Vol. 119 No.

1 January 2015

Adverse drug events in the oral cavity

Anna Yuan, DMD,a,b and Sook-Bin Woo, DMD, MMSca,b
Adverse reactions to medications are common and may have a variety of clinical presentations in the oral cavity.
Targeted therapies and the new biologic agents have revolutionized the treatment of cancers, autoimmune diseases, and
inflammatory and rheumatologic diseases but have also been associated with adverse events in the oral cavity. Some examples
include osteonecrosis, seen with not only bisphosphonates but also antiangiogenic agents, and the distinctive ulcers caused by
mammalian target of rapamycin inhibitors. As newer therapeutic agents are approved, it is likely that more adverse drug events
will be encountered. This review describes the most common clinical presentations of oral mucosal reactions to medications,
namely, xerostomia, lichenoid reactions, ulcers, bullous disorders, pigmentation, fibrovascular hyperplasia, white lesions,
dysesthesia, osteonecrosis, infection, angioedema, and malignancy. Oral health care providers should be familiar with such
events, as they will encounter them in their practice. (Oral Surg Oral Med Oral Pathol Oral Radiol 2015;119:35-47)

A multitude of medications that patients take to control

disease also exposes them to the risk for developing
reactions to the medications. One denition put forward
by Edwards and Aronson in 2000 for adverse drug
reaction is an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use
of a medicinal product, which predicts hazard from
future administration and warrants prevention or specic treatment, or alteration of the dosage regimen, or
withdrawal of the product.1 This denition attempts to
address several important issues related to appreciable
harm and unpleasantness and excludes minor reactions, addresses the issue of medication error, addresses injury from nonpharmaceutical agents
(including contaminants and inactive ingredients), and
does not assign disease mechanism. The authors make a
distinction between an adverse effect (adverse outcome
attributed to an action of the drug) and an adverse event
(adverse outcome that occurs when a patient is on the
drug but that may not be caused by the drug).1
The term used currently that satises both regulatory
bodies as well as patient safety advocates is adverse
drug event which includes (1) harm caused by a drug
(commonly known as adverse drug reaction), (2) harm
caused by appropriate drug use (usually referred to as a
side effect), and (3) medication errors.2 This review will
focus on common adverse drug events (ADEs), as
dened by Nebeker et al.2 from a clinical perspective.
Most fall under the category of side effects, although
Portions of this were presented at the Jonathan A. Ship Lecture at the
annual meeting of the American Academy of Oral Medicine in 2013
in San Antonio, Texas.
a
Division of Oral Medicine, Brigham & Womens Hospital, Boston,
Massachusetts.
b
Department of Oral Medicine, Infection and Immunity, Harvard
School of Dental Medicine, Boston, Massachusetts.
Received for publication Jun 4, 2014; returned for revision Aug 18,
2014; accepted for publication Sep 10, 2014.
2015 Elsevier Inc. All rights reserved.
2212-4403/$ - see front matter
http://dx.doi.org/10.1016/j.oooo.2014.09.009

whether the patients were signicantly harmed by the

event is probably subject to interpretation. Although the
term medication is preferred over drug, we are
using the term ADE because it is the convention.
Diagnosis is based on history and chronology of the
adverse oral reaction. Typically, these changes are
detected within weeks or months after taking the
medications. Some lesions, such as lichenoid drug
reactions, may present asymptomatically initially but
become symptomatic years later, making the relationship between start of drug use and development of
ADE difcult to ascertain. The presence of the oral
condition predating the administration of the medication must be excluded, and this may be difcult to
determine if the patient has not seen a health care
provider in a long time. Resolution should occur after
discontinuation of the suspected medication, although
this may necessitate the use of topical corticosteroids
for inammatory conditions. Recurrence with
rechallenge conrms the diagnosis, although this may
not be feasible if the ADEs are unpleasant, severe, or
life-threatening. Concurrent medications must be
noted.
The benets of using any particular medication must,
of course, always be weighed against the side effects,
and some considerations include the necessity for the
medication and availability of substitute agents, how
severe the side effects are (e.g., asymptomatic oral
pigmentation vs highly morbid necrolytic syndromes),

Statement of Clinical Relevance

Adverse drug events in the oral cavity are common
and will likely increase as newer therapeutic agents
are approved. Health care providers should familiarize themselves with such events. This review describes common and uncommon oral mucosal
reactions to medications.
35

