Herbal Drug – Drug Interaction

Definitions:

Pharmacovigilance:

Is the pharmacological science related to the detection, collection,

assessment, understanding and prevention of adverse effects particularly
long term, short term side effects of medicine.
Adverse Drug Reactions (ADRs):
A response to a drug which is noxious and unintended, and which occurs at
doses normally used in man for the prophylaxis, diagnosis, or therapy of
disease, or for the modification of physiological function.
Adverse Event/Experience (AE):
Any untoward medical occurrence that may present during treatment with a
pharmaceutical product but which does not necessarily have a causal
relationship with the treatment.
Side Effect (SE):
Any unintended effect of a pharmaceutical product occurring at doses
normally used in human which is related to the pharmacological properties
of the drug.
Serious Adverse Event (SAE):
Any adverse even which is fatal, life- threatening, permanently disabling or
which results in hospitalisation.
Expected adverse reaction:
As opposed to “unexpected”, an event that is noted in the brochure or
labelling.
Unexpected adverse reaction:
The nature or severity of which is not consistent with the domestic labelling
or market authorization, or expected from characteristics of the drug.
Signal:
Reported information on possible causal relationship between an adverse
event and a drug, the relationship being unknown or incompletely
documented previously. Usually more than one single report is required to
generate a signal.

WHO Guidelines for Safety Monitoring of Natural Medicine:

1. General introduction
 Introduction
 Problems
 Actions required
 Objectives
2. Safety monitoring of herbal medicine
  Sources of reports.
 Herbal products targeted for safety monitoring.
 Reporting for suspected adverse reactions.
 Assessment of case reports.
 Data management
3. Communication
General introduction

Introduction:

 Safety is a fundamental principle in the provision of herbal medicines

and herbal products for health care, and a critical component of quality
control.
 These guidelines provide practical technical guidance for monitoring
the safety of herbal medicines within pharmacovigilance systems.
 Herbal medicines are frequently used in conjunction with other
medicines, and it is essential to understand the consequences of such
combined use and monitor whether any adverse effects are arising.
 This can be achieved most readily within existing pharmacovigilance
systems.

Problems:

 Among consumers, there is a widespread misconception that “natural”

always means “safe”, and a common belief that remedies from natural
origin are harmless and carry no risk.
 However, some medicinal plants are inherently toxic.
 Herbal medicines are expected to have side effects, which may be of an
adverse nature. Some adverse events reported in association with
herbal products are attributable to problems of quality.
 Major causes of such events are:
Adulteration of herbal products with undeclared other medicines
and potent pharmaceutical substances, such as corticosteroids and
non-steroidal anti-inflammatory agents.
Adverse events may also arise from the mistaken use of the wrong
species of medicinal plants, incorrect dosing, errors in the use of
herbal medicines both by health-care providers and consumers,
interactions with other medicines, and use of products
contaminated with potentially hazardous substances, such as toxic
metals, pathogenic microorganisms and agrochemical residues.

Actions required:

For the safety of those using herbal medicines, four complementary actions
are needed:
  Clear identification of the nature of adverse events.
 Management of the risks.
 Institution of measure to prevent adverse events.
 Good communication of the risks and benefits of herbal medicines.

Objectives:

The objectives of these guidelines are to:

 Support member states, in the context of the WHO international drug
monitoring programme, to strengthen national pharmacovigilance
capacity in order to carry out effective safety monitoring of herbal
medicines.
 Provide technical guidance on the principles of good pharmacovigilance
and the inclusion of herbal medicines in existing national drug safety
monitoring systems; and where these systems are not in place, to
facilitate the establishment of an inclusive national drug safety
monitoring system.
 Provide standard definitions of terms relating to pharmacovigilance,
and safety monitoring of herbal medicines.
 Promote and strengthen internationally coordinated information
exchange on pharmacovigilance, and safety monitoring of herbal
medicines among member states.
 Promote the safe and proper use of herbal medicines.

Safety monitoring of herbal medicines:

