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Pharmacovigilance in clinical dentistry: Overlooked or axiomatic?

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 Pharmacotherapeutics
CDE
2 HOURS
CREDIT

Pharmacovigilance in clinical dentistry:

Overlooked or axiomatic?
Sunitha Carnelio, MDS   n  Sohil Ahmed Khan, MPharm (Clin Pharm)   n  Gabriel Rodrigues, MS, DNB (Gen Surg)

Developments in dental pharmacotherapeutics require dentists
to constantly update their knowledge of new drugs, drug safety,
and therapeutic trends. Recent incidents of bisphosphonate-
associated poor healing, spontaneous intraoral ulceration, and
bone necrosis in the oral and maxillofacial region stress the need
for vigilant spontaneous reporting of adverse events. This article
discusses the rationale for pharmacovigilance in dental practice
using specific methods and reviews the pros and cons of adverse
drug reporting among dental practitioners.
Received: April 27, 2010
Accepted: June 21, 2010

P
harmacovigilance refers to the
science of activities related
to the detection, assessment,
understanding, and prevention
of adverse effects or any possible
drug-related problems.1 Recently,
the scope of pharmacovigilance has
been widened to include herbals,
traditional and complementary med-
icines, blood and biological prod-
ucts, medical devices, and vaccines.
Pharmacovigilance seeks specifically
to improve patient care and safety
related to medicine and all medical
and paramedical interventions; to
improve public health and safety
in relation to the use of medicines;
to contribute to the assessment of
benefit, harm, effectiveness, and risk
of medicines, thus encouraging their
safe, rational, and more effective
(including cost-effective) use; and to
promote understanding, education,
and clinical training in pharmacovig-
ilance and effective communication
to the public.
Drug safety constitutes the cor-
nerstone of modern therapeutics.
The Medicines Team of the World
Health Organization (WHO)
aims to determine the safety of
medicines by ensuring a reliable and
timely exchange of information on
drug safety issues, by promoting
pharmacovigilance activities
throughout the organization, and
by encouraging participation in the
WHO Program for International
Drug Monitoring. The WHO’s
Uppsala Monitoring Centre manages
an international database of adverse
drug reactions (ADRs) received from
member countries’ national pharma-
covigilance programs.2
Pharmacovigilance for
dentists
Dentists prescribe a wide range
of drugs in their routine clinical
practice; these most commonly
include antibiotics, analgesics,
anti-inflammatories, and antipyret-
ics.3 Drug safety in dentistry is
an equally important parameter,
compared to the profession’s medi-
cal counterparts. A 2005 report of
bisphosphonate-associated osteone-
crosis of the jaws (ONJ) highlighted
the importance of promoting drug
safety. The dentists’ timely reporting
of this adverse reaction prompted
the FDA and the manufacturer
(Novartis) to make labeling changes
to reflect the possible risk of
ONJ with bisphosphonates.4 This
incident shows the effectiveness of
pharmacovigilance; however, it also
raises the issue of how frequently
ADRs are encountered in routine
dental practice and how many of
those remain unreported due to a
lack of understanding among den-
tists concerning pharmacovigilance.
Drug safety in the dental
scenario
Virtually all drugs have the potential
to cause adverse oral reactions; the
table includes a list of drugs that
commonly cause various adverse oro-
facial reactions, enabling dentists to
be vigilant in reporting any adverse
reactions to these drugs.5,6 While
most dentists likely are familiar with
ADRs caused by drugs that they pre-
scribe (such as antibiotics, analgesics,
and anti-inflammatories), they also
need to be aware of the other drugs
that can cause oral reactions that
require dental intervention.
Postmarketing surveillance in
dental therapeutics
The wider range of therapeutic
options from different classes of
drugs allows dental practitioners to
provide therapeutic interventions
that previously were unimaginable.
Dentists are responsible for under-
standing the relative benefits and
risks of available therapies and must
voluntarily report any unexpected

