY of




Level B Human study


Cimetidine inhibits an enzyme involved in

conversion of vitamin D to its active form in the

liver and affect vitamin D metabolism in men


Cimetidine

Vitamin D3


May increase drug effect via inhibition of P-gp


Digoxin Level B

Human study suggests no significant interaction


Heparin and LMWH decrease the metabolism of vitamin D to its active

form


Heparin and low-molecular-weight heparin

(LMWH)



by separating dose of medication and vitamin D by at least 2 hours

Vitamin D absorption may be decreased by orlistat


OrlistatLevel A

Clinical trials

Avoid concomitant useMay increase the

metabolism of sirolimusMay decrease drug

effectSirolimus

TheoreticalLevel B

Human study


Vitamin D3 may increase the risk of hypercalcaemia

if taken with calcium supplements and/or

thiazide diuretics


Thiazide diuretics

Level AMultiple case reports.

Clinical trial in hypoparathyroid patients taking vitamin D and

thiazide diuretics


Avoid concomitant useAntioxidant effects may reduce activity of drug


Chemotherapeutic agents Theoretical

Vitamin E

Level AClinical trials in patients taking

vitamin E and cisplatin


Vitamin E may decrease the incidence and severity of neurotoxicity caused by

cisplatin


side effect)Cisplatin









Vitamin E may prevent nitrate tolerance when given concurrently with

transdermal nitroglycerin


side effect)

Nitroglycerine



by separating dose of medication and vitamin E by at least 2 hours

Vitamin E absorption may be decreased by orlistat


Orlistat

Moderate - High

Moderate - High

High

Moderate

Moderate

Low

Low

Low

Low

Variable (depending

on drug and disease

state)

Possible

Possible

Possible

Possible


Clinical studies have found no interaction with warfarin or

aspirin, or inhibition of platelet aggregation.

Case reports of interaction with warfarin and reduced clotting exist


Vitamin E may increase risk of bleeding



Moderate - High

Unlikely

Likely

Likely

Likely

Likely

Moderate - High

Pg.56 Pg.57



SEVERITY of

OUTCOME

LIKELIHOOD of


SEVERITY of




Vitamin K


interaction was not directly studied)


Binding to dopamine-2 receptor and suppresses prolactin release due to

dopamine agonistic effects of vitex


Dopamine receptor antagonist and agonist Theoretical

Vitex Vitex agnus-

castus

Level Din vitro and animal studies

(Drug-herb interaction was not directly studied. Vitex may exhibit estrogen receptor binding effects and induce progesterone receptor

expression)


Via hormone modulating activity


Oestrogen, contraceptive drugs

Theoretical

Level C Case report


May have additive adverse effect to drug as willow contains salicin, a plant

salicylate which may increase unbound plasma

level of acetazolamide


Acetazolamide

Willow Salix alba

Level BCohort study reported increased

self-reported bleeding when taken with warfarin.

Clinical trial using herb alone found a mild antiplatelet effect

Avoid concomitant useMay have additive effect

to drug as willow contains salicin, a plant salicylate



Level D Animal study (Co-administration of extract of withania coagulans

Dunal dried fruit (1000 mg/kg) and glipizide (1 mg/kg or 2.5 mg/kg) for

4 weeks in rats)




Hypoglycaemic drugs (Glipizide)

Theoretical

WithaniaWithania coagulans



Urinary zinc excretion may be increased with long-term use of these drugs


ACE inhibitors, angiotensin receptor

blockers, thiazide diuretics

Zinc

Level DHuman study that suggests higher intake of vitamin K1 is associated with increased insulin sensitivity and reduced postprandial glucose

levels in adults but no direct study between vitamin K and

hypoglycaemic drugs




Hypoglycaemic drugs Theoretical Moderate - High

Moderate - High

Moderate - High

Moderate

Moderate

Moderate

Low

Level AClinical trials and meta-analyses Avoid concomitant use

Vitamin K may decrease activity of warfarin and

other coumarin (oral) anticoagulants. Avoid changes in vitamin K

intake whilst taking these drugs



Moderate - High

Likely

Possible

Possible

Possible

WithaniaWithania somnifera

See “Ashwagandha”