It consists of:
 Sources of reports.
 Herbal products targeted for safety monitoring.
 Reporting for suspected adverse reactions.
 Assessment of case reports.
 Data management
I. Sources of reports:
 The most common sources of information on adverse events and
reactions to medicines are clinical trials and spontaneous reports
(voluntary, unsolicited communications on marketed medicinal
products).
 In some countries, adverse reaction reporting by physicians is
mandatory; such reports are regarded as spontaneous.
 These are of:
Report from health care professionals.
Report from consumers.
Report from manufacturers.
Report from other sources
Report from health care professionals:
 Internationally, adverse drug reaction reporting systems in the post-
marketing safety surveillance setting depend primarily on voluntary
reporting by health-care professionals, preferably those directly
associated with the care of the patient/consumer.
 This is appropriate, since the understanding of adverse drug reactions
depends on medical knowledge and such professionals should be aware
of the patient’s medical history and attuned to the subtleties of clinical
differential diagnosis.
 A substantial proportion of herbal medicines are non-prescription
medicines, and many come directly into this category without prior
post-marketing safety monitoring as prescription medicines.
 It is therefore most important to take measures to strengthen
pharmacovigilance activity in the non-prescription medicines setting.
 Community pharmacists and nurses can play a particularly useful role
in monitoring the safety of non-prescription medicines, although many
such products are sold outside pharmacies.
Report from consumers:
 Consumer reports on adverse reactions should be accepted as a serious
source of information, which can contribute to the identification of
signals for unknown effects of herbal medicines.
 For non-prescription medicines, often taken without health
professional involvement, reports received directly from consumers may
provide the only source of signals.
 With herbal medicines in the non-prescription medicines setting, there
is clearly an essential role for consumer reporting.
 Consumer reporting, in one form or another, is therefore an essential
development if adequate information on risk is to be obtained.
 However, only a few national regulatory authorities currently explicitly
require collection of direct reports from consumers.
 The CIOMS Working Group proposes several policy approaches and
practices aimed at ensuring that consumer reports are treated with
appropriate respect and that there is a rational approach for handling
them.

Report from manufacturers:

 Manufacturers of herbal medicines could be a source of information on
adverse events associated with their products.
 Some countries include reporting of adverse events by manufacturers
as part of their regulatory framework.
Report from other sources:
Problems associated with herbal medicines may be reported as toxicity to the
following:
a) National poisons centres: Where resources are very limited in the
national situation and where no pharmacovigilance centre has been
established, a poisons centre could play a core role in
pharmacovigilance for and safety monitoring of herbal medicines.
b) Drug information centres may also be a first point of contact and may
provide a wealth of clinical information. National pharmacovigilance
centres should have a good level of communication with such centres.
c) Consumer organizations receive complaints about any type of product
in the marketplace and may obtain relevant information about herbal
medicines.
d) Clinical trials and studies can also be a source of information.
II. Herbal products targeted for safety monitoring

In order to obtain comprehensive coverage, it is useful to think of herbal

products in the following categories:

a) According to their regulatory status

Herbal medicines in the prescription medicines category.
Herbal medicines in the non-prescription medicine’s category.
Other herbal products intended for use in health care.
b) According to their registration and marketing status:
Herbal medicines undergoing the new drug development process
in clinical trials prior to national drug regulatory approval.
Herbal medicines undergoing the new drug development process
under post-marketing safety surveillance.
Herbal medicines undergoing re-evaluation under the current
protocol in clinical trials.
Herbal medicines undergoing re-evaluation under the current
protocol under post-marketing safety surveillance.
Herbal medicines on the market under post-marketing safety
surveillance.
Other herbal products marketed for health care, such as dietary
supplements.
III. Reporting for suspected adverse reactions

Who should report and to whom?

 The setting in which an adverse reaction is noted and the status of the
person noting the reaction will determine the most appropriate means
of reporting.
 Although the term “national pharmacovigilance centre” has been used
in these guidelines, it is recognized that in some countries the national
 pharmacovigilance system consists of a network of national and
regional centres.
 Reports should be sent to the appropriate centre in accordance with the
particular national reporting scheme.

The following should provide reports

 Health professionals who are providers of herbal medicines,

including physicians, pharmacists and nurses, should report to the
national pharmacovigilance centre.
 Patients/consumers should normally report to their physicians or
providers of herbal medicines. They may also report directly to the
national pharmacovigilance centre, consumer organizations or
manufacturers.
 Manufacturers should report directly to the national
pharmacovigilance centre or national regulatory authority.
What information should be reported?

Any suspected adverse reaction associated with the use of a herbal medicines
should be reported.

A case report should contain information on the following elements:

 Where it is permitted by the country health information privacy code,

and with appropriate confidentiality, some form of identification of the
patient/consumer in order to avoid duplications and facilitate follow-
up.
 Age, sex and a brief medical history of the consumer/patient.
 Details of suspected herbal product(s) if known: species name and/or
brand or ingredient name(s), including the part of medicinal plant used,
preparation methods; manufacturer, country of origin, batch number,
expiry date and provider.
 Administration details: dose and quantity supplied, dosage form, route,
start/stop dates.
 Indication or reason for use.
 Adverse reaction data: date of onset (or duration from first
administration to onset of event), description with symptoms and signs,
severity and seriousness, results of clinical investigations and tests,
course and outcome, and de challenge/re challenge with the same
product, where appropriate.
 All other medicines used, with administration details, risk factors, e.g.
age, impaired renal function, previous exposure to the herbal
medicine(s) concerned, previous allergies, drug misuse or abuse, the
social use of drugs.
  Name and address of reporter.