24 January/February 2011 General Dentistry www.agd.org

adverse effects from those therapies.
Most safety evaluations in humans
occur during pre-market clinical
trials. However, such clinical trials
do not answer every question
concerning safety and efficacy; as a
result, drug safety depends largely on
the surveillance of medicines once
they have been marketed. To make
drugs more safe and effective in
dental procedures, it is important to
promote a culture of safe drug usage
and vigilant reporting to avoid major
drug disasters. Postmarketing ADR
reporting is important because tests
in animals are insufficient to predict
human safety, because clinical trials
use a selective and limited number
of patients for a short duration with
different conditions than those
involved in clinical dental practice,
and because exposing fewer than
5,000 human subjects to a drug
allows only the more common ADRs
to be detected.7 At least 30,000
people need to be treated with a
drug to determine a causal relation
with an ADR that has an incidence
of 1 in 10,000 exposed individuals;
this can be done only during the
postmarketing surveillance phase.7
Information about rare but serious
adverse reactions, chronic toxicity,
use in special groups (children, preg-
nant women, or the elderly), or drug
interactions often is incomplete or
not available.7 Clinical trials may be
a better test of a drug’s efficacy than
its safety during everyday clinical
usage. Another reason for a lack of
vigilance in reporting ADRs is that
clinicians may be slow or passive in
detecting and reporting them.8
Methods for promoting a
culture of safe drug usage
When an adverse reaction is first
recognized, it is almost never cer-
tain that the hazard is drug-related,
which has led to the concept known
as signaling. A signal is an alert
Table. Major adverse effects in the orofacial region and the drugs
commonly related to those effects.
Adverse effect Related drugs
Altered taste Acarbose, allopurinol, atorvastatin, azathioprine, cholestyramine,
clarithromycin, enalapril, ethambutol, griseofulvin, imipenem, lithium,
phenytoin, ramipril, rivastigmine, selegiline, tetracyclines, venlafaxine
Angioedema ACE inhibitors, aspirin, captoril, cephalosporins, clonidine,
indomethacin, penicillamine, quinine, streptomycin
Cheilitis Atorvastatin, busulphan, gold, indinavir, isoniazid, lithium, methyldopa,
selegiline, streptomycin, tetracyclines, vitamin A
Erythema Allopurinol, amlodipine, carbamazepine, co-trimoxazole, ethambutol,
multiforme fluconazole, furosemide, minoxidil, phenytoin, rifampicin, tetracyclines,
valproate, vancomycin
Gingival swelling Amlodipine, cyclosporine, diltiazem, oral contraceptives, phenytoin,
valproate
Hypersalivation Amiodarone, clonazepam, gentamicin, haloperidol, lamotrigine,
nicardipine, pentoxifylline, risperidone, venlafaxine, zaleplon
Lichenoid ACE inhibitors, allopurinol, carbamazepine, chloroquine, dapsone, gold,
reactions griseofulvin, ketoconazole, lithium, metformin, methyldopa, phenytoin,
prazosin, propylthiouracil, quinidine, rifampicin, sulfonamides, tetracyclines
Lupoid Gold, hydralazine, isoniazid, penicillamine, phenytoin, sulphonamides,
reactions tetracyclines
Oral candidiasis Corticosteroids, broad spectrum antimicrobials, immunosuppresives
Oral mucosal Arsenic, bismuth, busulphan, carbamazepine, chloroquine, cyclophos-
pigmentation phamide, gold, iron, methyldopa, oral contraceptives, zidovudine
Oral ulceration Alendronate, allopurinol, captopril, diclofenac, gold, indomethacin,
losartan, naproxen, olanzapine, phenytoin, sulindac, vancomycin
Orofacial pain Biperidin, griseofulvin, lithium, penicillins, vitamin A
Paresthesia Amitryptiline, hydralazine, interferon alpha, isoniazid, mefloquine,
nitrofurantoin, phenytoin, streptomycin, vincristine
Pemphigoid-like Amoxicillin, clonidine, furosemide, ibuprofen, isoniazid, penicillin,
reaction salicylic acid, sulphonamides
Salivary gland pain Clonidine, insulin, methyldopa, naproxen, phenytoin
and/or swelling
Tooth discoloration ACE inhibitors, doxycyline, penicillins, zopiclone
from one of many different sources signal, with five cases indicating a
that a drug could be associated with strong signal. A causal association
a previously unrecognized hazard is evaluated through a validated
or that a known hazard may differ questionnaire provided by the
quantitatively (that is, in frequency) WHO and other sources; the
or qualitatively (that is, in severity) judgment is made by a registered
from existing knowledge. Sponta- health care professional (a clinician/
neous ADR reporting is the classic dentist/surgeon).2,7
signaling system. Three cases of a Once a signal has been identified
causal association between a drug from any source, the next step is
and an ADR may be considered a an assessment, which usually is
www.agd.org General Dentistry January/February 2011 25
Pharmacotherapeutics  Pharmacovigilance in clinical dentistry: Overlooked or axiomatic?