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36 Yuan and Woo

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Table I. Drug-induced oral reactions

Hyposalivation/xerostomia
Lichenoid reaction/lichen planus
Aphthous-like ulcers
Bullous disorders
Pigmentation
Fibrovascular hyperplasia
Keratosis/epithelial hyperplasia
Dysesthesia
Osteonecrosis of the jaws
Infection
Angioedema
Malignancy

the frequency of occurrence of such ADEs, whether the

ADE can be eliminated by lowering the dose, and
whether the ADE may be easily treated.1,2
Drug-induced cutaneous reactions are common and
varied in presentation, but only a limited number of
reaction patterns occur in the oral cavity. This is likely
due to the higher turnover rate in the oral mucosa
compared with that on the skin, and this does not allow
easy detection of the spectrum of subtle clinical
changes on the skin. The oral lesions to be discussed
fall into several categories (Table I).

HYPOSALIVATION/XEROSTOMIA
Medication use is one of the most common causes of
both xerostomia and hyposalivation. Many middle-aged
and older patients in the United States are on multiple
medications (polypharmacy), and even medications
with small anticholinergic effects may act synergistically in combination to cause oral symptoms of dryness
and discomfort (Figure 1). Dry mouth is listed as an
adverse effect for over 500 medications.3 In a systematic review, xerostomia was reported to be one of the
most common oral adverse effects associated with over
80% of the 100 most prescribed medications in the
United States.4 The most frequently reported medication classes that result in hyposalivation are antidepressants, antipsychotics, antihistamines, muscarinic
receptor and a-receptor antagonists, antihypertensives
(e.g., diuretics, b-blockers, and angiotensin-converting
enzyme [ACE] inhibitors), bronchodilators, and skeletal
muscle relaxants.3,5 Other culprits include chemotherapy agents, appetite suppressants, decongestants,
antimigraine drugs, opioids, benzodiazepines, hypnotics, histamine 2 (H2) receptor antagonists and proton
pump inhibitors, systemic retinoids, antiehuman immunodeciency virus medications, and cytokine
therapy.3,5
A study of 601 patients reported that older individuals were almost three times more likely to report
xerostomia, and patients taking one or more drugs were

Fig. 1. Hyposalivation from polypharmacy.

more than twice as likely to do so compared with

medication-free patients; this prevalence increased with
increasing number of medications used (16.7% of patients reported xerostomia with one medication daily vs
33.3% with two to three medications daily vs 36.9% at
greater than three medications daily).6 Persistent
hyposalivation can lead to infections, such as candidiasis and dental caries, as well as bacterial sialadenitis.7
The loss of lubrication also results in erythema and
susceptibility of the mucosa to frictional trauma against
teeth; discomfort and burning may be profound.

LICHENOID REACTION/LICHEN PLANUS

One of the most common inammatory conditions
affecting the skin and oral mucosa is lichen planus (LP).
LP is an immune-mediated process, where T cells
mediate the destruction of the basal cells of the
epithelium.8 Oral LP presents as white striations or
papules often associated with erythema or erosion and
ulcers, most commonly in a bilaterally symmetric
manner, often on the buccal mucosa, tongue, and
gingiva.9 Many medications are known to cause cutaneous lichenoid hypersensitivity reactions (LHRs),
which are often difcult to distinguish clinically and
histopathologically from idiopathic cutaneous LP.10,11
Cutaneous LHRs present as skin eruptions characterized by purplish, pruritic keratotic papules and plaques,
usually without the classic Wickham striae, on the trunk
and extremities instead of the exural regions.11-13 It
has been postulated that active thiol groups found in the
chemical structure of such medications as piroxicam,
sulfasalazine, and glipizide play a role in inciting such
reactions.14,15 It is, therefore, likely that these same

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Fig. 2. Lichenoid tissue reaction from rituximab.