How to report?
 A single reporting form covering all medicines, including herbal
medicines, should be used.
 For health-care providers already included in a national
pharmacovigilance system, a familiar form will facilitate reporting the
introduction of a second type of reporting form may cause confusion.
 It is desirable to use a standard printed or electronic reporting form and
to ensure that forms are widely available.
 It should also be acceptable to receive reports by telephone, letter or e-
mail.
 If possible, a sample of the herbal product and its packaging should be
submitted with the report.
IV. Assessment of case reports
Individual case reports:
 Assessment of reports on adverse reactions to herbal medicines should
be undertaken by national pharmacovigilance centres in the same way
as for other medicines.
 Each data element in the report should be considered and a causality
assessment made using a standard approach.
 The assessment is usually based on:
The association in time between administration of the herbal
product and the event.
The outcome of de challenge and re challenge.
Known pharmacology (including current knowledge of the nature
and frequency of adverse reactions).
Medical or pharmacological plausibility (the sequence of
symptoms, signs and laboratory tests and also pathological
findings and knowledge of mechanisms).
Likelihood of other causes or their exclusion.
Testing for adulterants or contaminants that could be the source
of adverse events.
Feedback to reporters:
 The receipt of each report should be acknowledged and a new
reporting form supplied to the reporter.
 The reporter will also appreciate receiving further information about
the reaction concerned.
Detection of signals at national level
 The national pharmacovigilance centre should, at regular intervals,
analyse the case reports in its database by class of organ system and
in smaller groups of clinically related events.
  This may reveal case series of similar events that could constitute a
signal and/or indicate the need for further study or regulatory action.
 Such signals should be communicated to UMC (Uppsala Monitoring
Centre).
 Weak signals may be strengthened by examination of reports from other
countries held in the global WHO database.
Detection of signals at international level
 The major aim of pharmacovigilance is the early detection of signals of
previously unrecognized adverse reactions.
 Early signals may be strengthened by combining the experiences
reported in various countries.
 Regional studies may be of particular value in the monitoring of herbal
medicines.
 Data-mining techniques can be helpful in individual countries, but are
most effective in the global WHO database managed by UMC.
Use of an advisory committee
Each national pharmacovigilance centre should have an advisory committee
composed of experts to give advice on:
 Maintaining quality standards in data collection and assessment
procedures.
 Data interpretation.
 Publication of information.
 Follow-up action required.
Investigation and analysis of the cause of suspected adverse reactions
Some adverse reactions, particularly serious ones should be further
investigated scientifically.
The investigations may include the following:
 Medical investigation of the adverse reactions: pathology, clinical
pharmacology, clinical toxicology, pharmacogenetic studies.
 Pharmaceutical investigation of the adverse reactions:
pharmacokinetics, pharmaco-dynamics and pharmaceutical,
pharmacological and toxicological analysis.
 Pharmacognosical/phytochemical investigation (including
authentification) of the herbal medicines.
 Physicochemical analysis to identify the constituents of the herbal
medicines.
 Pharmacoepidemiology.
Technical expertise and basic equipment
Where possible, national pharmacovigilance centres should have the
necessary technical expertise to handle herbal medicines.
This might include:
 Access to reliable information support on herbal medicines.
  Trained personnel in relevant technical areas (e.g. Pharmacognosy,
phytochemistry, ethnobotany, ethnopharmacology) and in the use and
provision of herbal medicines.
 Access to facilities for analysis of potentially causative products about
which there is often insufficient information.
V. Data Management
Data quality: Strenuous efforts should be made to ensure that there are
quality controls on data processing and that the data elements of reports are
as complete and accurate as possible. Mechanisms to check for duplications
should be instituted.
Data storage: Computer databases should be managed to as high a standard
as possible to facilitate access to and use of the data. Software should be
selected with expert advice so that analytical needs can be met.
Data analysis: Programmes should be developed to provide for regular
analyses and data output appropriate for local needs.
Analysis of the global WHO database:
 The global WHO database managed by UMC is being improved on the
basis of the proposed “Database management and classification for
coding of herbal medicines”.
 Data-mining techniques that have proved effective on the very large
numbers of reports for other medicines will be used for signal detection
on reports for herbal medicines. The success of these techniques
depends on the volume and quality of data submitted by national
pharmacovigilance centres. Support on technical and data
management is available from the WHO Collaborating Centre for
International Drug Monitoring, UMC.