Chart 1. A model for initiating Chart 2. Organization of a medication safety

a proactive pharmacovigilance team reporting system at a dental institution.
system in dentistry.

Board of directors
Organizational level
1. Create liaisons with health
ministry, pharmaceutical Dental board
industries
2. Build a robust pharmacovigi-
lance system
3. Make ADR reporting mandatory
4. Conduct periodic inspections
5. Promote research in ADRs Pharmacy and
Patient safety Medication safety therapeutic
committee team in dentistry committee

Institutional level
1. Build medication safety team
2. Increase awareness of drug
safety (newsletters, meetings)
3. Emphasize pharmacovigilance
at the undergraduate and
postgraduate level Clinical Clinical
Individual dentists
pharmacologists pharmacists

Individual level
1. Train in pharmacovigilance
2. Build liaisons with other health
care professionals in medication
safety promotion
performed by a clinical pharmacist.
The assessment includes reviewing
the strength of the evidence that
indicates a possible drug-related
ADR as well as considering other
immediately available evidence that
might help to support or oppose
a hypothesis. The resultant action
will depend on several factors,
including the seriousness, frequency,
and preventability of the ADR, the
nature of the disease for which the
patient is being treated, the benefits
of treatment, and the availability of
alternative treatments.
Dose and duration of treatment
can be important. For example, an
elderly patient with renal failure
would have a different pharmacoki-
netic profile than a younger, healthy
patient and therefore would require
adjustments to dose and duration
of treatment to avoid an ADR
from accumulation of medication.9
Life-threatening ADRs require
prompt intervention, whereas
milder ones (such as nausea) can be
considered during the next routine
labeling revision.
Currently, ADR management
relies heavily on statistical evalu-
ation of signals and mathematical
quantification of risk of patients
with ADRs. Pharmacogenetics
can play a specific role in targeting
the risk of occurrence of ADRs in
patient populations with diverse
ethnic backgrounds through
genetic mapping. Risk communica-
tion plays an important role in
preventing and managing adverse
reactions and should be accurate,
balanced, open, understandable,
and targeted.9
Building an effective
pharmacovigilance system
in dentistry
Chart 1 presents the three-tier
approach that can be used to build
a proactive pharmacovigilance
system in dentistry. A strong
regulatory framework with dental
organizational support is important
for introducing and implementing a
robust pharmacovigilance program
at a national level. Dental schools
can collaborate and integrate organi-
zational approaches to patient safety
through the initiation of a medical
safety team at an institutional level
(Chart 2). A medication safety team
can be a stand-alone entity that