medications may cause an oral LHR and that it can

resemble idiopathic oral LP (Figure 2).
The two classes of medications historically associated with oral LHRs are nonsteroidal anti-inammatory
drugs (NSAIDs) and antihypertensive agents, including
b-blockers, ACE inhibitors, and diuretics (in particular
hydrochlorothiazide).7,16,17 Sulfonylurea antidiabetic
medications (e.g., tolbutamide and glipizide), antifungals (e.g., ketoconazole), anticonvulsants (e.g., carbamazepine), immunomodulatory drugs (e.g., gold salts
and penicillamine), sulfasalazine, allopurinol, and
lithium have been reported to elicit oral LHRs.18,19 Of
historical interest, Grinspan syndrome was introduced
at the 1963 Congress of Dermatology as a clinical
presentation of a triad of oral LP, diabetes mellitus, and
hypertension; it is now generally accepted that drug
therapy for hypertension in particular and likely diabetes mellitus is capable of provoking oral
LHRs.11,20,21
One theory regarding the pathogenesis of LHRs is
that susceptible patients have polymorphisms of the
cytochrome P450 enzymes (CYPs), which results in
poor or intermediate CYP metabolism of some medications. One group of investigators reported higher
CYP2-D6 among females (P > .05) and higher CYP2D6*4 among patients with oral LP (50%) versus those
in the general population (30%), although this is of
questionable clinical signicance.22,23
It is often difcult to reach a consensus on diagnostic
criteria, in part due to the fact that LHRs, once wellestablished, may persist after cessation of the drug
unless rigorously treated. However, McCartan et al.
suggested that a history of the current use of an LHRinducing medication in combination with consistent
histopathology is likely sufcient, although the authors
also suggested that testing for the presence of circulating basal cell cytoplasmic autoantibodies may be
helpful.24,25
LP has been associated with thyroid disease in
several studies. Siponen et al. reported that 15% and

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Yuan and Woo 37

13% of patients with oral LP and oral lichenoid lesions,

respectively, had thyroid disease compared with 8% of
controls.26 This raises the question of whether the lesions result from the disease or from the medications
used to treat the disease. A subsequent study found that
patients with oral LP were 3.4 times more likely to be
taking levothyroxine than not (P .001).27 Lo Muzio
et al. noted that oral LP occurred in 14.3% of patients
with Hashimoto thyroiditis versus 1% of the general
population.28
Several other classes of medications are also associated with the development of cutaneous LP or LHRs.
3-hydroxy-3-methylglutaryl-coenzyme A inhibitors,
such as pravastatin, simvastatin, uvastatin, and lovastatin, have been implicated in causing cutaneous LHRs
with mucosal involvement.29-31 The tyrosine kinase
inhibitor imatinib has been implicated in LHRs,
particularly in the oral cavity.32-36 In a study of the
aromatase inhibitor letrozole used for breast cancer,
32.4% of patients were noted to have an adverse cutaneous reaction, and another group reported that 16
patients (0.9%) developed lichenoid keratosis over an
8-year study period.37,38 Antituberculosis drugs, such
as ethambutol, pyrazinamide, isoniazid, and rifampicin,
also have been reported to cause cutaneous LHRs.39-41
A recent case report noted an association between
antituberculosis medications and hyperpigmented
macules and lichenoid papules in the oral cavity; these
lesions were bilateral and symmetric, but classic LP
reticulations were absent.42
Biologic agents are being used with increasing frequency for the management of rheumatoid arthritis,
ankylosing spondylitis, and psoriatic arthritis and in
oncology, and reports of LHRs have begun to appear in
the literature. The novel anti-CD20 monoclonal antibody obinutuzumab was reported to cause LHRs on the
skin and oral ulcers.43 Asarch et al. reported two cases
of oral LP (more accurately, LHRs) in patients taking
tumor necrosis factor alpha (TNF-a) inhibitors iniximab and adalimumab and 12 cases involving the TNF
receptor fusion proteins etanercept and abatacept.44
Iniximab and certolizumab used to treat Crohn disease
have both been linked to biopsy-proven oral LP.45,46
This seems paradoxical, since oral LP is mediated by
TNF-a. However, it has been suggested that there may
be upregulation of interferon alpha when TNF-alpha is
inhibited.44 Interferon alpha then activates T cells and
dendritic cells, causing an inammatory response.44,47
Fixed drug eruptions (FDEs) in the oral cavity are
lesions that recur at the same site each time the
offending medication is taken.48 Oral mucosal lesions
are infrequently reported and can be accompanied by
skin or genital involvement.49,50 The presentation can
range from bullous to erosive, hyperpigmented, pruitic,
or erythematous lesions.49 A number of rst- and

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38 Yuan and Woo

Fig. 3. Sirolimus-induced aphthous-like ulcers.