Communication
 The successful safety monitoring of herbal medicines depends on good
communication.
 There are many barriers to be broken down if all the players in this field
are to be involved.
 There is distrust between some and ignorance of the work and function
of different groups.
 Transparent communication is essential to overcome these problems
and ensure that all players collaborate to meet the goal of the safe and
effective use of herbal medicines.
 National pharmacovigilance centres should ensure that manufacturers
receive timely information so that they can take appropriate action
regarding their products.
  Effective communication of the results of monitoring is also essential so
that pharmacovigilance activities can have a positive impact on the
health of the people.
 If there is no national pharmacovigilance centre, consideration should
be given to designating other relevant organizations, such as the
national regulatory authority, poisons centres, drug information
centres and consumer complaints authorities as the focal point.

AYUSH guidelines for safety monitoring of natural medicine

Safety monitoring of natural medicine was done by pharmacovigilance

systems. In India AYUSH and Drugs and Cosmetics act regulations are
established to report adverse events of natural medicine in India. In India
several pharmacovigilance centres are established under AYUSH and these
are divided into National pharmacovigilance resource centre (NPRC), Regional
pharmacovigilance centre (RPC), Peripheral pharmacovigilance centre (PPC).
National pharmacovigilance programme (NPP) for natural medicine i.e.
ASU {Ayurveda, Siddha, Unami} as per AYUSH guidelines:
 ASU drugs are considered as safe drugs.
 This perception is likely to change in the light of some recent incidences
of ADR during their use.
 The purpose of the programme is to collect and collate data, analyse it
and use the inferences to recommend informed regulatory
interventions, beside communicating risks to healthcare professionals
and the public.
Objectives:
Short-term objectives
To develop the culture of notification.
Medium-term objectives
To involve healthcare professionals and professional associations in the drug
monitoring and information dissemination processes.
Long-term objectives
To achieve operational efficiencies that would make NPP for ASU drugs a
benchmark for global drug monitoring endeavours.
Reporting culture:
a. What to report?
b. Who can report?
c. Where to report?
What to report?
 All suspected adverse reactions.
 Lack of effects.
 Resistance.
  Drug interactions.
 Reactions suspected of causing:
Death
Life threatening (real risk of dying)
Hospitalisation (initial or prolonged)
Disability (significant, persistent or permanent)
Congenital anomaly

Who can report?

 Any health care professional can report.
 Shall not accept reports from lay members of the public.
 Others can report through the physicians under whom he / she had
undergone treatment.
 Consumer can directly report to the concerned PPC (Peripheral
pharmacovigilance centre) / RPC (Regional pharmacovigilance centre)
/ nearest health centre or physician regarding the suspected ADR.
Where to report?

Regional Centre
Hospital

Patient Health National

professional center

Manufacturer

What happens to the information submitted?

 It was kept confidential.
 PPC forward the form to the respective RPC (causality analysis). This
information shall be forwarded to the NPRC (National
pharmacovigilance resource centre).
 The data will be statistically analysed and forwarded to the Dept. of
AYUSH.
Responsibilities of pharmacovigilance centres:
 To collect ADR reports.
 To fill in the ADR form properly.
 To forward duly filled in ADR forms to next higher centre.
 To maintain a log of all ADR notification forms.
 To provide general technical support, coordinate and monitor the
functioning of Centres.
 To carry out causality analysis of all ADR forms.
 To forward all duly-filled ADR forms as per pre-determined time line.
 To report all ADRs within 24 Hrs.
 To forward periodic reports to next higher centre.
 To organize and attend training programs/ interactive meetings for all
lower level centres.
 Organize the public campaigns.

Spontaneous reporting schemes for bio drug adverse reactions:

Health professionals are encouraged to report adverse reactions which they
believe to be drug-related directly to
 The regulatory authority or
 The company marketing the suspected product on a voluntary basis.
The spontaneous reporting system process:
1. Data acquisition
2. Data assessment
3. Data interpretation
Data acquisition:
Which depends largely on the input of information derived from reports
submitted by the health professionals who have encountered what they
suspect is an ADR.
Data assessment:
Which involves assessment of the individual case reports and assessment of
pooled data obtained from various sources such as the international database
of the WHO.
Data interpretation:
Based on the available data and the assessments made, a signal related to
the adverse reaction may be generated.
Schemes for reporting ADRS in various countries are:
 India – ‘Suspected Adverse Drug Reaction Reporting Form’
 UK – ‘Yellow Card’, since 1964
 Australia – ‘Blue Card’, since 1964
 US – ‘Med Watch’
Form FDA 3500 – voluntary reporting
Form FDA 3500A - mandatory reporting
Spontaneous reporting - UK
 Licencing authority: Ministers, including Sect., of state for health.
 Authority’s key function: control of medicines by the UK Medicines and
Healthcare Products Regulatory Agency (MHRA).
 Key functions: safety, quality and efficacy of medicines and public
health.
 The vigilance and risk management of medicines of MHRA:
Monitoring safety of all licensed medicines in UK, investigates
possible hazards and takes appropriate action to minimise risk and
maximise benefits to users.
 On introduction of yellow card scheme 6,00,000 lakh ADR reports have
been received in UK.
 MHRA can detect duplicate reports.
Information to include on a Yellow Card
Four critical pieces of information that must be included on the report: -
 Suspected drug(s)
 Suspect reaction(s)
 Patient details
 Reporter details
Suspected Drug(s)
 Name of medicine including brand and batch number if known.
 Route of administration
 Daily dose
 Date medicine started and stopped if applicable.
 Reason why the medication was given.
 Multiple drugs can be listed if more than one drug is suspected of
causing the reaction.
Suspect reaction(s):
 Describe the reaction
 Include a diagnosis if relevant
 Include when the reaction occurred whether the reaction was
considered to be serious and complete tick box for reasons why
 Document if any treatment was given for the reaction
 Eventual outcome tick relevant box
Patient Details
 Sex of the patient
 Age at time of reaction
 Weight if known
 Do not need to know name or DOB as this could identify patient and
break patient confidentiality.
  Patients initials and local identification number (hospital or practice
number) which will identify patient to you in the event of future
correspondence.
Reporter details:
 Must be completed in all cases
 Name and full address
 Need to acknowledge receipt of report and follow up further
information if necessary.
 Profession
Drug Analysis Prints (DAPs)
 Complete list of all suspected ADRs reported via yellow card scheme for
named suspect drug.
 Inclusion of a particular reaction does not necessarily mean it has been
caused by the drug.
 Certain reported reactions are conditions which occur spontaneously
 Reporting rates are influenced by seriousness of ADR, ease of
recognition, extent of use.
Examples of ADRs identified by Yellow Card Scheme:
 Vigabatrin - visual field defects
3 reports severe persistent visual field constriction detected 2-3
years after starting therapy resulted in a change of recommended
dosage, range of indications and addition of warnings.
 Cyproterone acetate - hepatotoxicity
dose related
restricted indications
requirement for hepatic function monitoring
 Alendronate - severe oesophageal reactions
warnings and revised dosing instructions
 Varenicline - depression and suicidal ideation
reports received in the 1st 12 months after launch
addition of warnings and monitoring in patients with history of
psychiatric illness
 Kava-Kava produces severe hepato-toxicity and it’s supply in UK was
prohibited.
 Cisapride use is banned in UK due to serious cardiovascular reactions.
 Aristolochia in Chineese herbal remedy was banned due to renal failure.
Spontaneous reporting in India:
 Indian Pharmacopoeia Commission (IPC), Ghaziabad is functioning as
a National Coordination Centre (NCC) for Pharmacovigilance
Programme of India (PvPI).
  150 ADR monitoring centres (AMCs) were established in various
medical institutions/hospitals across India to monitor and collect ADR
reports under NCC-PvPI
What to Report
 PvPI encourages all types of suspected ADRs reporting whether they are
known, unknown, serious, or nonserious, frequent.
 ADRs related with the use of allopathic medicines, vaccines, traditional
medicines, medical devices, contrast media, etc., can be reported.
Where to Report
 All healthcare professionals (clinicians, dentists, pharmacists, nurses)
and patient/consumers can report ADRs to NCC or AMCs.
 The pharmaceutical companies can also send individual case safety
reports for their product to NCC.
How to Report
 Suspected ADR reporting forms for healthcare professionals and
consumers are available on the website of IPC to report ADR.
 To remove language barrier in ADR reporting, the consumer reporting
form are made available in 10 vernacular languages (Hindi, Tamil,
Telugu, Kannada, Bengali, Gujarati, Assamese, Marathi, Oriya, and
Malayalam).