26 January/February 2011 General Dentistry www.agd.org

reports directly to the institution’s
board of directors or dental board
or it can be a subcommittee of a
larger group, such as a patient safety
committee or a pharmacy and thera-
peutic committee.10
Dentists need to be trained in
pharmacovigilance programs.
The mutual exchange of informa-
tion regarding ADRs between
the dentist, clinical pharmacist,
pathologist, or microbiologist is
crucial. Collaboration with clini-
cal pharmacologists and clinical
pharmacists can play a key role
in the medication safety team, as
professionals from a pharmacol-
ogy/pharmacy background have
a focused knowledge in regard to
drug therapy. By being part of a
medication safety team, these spe-
cialists can play an important role
in promoting a culture of safe drug
usage via ADR reporting (to estab-
lish a causal relationship between
a drug and an ADR), education
through seminars/workshops for
drug safety, and surveillance.
What dentists need to know
How to recognize an ADR
ADRs may be difficult to recog-
nize, as they can act via the same
physiological and pathological
pathways as other diseases. When
evaluating a possible drug-related
ADR, confirm that the drug and
the prescribed dosage are correct.
The onset of an ADR should be
verified; it should manifest only
after the drug is administered.
The amount of time that elapses
between the administration of the
drug and the onset of the reac-
tion must be established. After
discontinuing the drug or reducing
the dose, evaluate the suspected
ADR and monitor the patient’s
status. Restart the drug treatment
(if appropriate) and monitor the
recurrence of any adverse events;
alternative conditions (other than
the drug) that might have caused
the reaction should be analyzed as
well. Using relevant evidence-based
literature and dental experience,
determine whether there are any
conclusive reports that match or
mirror this patient’s reaction.
National pharmacovigilance
centers and drug information
centers are important resources for
obtaining information on ADRs.
Other resources that include
information on ADRs are standard
pharmacology/pharmacotherapeutic
textbooks, clinical trials/case reports
as published in scientific journals,
drug safety conferences, and so
forth. Suspected ADRs should be
reported to the person on the medi-
cation safety team who is responsible
for ADR reporting or directly to the
national pharmacovigilance center.
What should be reported
For new drugs, all suspected reac-
tions—including minor ones—
must be reported. For established
or well-known drugs, all serious or
unusual ADRs should be reported.
In addition, a report should be filed
whenever there is a given reaction
with increased frequency, when
suspected ADRs are associated with
drug withdrawal, when ADRs result
from an overdose or error in admin-
istering medication, when a lack of
efficacy or suspected pharmaceutical
defects (such as contamination
during formulation and use of
additives/preservatives) are observed,
and when there is a suspected ADR
in special fields of interest such as
drug abuse and drug use during
pregnancy and lactation.2,7
How to measure the outcome
of a pharmacovigilance
program
The proper evaluation/decision
must be made while establishing
www.agd.org General Dentistry
a causal relation between a drug
and an ADR. Medication safety
data can be aggregated and ana-
lyzed using tools that measure
how changes in drug prescription
trends and safety measures have
modified the medication use
process and affected the potential
for patient harm. Process measure-
ments include a percentage of staff
completing training in medication
safety, the number of pharmacist
interventions per 100 admissions,
the number of self-reported medica-
tion errors, and the number of
potential or near-miss medication
errors with high-alert drugs. Out-
come measurements include the
percentage of emergency room visits
caused by adverse drug events, the
number of preventable adverse drug
events per 1,000 doses, the average
length of an inpatient hospital stay
for someone experiencing an ADR,
the severity of an ADR (that is, seri-
ous, life-threatening, or fatal), and
patient satisfaction scores.11
The other side of the story:
Problems in reporting events
The WHO has highlighted severe
deficiencies in the culture of report-
ing ADRs.7 The concept of generat-
ing a signal from ADRs is useful
only if the signal is taken seriously
and the action taken is prompt
and addresses the level of concern.
The bane of pharmacovigilance
today remains that drug companies
continue to invest large sums of
money in promotional launches
instead of committing a portion of
their funds to propagating training
and awareness programs that would
promote early reporting of ADRs.12
Increasing and updating the aware-
ness of pharmacovigilance in dental
therapeutics requires proactive
participation among health care
professionals in general and among
dentists in particular.
January/February 2011 27
 Pharmacotherapeutics  Pharmacovigilance in clinical dentistry: Overlooked or axiomatic?
Summary
During the transition from dental
school to dental clinic, it is impor-
tant for dentists to make a subtle
shift from emphasizing pharmaco-
kinetics to appreciating pharma-
codynamics. The authors believe
that this change in philosophy will
occur only when the clinicians of
tomorrow are motivated in dental
school to adopt pharmacovigilance
in their clinical practices. Dentists
must understand how reporting
ADRs benefits the practice of
dentistry as a whole. Early and
more thorough reporting of ADRs
will directly influence the speed
with which problematic drugs can
be withdrawn from the market,
directly affecting the lives of
patients who otherwise would have
used these drugs.
Author information
Dr. Carnelio is an associate profes-
sor, Department of Oral and Maxil-
lofacial Pathology, Manipal College
of Dental Sciences, Manipal, India,
where Dr. Khan is on the faculty,
Department of Pharmacy Practice.
Dr. Rodrigues is a professor,
Department of Surgery, Kasturba
Medical College, Manipal.
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Published with permission by the Academy of
General Dentistry. © Copyright 2011 by the
Academy of General Dentistry. All rights reserved.
General Dentistry www.agd.org