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Fig. 4. Methotrexate-induced oral ulcer.

second-generation antihistamines have been known to

cause FDEs on the skin.51,52 The third-generation
antihistamine levocetirizine was reported in a case of
FDE involving the oral (lower lip and tongue) and
genital tissues (glans penis).53 Use of acetaminophen
was reported to result in erythematous and papular
FDEs on the hard palate and skin; naproxen and oxicams have caused lesions on the lips48,54; and uconazole has caused lesions of the palatal mucosa and oral
bullae.55,56 Co-trimoxazole, oxyphenbutazone, tetracycline, clarithromycin, and gabapentin have also been
implicated in the occurrence of oral FDEs.50,57,58
Fig. 5. Ulcerative mucositis secondary to chemotherapy.

APHTHOUS-LIKE AND NONeAPHTHOUSLIKE ULCERS

Idiopathic aphthous ulcers usually begin in the rst two
decades of life and appear as ovoid to round ulcers
usually 1 cm or less with a yellowish brinous membrane and surrounding erythema involving the nonkeratinized mucosa.5 Aphthous-like or aphtheiform
ulcers is the term used for oral ulcers where there is a
known etiology, as these resolve when the underlying
etiology is effectively managed.
NSAIDs were one of the earliest classes of drugs
associated with the development of aphthous-like ulcers
in the oral cavity.59-61 Piroxicam, in particular, was
shown to cause such ulcers, possibly because it contains
a thiol group.5,60,62,63 Naproxen, trimethoprim-sulfamethoxazole, cyclooxygenase-2 inhibitors (e.g., refecoxib), and the angiotensin receptor blocker losartan
have been implicated in the development of aphthouslike ulcers.49,64,65
More recently, aphthous-like ulcers have been
documented in patients with metastatic tumors treated
with mammalian target of rapamycin inhibitors,
including sirolimus, temsirolimus, everolimus, and
ridaforolimus (Figure 3).66-68 However, unlike idiopathic recurrent aphthous ulcers, on withdrawal of
therapy, these regress completely without recurrence.

Conventional chemotherapy agents, such as 5-uorouracil, cisplatin, methotrexate, and hydroxyurea, are
stomatotoxic and cause oral ulcers and ulcerative
mucositis (Figure 4).69-71 These ulcers tend to be larger
and more diffuse and do not have the ovoid, welldemarcated appearance of aphthous ulcers (Figure 5).
Mycophenolate mofetil has been reported to cause
ulcers on the tongue, palate, labial mucosa, and gingiva
in recipients of solid organ transplants, but these ulcers
resolve on cessation of medication, as in the case of
tacrolimus.72-77 Rare cases of ulcers associated with
multitargeted kinase inhibitors (MTKIs) have been
reported.78

BULLOUS DISORDERS
Medication-induced autoimmune bullous disorders of
the skin are not uncommon, whereas such disorders
presenting in the oral cavity are rare. The development
of simultaneous oral and cutaneous pemphigus vulgaris
has been noted with the use of thiol radicalecontaining
drugs,64,79,80 such as penicillamine81,82 and NSAIDs
(see Figure 4).83 Cutaneous bullous pemphigoid has
been associated with antipsychotic medications,
spironolactones, and sulfonamides.80,84-86 Lupus

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Fig. 6. Palatal mucosal pigmentation associated with

imatinib.

erythematosus of the skin has been observed in patients

using procainamide, hydralazine, and biologic agents,
such as anti-TNF inhibitors.87-89
Erythema multiforme (EM), major or minor, can
affect both the skin and mucous membranes. It presents
as irregular oral ulcers with diffuse erythema and target
lesions of the skin. It is a hypersensitivity reaction, most
commonly to an infectious agent, such as herpes simplex virus and less commonly to Mycoplasma pneumonia in children; approximately 18% of cases
represent hypersensitivity reactions to medications.90-92
EM of the skin and oral mucous membranes has been
reported with the administration of iniximab and
adalimumab.93,94
Steven Johnson syndrome (SJS) and toxic
epidermal necrolysis (TEN) are severe necrolytic hypersensitivity reactions, which, unlike EM, are much
more commonly associated with the use of medications and may be life-threatening.92 SJS and TEN
almost always involve the mucous membranes of the
mouth, eye, and genitalia, sometimes extensively.
Antimicrobials (amoxicillin/clavulanic acid)95 and
anticonvulsants (phenytoin and lamotrigine) have been
implicated.96,97 In the Han Chinese populations, SJS
and TEN caused by anticonvulsants, such as phenobarbital, phenytoin, and carbamazepine, are associated
with HLA-B*1502 (odds ratio [OR] 1357), whereas
reactions to allopurinol are associated with HLAB*5801 (OR 580).98-100 In the Thai population, carbamazepine is also associated with SJS and TEN in a
large number of patients (OR 75).99 In Europeans, SJS
and TEN caused by sulfamethoxasole has been associated with HLA-B*38, NSAIDs with HLA-B*73,101
and HIV-1 reverse-transcriptase inhibitor abacavir
with HLA-B*5701.102 Other drugs implicated include
lamotrigine, phenytoin, phenobarbital, lenalidomide103; co-trimoxazole, sulfonamides, sulfasalazine,
and oxicam104,105; nivirapine106; transexamic acid107;
and rituximab.108