Bio Drug- Drug and bio Drug-Food interactions with suitable examples:

Bio Drug- Drug interactions with suitable examples:

1. Interactions of Aloe and Some Allopathic Drugs
Antidiabetic Medications: The combination of aloe vera and glyburide, a
medication used to treat type 2 diabetes, may help control blood sugar and
triglyceride (fat) levels in the blood. People with diabetes who use aloe latex
either alone or in combination with other medications must be monitored
closely by health care providers to avoid potential complications from low
blood sugar levels.
Hydrocortisone: Aloe gel may enhance the ability of hydrocortisone to reduce
swelling.
Digoxin and Diuretics: Because oral aloe can decrease levels of potassium,
aloe latex should not be used by individuals taking diuretics or digoxin (a
medication used to treat irregular heart rhythms and congestive heart failure).
These medications lower potassium levels in the body, so a combination of
aloe and digoxin or diuretics can result in dangerously low levels of this
important mineral.
2. Interactions of Garlic and other medications:
Antiplatelet medications: Garlic may exaggerate the activity of medications
that inhibit the action of platelets in the body. Examples of such medications
include indomethacin, dipyridamole, Plavix, and aspirin.
Blood-thinning medications: There have been reports of a possible
interaction between garlic and warfarin that could increase the risk of
bleeding in people taking this blood thinning medication. Therefore, when
taking medications that may thin the blood, such as aspirin and warfarin,
you not use garlic supplements unless you are under the supervision of a
doctor.
Protease inhibitors: Garlic may reduce blood levels of protease inhibitors, a
medication used to treat people with the human immunodeficiency virus
(HIV). Protease inhibitors include indinavir, ritonavir, and saquinavir.
3. Interactions of HYPERCIUM PERFORTUM with Other Drugs
Antidepressants: St. John's wort may interact with medications used to treat
depression or other mood disorders, including tricyclic antidepressants,
SSRIs, and monoamine oxidase inhibitors (MAOIs). Taking St. John's wort
with these medications tends to increase side effects, and could potentially
lead to a dangerous condition called serotonin syndrome.
Allergy drugs (antihistamines): St. John's wort may reduce levels of these
drugs in the body, making them less effective i.e. Loratadine, Cetirizine,
Fexofenadine.
Drugs to fight HIV: St. John's wort appears to interact with at least two kinds
of medications used to treat HIV and AIDS: protease inhibitors and non-
nucleoside reverse transcriptase inhibitors. The Food and Drug
Administration recommends that St. John's wort not be used with any type
of antiretroviral medication used to treat HIV or AIDS.
4. Interactions of Turmeric and Allopathic Drugs
Blood-thinning medications: Turmeric may make the effects of these drugs
stronger, raising the risk of bleeding. Blood- thinners include warfarin
(Coumarin), clopidogrel, and aspirin, among others.
Drugs that reduce stomach acid: Turmeric may interfere with the action of
these drugs, increasing the production of stomach acid: Cimetidine,
Famotidine, Ranitidine, Esomeprazole, Omeprazole, Lansoprazole.
Drugs for diabetes: Turmeric may make the effects of these drugs stronger,
increasing the risk of hypo glycemia (low blood sugar).
Other herb drug interactions are:

Herb Drug Interaction

Echinacea Acetaminophen - Potentiation of Hepatotoxicity
Lovastatin - Inhibition of CYP3A4 leading to
increase in drug concentration
Shankpushpi Phenytoin - Decreased therapeutic effect
 Ginseng Digoxin - Increased drug concentrations
ACE inhibitors - Increased risk of developing cough.
Capsicum Theophylline - Enhanced bioavailability can lead to
theophylline toxicity.
Ginkgo Digoxin - Increased bioavailability of digoxin
Diltiazem - Increased bioavailability of drug
Kava Anaesthetics - Prolongation of anaesthesia
Alprazolam - Potentiation of sedation
Valerian Barbiturates - Additive sedation
Yohimbine Clomipramine - Increased blood pressure

Bio Drug and Food Interactions with examples:

1. Interaction of Fruit Juices and Drugs

 Among all fruit juices, grape fruit juice (GFJ) possesses high interaction
with almost all types of drugs. The juice modifies the body’s way of
metabolizing the medication, affecting the liver’s ability to work the drug
through a person’s system.
 Taniguchi in 2007 reported a case of purpura associated with
concomitant ingestion of cilostazol, aspirin and grape fruit juice in 79
years old man. His purpura disappeared upon cessation of grape fruit
juice, although his medication was not altered.
 The most probable cause of his purpura is an increase in the blood level
of cilostazol because of the inhibition of cilostazol metabolism by
components of grape fruit juice.
 Numerous reports have documented drug interactions with GFJ that
occur via inhibition of CYP3A enzymes.
 Furanocoumarins present in GFJ inhibit the intestinal CYP3A4 and have
been shown to increase the oral bioavailability of medications that are
CYP3A4 substrates like Felodipine, midazolam, cyclosporine and raise
their concentrations above toxic levels.
 With new anticonvulsants, serum iron and sodium need to be
monitored. Additionally, users are advised to avoid drinking grape fruit
juice within 1-2 hr(s) of taking these anticonvulsants.
Furanocoumarins and active bioflavonoids present in GFJ are also
inhibitors of ATP and when ingested concomitantly, can reduce the oral
bioavailability of the ATP substrate, fexofenadine.
 Overall, a series of flavonoids present in GFJ are identified as esterase
inhibitors, of which kaempferol and naringenin are shown to mediate
pharmacokinetic drug interaction with most of the calcium channel
 antagonist and the statin groups of drugs such as enalapril and
lovastatin due to their capability of esterase inhibition.
 Cholesterol-lowering agent lovastatin should be taken with food to
enhance gastrointestinal absorption and bioavailability. The absorption
of rosuvastatin, another anti- hyper lipidemic agent, was significantly
decreased in the fed state compared with the fasting state, which
suggests that rosuvastatin should be administered on an empty
stomach.
 Simvastatin, Ezetimibe, pravastatin and Fluvastatin may be taken
without regards to food. However, high fibre diets may lower the efficacy
of these drugs. Concomitant administration of statins with food may
alter statin pharmacokinetics or pharmacodynamics, increasing the
risk of adverse reactions such as myopathy or rhabdomyolysis or
reducing their pharmacological action.
 Consumption of pectin or oat bran together with Lovastatin reduces
absorption of the drug, while alcohol intake does not appear to affect
the efficacy and safety of Fluvastatin treatment.
2. Interaction of Warfarin with Dietary Supplements
 Warfarin is commonly used to treat or prevent thromboembolic events.
Patients taking warfarin are at particular risk of interactions with
dietary supplements, yet approximately 30% use herbal or natural
product supplements on a regular basis.
 There is a possible interaction between warfarin and a high-protein diet.
The potential for increased dietary protein intake to raise serum
albumin levels and/or cytochrome P450 activity has been postulated as
mechanisms for the resulting decrease in international normalized ratio
(INRs).
 Some vegetables (broccoli, Brussels sprouts, kale, parsley, spinach, and
others) are high in vitamin K. Eating large quantities or making sudden
changes in the amounts eaten of these vegetables, interferes with the
effectiveness and safety of warfarin therapy.
 A number of studies have been documented on the interaction of
warfarin and cranberry juice.
 Cranberry juice is a flavonoid, which has been shown to induce, inhibit,
or act as a substrate for the biosynthesis of several cytochrome P450
(CYP) isoenzymes.
 Specifically, cranberry juice may inhibit the activity of CYP2C9, the
primary isoenzyme involved in the metabolism of S-warfarin.
 It was suggested that cranberry juice increased the International
Normalized Ratio (INR) of patients taking warfarin, but neither clearly
identified cranberry juice as the sole cause of INR elevation.
  If warfarin sodium is ingested with leafy green vegetables, the hypo -pro
thrombinemic effect of warfarin may be decreased and thromboembolic
complications may develop.
3. Antihypertensive drugs and Food interaction
 Patients placed on antihypertensive drugs will benefit from concomitant
moderate sodium restricted diets.
 Propranolol serum levels may be increased if taken with rich protein
food. A change in diet from high carbohydrates/low protein to low
carbohydrate/high protein may result in increased oral clearance.
 Smoking may decrease its plasma levels of by increasing its
metabolism.
 The intestinal absorption of celiprolol (beta-blocker) is inhibited when
it is taken with orange juice. Hesperidin, present in orange juice, is
responsible for the decreased absorption of celiprolol.
 The absorption of ACEs inhibitors is increased when taken on an empty
stomach. While GFJ increases the bioavailability of felodipine.
 Liquorice extract, a common ingredient of dietary supplement contains
glycyrrhizin and glycyrrhetinic acid. It is a potent inhibitor of 11- bet-
hydroxyl steroid dehydrogenase, it increases excess of cortisol to
mineralocorticoid receptors causing sodium retention and potassium
depletion, so it may interfere with various medicines including
antihypertensive and antiarrhythmic agents. A high intake of liquorice
can cause hyper mineralocorticoidism with sodium retention and
potassium loss, oedema, increased blood pressure and depression of
the renin-angiotensin-aldosterone system.
4. Interactions of Antibiotics with Food
 Antibiotics are widely prescribed in medical practice. Many of them
induce or are subject to interactions that may diminish their anti-
infectious efficiency or elicit toxic effects.
 Food intake can influence the effectiveness of an antibiotic. Avoid co-
administration of antibiotics with milk products which are rich sources
of divalent ions, such as calcium and magnesium that complex with
some antibiotics and prevent their absorption.
 A number of studies give evidence that fluoroquinolones forming
slightly soluble complex with metal ions of food show reduced
bioavailability. Casein and calcium present in milk decrease the
absorption of ciprofloxacin.
 Azithromycin absorption is decreased when taken with food, resulting
in a 43% reduction in bioavailability.
 Tetracycline should be taken one hour before or two hours after meals,
and not taken with milk because it binds calcium and iron, forming
insoluble chelates, and influencing its bioavailability.
  Food-drug interactions may reduce the bioavailability of drugs taken
after meals (negative food effects). However, enteric- coated tablets that
start to disintegrate when they reach the middle-to-lower region of the
small intestine could reduce negative food effects. Results indicated
that food-drug interactions were avoided by separating the main
absorption site of drugs from that of food components.
5. Interaction of Analgesics and Food
 Analgesics and antipyretics are used to treat mild to moderate pain and
fever. For rapid relief, Acetaminophen should be taken in an empty
stomach because food may slow the body absorption of acetaminophen.
 Co-administration of acetaminophen with pectin delays its absorption
and onset.
 NSAIDs like ibuprofen, naproxen, ketoprofen and others can cause
stomach irritation and thus they should be taken with food or milk.
 The absorption of ibuprofen and oxycodone when given in the
combination tablet was affected by the concomitant ingestion of food.
 The Cmax and AUC (area under curve) of ibuprofen were significantly
increased after single and multiple doses of Coca-Cola, thereby
indicating increased extent of absorption of ibuprofen. The daily dosage
and frequency of ibuprofen must be reduced when administered with
Coca-Cola.

