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Adverse Ocular Drug Reactions Recently
Identified by the National Registry of
Drug-Induced Ocular Side Effects
F. W. Fraunfelder, MD, F. T. Fraunfelder, MD
To report recent ocular adverse drug reactions identified by the National Registry of Drug-Induced
Case reports from the National Registry and the World Health Organization were collected and
adverse drug reactions categorized as follows: certain, probable/likely, possible, unlikely, and conditional/unclassifiable.
Bisphosphonates are associated with ocular inflammation, including the first reports of drug-
related scleritis. Topiramate is shown to cause angle-closure glaucoma. Cetirizine can cause an oculogyric crisis,and there is strong evidence retinoids cause intracranial hypertension.
Recent reports to the National Registry have led to identification of new ocular adverse drug
reactions. Ophthalmology 2004;111:1275–1279 2004 by the American Academy of Ophthalmology.
Recently identified ocular adverse drug reactions from
Table 1. World Health Organization Definitions—Causality
bisphosphonates, cetirizine, retinoids, and topiramate are
Assessment of Suspected Adverse Reactions
described. Conclusions are made after reviewing case re-
a clinical event, including laboratory test abnormality,
ports from national and international databases and from a
occurring in a plausible time relationship to drug administration, and
which cannot be explained by concurrent disease or other drugs orchemicals. The response to withdrawal of the drug (dechallenge)should be clinically plausible. The event must be definitive
Materials and Methods
pharmacologically or phenomenologically, using a satisfactoryrechallenge procedure if necessary.
a clinical event, including laboratory test
Case reports from the National Registry of Drug-Induced Ocular
abnormality, with a reasonable time sequence to administration of
Side Effects (Casey Eye Institute, Portland, Oregon), the Food and
the drug, unlikely to be attributed to concurrent disease or other
Drug Administration (Rockville, Maryland), the World Health
drugs or chemicals, and which follows a clinically reasonable response
Organization (WHO; Uppsala, Sweden), and the literature were
on withdrawal (dechallenge). Rechallenge information is not required
reviewed to determine the relationship between the drug and the
adverse ocular side effects. The WHO’s Causality Assessment
a clinical event, including laboratory test abnormality, with
was used to categorize adverse drug reactions
a reasonable time sequence to administration of the drug, but whichcould also be explained by concurrent disease or other drugs orchemicals. Information on drug withdrawal may be lacking orunclear.
a clinical event, including laboratory test abnormality, with
a temporal relationship to drug administration that makes a causal
relationship improbable, and in which other drugs, chemicals, orunderlying disease provide plausible explanations.
Bisphosphonates are used to inhibit bone resorption in postmeno-
a clinical event, including laboratory test
abnormality, reported as an adverse reaction, about which more data
pausal women, in the management of hypercalcemia of osteolytic
are essential for a proper assessment or the additional data are underexamination.
Originally received: August 12, 2003.
a report suggesting an adverse reaction
that cannot be judged because information is insufficient orcontradictory, and which cannot be supplemented or verified.
From the Casey Eye Institute, Oregon Health & Science University,Portland, Oregon.
This study was supported in part by an unrestricted grant from Research toPrevent Blindness, New York, New York.
bone cancer, and to treat metastases of breast cancer, multiple
The authors have no proprietary interest in these materials.
myeloma, and Paget’s disease of the bone. Four hundred thirty-
Presented at: American Academy of Ophthalmology Annual Meeting,
eight ocular side effects have been reported to the National Reg-
November 15–18, 2003; Anaheim, California.
istry due to bisphosphonate therapy. The majority of adversereactions are inflammatory (i.e., conjunctivitis, uveitis, and
Reprint requests to F. W. Fraunfelder, MD, Casey Eye Institute, 3375 SWTerwilliger Boulevard, Portland, OR 97239-4197. E-mail: eyedrug@
episcleritis), with symptoms of eye pain and photophobia fre-
quently reported as well Scleritis in particular was
2004 by the American Academy of Ophthalmology
Table 2. Bisphosphonates and Adverse Ocular Side Effects
seasonal allergic rhinitis, perennial allergic rhinitis, and chronicurticaria. Ocular side effects from this class of medicine include
No. of Cases
pupillary changes, blurred vision, and keratoconjunctivitis sicca.