Pg.58 Pg.59



SEVERITY of

OUTCOME

LIKELIHOOD of


SEVERITY of




Level B Human study

Interaction may be minimised by separating dose of zinc at least 3 hours

after taking cephalexin

Zinc may decrease absorption of drug by chelating with drug


CephalexinZinc


Assess nutrient status and supplement if indicated. Monitor blood glucose level and alter drug dose if required under the supervision of a healthcare professional

Low zinc status is common in diabetic patients. Zinc

supplementation and normalisation of zinc

levels has been shown to improve glycaemic control


efficacy)

Hypoglycaemic drugs

Level A Systematic review Avoid concomitant use

May decrease blood level of drug by chelating with

drug

May decrease drug effect Integrase inhibitors


Interaction may be minimised by separating dose of medication and zinc

by at least 2 hours

Zinc may decrease the activity of penacillamine


Penicillamine

Level BMultiple studies

Interaction may be minimised by taking tetracycline at least 2 hours before, or

4-6 hours after zinc supplement

Zinc may decrease the absorption and blood levels of these drugs


Tetracycline or quinolone antibiotics (not

doxycycline)

High

High

Moderate

Moderate

Low

Possible

Possible

Likely

Possible

Possible

Pg.60 Pg.61

INDEX

EchinaceaEchinacea purpureaEvening primrose oil

FFenugreek Trigonella foenum-graecum Feverfew Tanacetum partheniumFish oilFlaxseed oilFolic acid

GGarlicAllium sativumGingerZingiber officinaleGinkgoGinkgo bilobaGinseng (Korean) Panax ginsengGinseng (Siberian) Elutherococcus senticosusGlucosamineGreen-lipped musselGrape seedVitis vinifera

HHawthornCrataegus monogyna Holy basilOcimum tenuiflorumHopsHumulus lupulusHorsetailEquisetum arvense

IIodineIron

K Kelp Fucus vesiculosus

AAcidophilusSee “Probiotics”Alpha-lipoic acid (ALA)AndrographisAndorgraphis paniculataAshwagandha Withania somniferaAstragalusAstragalus membranaceus

BBacopaSee “Brahmi”BetacaroteneBilberry Vaccinium myrtillusBlack cohoshCimicifuga racemosaBoswellia Boswellia serrataBrahmi Bacopa monnieriBromelain

CCalciumCelery Apium graveolens) Chaste TreeSee “Vitex”Chondroitin sulfateChromium Co-enzyme Q10 (CoQ10)ColeusColeus forskohlii CranberryVaccinium macrocarpon

D Dong quai Angelica polymorpha

E EchinaceaEchinacea angustifolia

INDEX

L Liquorice Glycyrrhiza glabra Lutein

MMagnesiumL-methionineMilk thistle/St Mary’s thistle Silybum marianum

N Nicotinic acid

O Oats (Avena sativa)

PPara-aminobenzoic acid (PABA)Pau d’Arco Tabebuia avellanedaePelargonium Pelargonium sidoidesPeppermint Mentha x piperitaPhytosterols / Plant sterolsPotassiumProbioticsLactobacillus species including:L. acidophilusL. reuteriL.Rhamnosus GR-1L. Reuteri RC-14Psyllium husk

Q Quercetin

R Red clover/Isoflavones Trifolium pratense

SSaw palmetto Serenoa repensSoy/isoflavonesGlycine maxSt John’s wortHypericum perforatum

T Tribulus Tribulus terrestrisTurmericCurcuma longa

V ValerianValeriana officinalisVitamin AVitamin B2Vitamin CVitamin D3Vitamin E Vitamin KVitex Vitex agnus-castus

W Willow Salix albaWithania Withania somniferaSee “Ashwagandha”WithaniaWithania coagulans

Z Zinc

Pg.62

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