Challenges in monitoring the safety of herbal medicine

1. Regulation quality assurance and control

2. Appropriate use
Regulation quality assurance and control:
Regulation:
 National regulation and registration of herbal medicines vary from
country to country.
 Herbal medicines are categorized as either prescription or non-
prescription medicines.
 Almost all new medicines are introduced to the market as prescription
medicines, and a significant volume of post-marketing safety data from
spontaneous reporting will have been realized over time.
 At some stage, some of these medicines will subsequently be reclassified
as non-prescription medicines and will become major sources of self-
medication.
 However, in many countries, a significant proportion of herbal products
enters directly into the non-prescription medicine’s category.
Quality assurance and control:
Quality assurance and control measures, such as
  National quality specification,
 Standards for herbal materials,
 Good manufacturing practices (GMP) for herbal medicines,
 Labelling, and licensing schemes for manufacturing,
 Imports and marketing, should be in place in every country where
herbal medicines are regulated. These measures are vital for ensuring
the safety and efficacy of herbal medicines.
 Weak regulation and quality control may result in a high incidence of
adverse reactions attributable to poor quality of herbal medicines, in
particular resulting from adulteration with undeclared potent
substances and/or contamination with potentially hazardous
substances and residues.
Appropriate use:
a) Providers of herbal medicines:
 A variety of health-care professionals serve as qualified providers of
herbal medicines, according to each country’s national health-care
delivery system and legislative framework.
 In those countries where herbal medicines are classified as prescription
medicines, prescribers and dispensers other than physicians, dentists
and pharmacists are sometimes excluded from current reporting
systems.
 In many countries, prescriptions are not required to obtain herbal
medicines since these are categorized as non-prescription medicines or
products suitable for self-care.
Action required: All providers of herbal medicines should play a role in
monitoring the safety of non-prescription herbal medicines. Nurses are
becoming increasingly involved in this area and are making a valuable
contribution to safety monitoring.
b) Lack of proper knowledge of herbal medicines:
 Providers of medicines, such as physicians, nurses and
pharmacists, may have little training in and understanding of how
herbal medicines affect the health of their patients, who are often
also taking other medicines, prescription or non-prescription.
 Health professionals who work in poisons centres and health
information services also need to be informed about herbal
medicines.
c) Patient/consumer attitudes to herbal medicines:
 A misconception that “natural” means “safe” and many consumers
believe that remedies of natural origin carry no risk.
 Patients who use herbal medicines and other medicines together, as is
often the case, will often not mention the use of herbal medicines to
their physician.
  Likewise, patients commonly fail to mention the use of other medicines
to their providers of herbal medicines.
 Health-care professionals and providers of herbal medicines should ask
patients directly, respectfully and persistently what other medicines
they are taking, including prescription medicines, herbal medicines and
other health products for self-care.

Action required
The education of health-care professionals, providers of herbal medicines and
patients/consumers is vital for the prevention of potentially serious risks from
misuse of herbal medicines.