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Yuan and Woo 39

PIGMENTATION
Metabolites of such medications as the tetracyclines,
minocyclines, antimalarial drugs (e.g., hydroxychloroquine, mepacrine, and quinacine), and phenazine
dyes (e.g., clofazimine) may be deposited in the oral
mucosa. Such drug metabolites chelate with iron and
melanin, which results in pigmentation of the hard
palatal mucosa, and have a specic histopathology
(Figure 6).109-113 Tetracycline and minocycline are also
deposited in teeth, bones, thyroid, and sclera and cause
mucosal and nail pigmentation.114,115 The tyrosine kinase inhibitor imatinib, used to treat chronic myelogenous leukemia and acute lymphoblastic leukemia, can
cause hyper- or hypopigmentation of the skin, hyperpigmentation of nails, and diffuse blue-gray pigmentation on the palatal mucosa, with similar characteristic
histopathology.116,117 It is unclear whether secondgeneration tyrosine kinase inhibitors such as dasatinib,
nilotinib, and bosutinib will have the same effect.
Other medications that have been noted to cause oral
mucosal pigmentation are zidovudine (on the
tongue)118,119; oral contraceptives (on the maxillary and
mandibular gingiva)120; and chemotherapy agents, such
as such as doxorubicin, docetaxel, and cyclophosphamide (on the tongue dorsum, buccal mucosa, and
nails).121-123 Pigmentation of the facial skin has been
noted with the use of amiodorone and phenothiazines
(chlorpromazine).124,125 Stimulation of melanocytes
without metabolite deposition is postulated to be the
mechanism, and, interestingly, pigmentation does not
occur on the palatal mucosa.
FIBROVASCULAR HYPERPLASIA
Calcium channel blockers, in particular, nifedipine and
amlodipine, are antihypertensive agents that induce
hyperplasia of the gingival tissues.126,127 This presents
as a diffuse, generalized, often nodular overgrowth of
densely brous gingival tissue. The resulting gingival
enlargement is exacerbated by plaque-induced inammation, and there may be a genetic predisposition.128 It
has been suggested that the mechanism is due to
decreased cellular folic acid uptake leading to decreased
activity of matrix metalloproteinases and the failure to
activate collagenase.129-131
Calcineurin inhibitors, such as cyclosporine or, less
frequently, tacrolimus, also induce inammatory brovascular hyperplasias in the oral cavity. However, these
present as localized polypoid brous tumors and are
more often seen on the tongue and buccal mucosa rather
than on the gingiva (Figure 7).132,133 The increased
production of collagen is thought to be due to both the
reduced activity of matrix metalloproteinases and the
increased activity of tissue inhibitors of metalloproteinases.134-136 It has also been proposed that

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40 Yuan and Woo

Fig. 7. Fibrovascular hyperplasia with ulceration associated

with tacrolimus.

phenytoin and cyclosporine cause an increase in the

expression of interleukins (IL-1, IL-6), which may
induce oral mucosal mesenchymal stem cells to
differentiate toward a pro-brotic phenotype.137-139

KERATOSIS/EPITHELIAL HYPERPLASIA
Palifermin is a recombinant keratinocyte growth factor
delivered intravenously to reduce the incidence and
severity of mucositis related to autologous hematopoietic stem cell transplantation, chemotherapy, and
radiotherapy.140,141 It has been associated with mouth
or tongue thickness and white discoloration in 17% of
patients.142 The diffuse, thickened white plaques
observed in the mouth as a response to palifermin are
likely due to increased thickness of the oral epithelium
and/or keratin layer as a result of the proliferation of
epithelial cells.143
DYSESTHESIAS
Oral dysesthesias, such as sensitivity, burning, dysgeusia, and other altered sensations without clinical signs,
may be caused by medications. It must be noted that
dysgeusia can be secondary to hyposalivation instead of
being the direct effect of a drug.144 Damage to the salivary glands reduces the production of saliva, the solution
in which chemoreceptors in the taste buds of the tongue
bind their receptor molecules.145 A study on dysgeusia
and dysosmia was reported for several drug classes,
including macrolides, such as clarithromycin (17%);
antimycotics, such as terbinane (9%); and uoroquinolones (8%), as well as protein kinase inhibitors,
ACE-inhibitors, statins, and proton pump inhibitors (3%5% each).146 The mechanism is multifactorial and may
be a combination of drugereceptor inhibition, alteration
of neurotransmitter function, disturbance of action potentials in neurons, and dysfunctional sensory modulation in the brain.146,147 Vismodegib, a rst-in-class,
small-molecule inhibitor of the hedgehog pathway

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produced dysgeusia in 51% of participants in a phase 1

trial for management of advanced basal cell
carcinomas.148
Neurologic complications of chemotherapy are well
described in the literature. The pathobiology of peripheral neuropathy is complex and could be attributed
to neuronopathy, axonopathy, myelinopathy, and
intraepidermal nerve ber degeneration.149 Chemotherapy-associated peripheral neuropathies are often
associated with the use of taxanes,150 platinum compounds, thalidomide, bortezomib,151 and vinca alkaloids, such as vincristine and vinblastine.152-155
MTKIs (e.g., sunitinib and sorafenib) downregulate a
variety of receptors, including vascular endothelial
growth factor (VEGF), platelet-derived growth factor,
broblast growth factor, c-kit, FMS-like tyrosine kinase
3 (FLT-3), BRAF, and RET. The development of oral
dysesthesias is signicantly associated with the development and severity of palmareplantar erythrodysesthesia in patients on MTKIs.156,157 A study of
over 200 patients reported stomatitis symptoms in
26% of patients on sorafenib and in 36% of patients on
sunitinib in the absence of oral ndings.157 Kollmannsberger et al. reported oral toxicities in up to 60%
of patients and noted that the type of stomatitis
observed was characterized by oral mucosal sensitivity,
taste changes, and xerostomia without noticeable
physical changes.158 They may fall within the spectrum
of burning mouth syndrome or oral dysesthesia
disorders.

OSTEONECROSIS OF THE JAWS

Bisphosphonates and denosumab (monoclonal antibody
against receptor activator of nuclear factor kappa-B
ligand) are antiresorptive medications that markedly
slow bone turnover and remodeling and therefore increase bone density; they are used to treat postmenopausal osteoporosis and reduce skeletal-related
events during cancer therapy (e.g., for plasma cell
myeloma and metastatic cancers).159-161 Osteonecrosis
is an ADE presenting as either exposed bone or a
nonhealing extraction socket (Figure 8).162-164 A stage
0 variant exists where bone is not exposed.159,165,166
Bisphosphonates also exhibit antiangiogenic activity.167 Antiangiogenic agents, such as bevacizumab and
sunitinib, which act against VEGF, either used alone or in
combination with bisphosphonates, also lead to the
development of osteonecrosis in some patients.168-173 In
fact, higher incidences of osteonecrosis have been seen
with combination of such anti-VEGF therapies and
bisphosphonates than with bisphosphonates alone.174-177
It is unclear whether mammalian target of rapamycin
inhibitors alone may cause osteonecrosis, since it has
been recently reported that patients who developed this
condition had also been on intravenous bisphosphonates

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Yuan and Woo 41

Fig. 8. Osteonecrosis of the jaw associated with denosumab.

Fig. 9. Candidiasis from topical steroid therapy.

for years.177-179 The term medication-induced osteonecrosis may be a more appropriate general term for
such osteonecrotic lesions, since medications other than
antiresorptive agents may be involved.

MALIGNANCY
A number of chemotherapy and immunomodulating
agents have been shown to increase the risk of lymphoproliferative disorders and neoplasms.203 Patients taking
methotrexate for rheumatoid arthritis sometimes develop
lymphoproliferative diseases; in 23% of cases, the disease
regressed after discontinuation of the medication204-206;
these diseases are often associated with Epstein-Barr virus
infection and occur infrequently.205,207,208
Topical tacrolimus applied on the skin in the murine
model exhibited development of squamous cell carcinomas in 8.5% of cases and benign papillomas 91.5%
of cases.209 There have been anecdotal reports of
squamous cell carcinoma developing in patients with
oral LP treated with tacrolimus ointment.210,211 Tacrolimus has been shown to have an effect on both the
MAPK and the p53 pathways, which are important in
cancer signaling.211 In a long-term study of recipients
of liver transplants, 45% of de novo malignancies were
on the skin, with tacrolimus immunosuppression cited
as a risk factor (hazard ratio 2.06).212 There have been
only sporadic case reports of squamous cell carcinomas
of the skin and cutaneous T-cell lymphomas occurring
after tacrolimus and pimecrolimus application.213-216
It has also been reported that 9.6% of patients on
combinations of immunomodulating agents, such as
azathioprine, cyclophosphamide, cyclosporine, or
mycophenolate mofetil, for pemphigus or pemphigoid
may develop a secondary malignancy.217
Malignancies induced by biologic agents have been
reported in the literature. Bongartz et al. analyzed nine
randomized, controlled trials of iniximab and adalimumab used in 3493 patients and found a three-fold
increase of malignancy (OR 3.3).191 The secondary
cancers were signicantly more common in patients
treated with higher doses of anti-TNF antibodies and
primarily consisted of basal cell carcinomas and lymphomas.191 However, another study evaluated 18 clinical trials using TNF-a inhibitors and found no increase
in malignancy or infection.218

INFECTION
Patients on long-term immunosuppressive therapy may
develop a variety of opportunistic infections in the oral
cavity (Figure 9). It is well established that immunosuppressed patients frequently develop pseudomembranous candidiasis,180 fungal infections,181-183 and
viral infections.184-188 TNF-a therapy specically has
been linked to an increased risk of serious infections,
such as tuberculosis and meningitis, especially when
combined with other immunomodulatory agents.189,190
Patients receiving iniximab and adalimumab have
been shown to be at an increased risk for tuberculosis
(OR 2.0) as well as histoplasmosis and coccidiomycosis.191 Disease-modifying antirheumatic drugs, such
as methotrexate, abatacept, and alefacept, have been
associated with herpes simplex or herpes zoster infection, deep fungal infections, and tuberculosis.192
ANGIOEDEMA
Medication-induced angioedema has been observed
with the use of multiple agents, most commonly ACE
inhibitors.193,194 This abrupt-onset swelling of the
orofacial region and lips can compromise the airway
and be life-threatening. Angioedema is mediated by
inammatory cytokines, complement activation, and
vascular permeability. It has also been reported with the
use of other antihypertensive agents, such as angiotensin receptor blockers,195 calcium channel
blockers,196 and hydrochlorothiazide,197 as well as antiplatelet agents, such as thienopyridine and clopidogrel.198 The use of the statin class of medications,
including simvastatin, uvastatin, atorvastatin, and
pravastatin, is infrequently associated with this side
effect.199-202

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42 Yuan and Woo

The issue of drug-induced malignancy is still

controversial, and it is difcult to remove confounding
factors from studies that show an association. Some
conditions themselves predispose the patient to developing malignancy regardless of the therapy received
(e.g., severe rheumatoid arthritis and the development
of lymphoma219) and the use of powerful immunosuppressive medications likely increase the risk.
Furthermore, the patient may have received many years
of other immunosuppressive therapies that predisposed
them to malignancy.210,220 In cases of oral LP, for
example, that are resistant to topical steroid therapy, the
clinician should carefully weigh the benet of using
topical tacrolimus against the rare anecdotal cases of
squamous cell carcinoma that developed as a result of
its use.

OOOO
January 2015

10.

11.

12.

13.
14.
15.
16.

CONCLUSION
Adverse drug events in the oral cavity are common and
may have a variety of clinical presentations. With new
therapeutic agents being introduced into clinical practice, it is likely that more ADEs will be encountered.
The advent of targeted therapies in oncology has produced a number of novel complications in the oral
cavity. Oral health care providers should be aware of
the manifestations of ADEs encountered in their
practice.
The authors would like to thank Dr Jennifer Frustino for her
assistance with this manuscript.

17.

18.
19.

20.

21.
22.

23.

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Reprint requests:
Anna Yuan
Division of Oral Medicine and Dentistry
Brigham and Womens Hospital
Boston, MA
annayuan@post.harvard.edu