Oculogyric crisis is a bilateral condition in which the eyes and
lids are tonically elevated and the neck is hyperextended, usually
without visual complaints. Oculogyric crisis is seen most com-
monly in association with phenothiazine toxicity and can also
occur after postencephalitic parkinsonism. Seventy-two drugs have
been reported as possibly causing oculogyric Nine cases of
oculogyric crisis due to cetirizine therapy were reported to the
National Registry, with 8 occurring in the pediatric age
Two patients in this series were using other antihistamines that
could have caused an additive effect. Dosage ranged from 5 to 10
mg orally, and time to onset of symptoms ranged from 3 to 184
days. Six cases of oculogyric crisis had positive rechallenge data
Eight cases had complete neurologic consultation, in-
The WHO category of the relationship of cetirizine as a cause
Retinoids are used to treat severe recalcitrant nodular acne, acne
vulgaris, and severe recalcitrant psoriasis, and to induce remission
of leukemia. The National Registry received 327 case reports ofocular side effects associated with retinoids, and these have beenclassified for isotretinoin, a retinoid, in previous
recently shown to have a cause-and-effect relationship with
Recent data suggest that, in rare instances, all retinoids
bisphosphonate therapy. This is the first class of drug ever shown
may be associated with and can likely cause intracranial hyperten-
to cause scleritis, which in turn is the most vision-threatening side
sion when used at prescribed therapeutic (also Fraun-
effect attributed to this class of drugs.The time to onset of
felder and Fraunfelder, unpublished data) Onset of
scleritis is different for each medication within this class; for
symptoms (blurred vision, headache) occurred an average of 2 to
pamidronate (IV), the scleritis appeared within 48 hours in 82% of
3 months after patients commenced therapy (range, 5 days–2
years). From the available information, we note that all but 3 cases
The WHO classification for bisphosphonates is included in
resolved within a few months after retinoid use was discontinued.
In 6 reports, patients were taking a tetracycline, a drug associatedwith intracranial hypertension. It is possible that the combination
of a retinoid and a tetracycline may lead to a higher incidence ofintracranial hypertension.
Cetirizine (Zyrtec, Pfizer Laboratories, New York, NY) is a selec-
The WHO category of the relationship of retinoids as a cause of
tive inhibitor of peripheral H receptors indicated for treatment of
intracranial hypertension is “certain.”
Table 3. World Health Organization Classification of
Topiramate is used to treat refractory epilepsy and off label to treat
migraine headaches and as a weight loss medication. Eighty-six
cases of acute onset glaucoma (83 bilateral and 3 unilateral), 17
cases of acute bilateral myopia (up to 8.75 diopters), 9 cases of
suprachoroidal effusions, 3 cases of periorbital edema, and 4 cases
of scleritis were reported to the National Registry due to topira-
mate therapy. Onset of angle-closure glaucoma was acute, and
ranged from 1 to 49 days, with a mean of 7 days from the onset of
therapy. Eighty-five percent of cases occurred in the first 2 weeks
of treatment with topiramate. In those cases for which management
was reported, 38% had laser or surgical peripheral iridectomy (21
In the “certain” category of the WHO classification system, the
following are caused by topiramate therapy: abnormal vision,
acute secondary angle-closure glaucoma, acute myopia, and supra-
choroidal effusions All findings are reversible if recog-
nized early and if the drug is discontinued. The first presenting
symptom of acute secondary angle-closure glaucoma in manypatients was blurred
Fraunfelder and Fraunfelder
⅐ Adverse Ocular Drug Reactions
Table 4. Case Reports of Cetirizine and Oculogyric Crisis
F ϭ female; M ϭ male.
*The adverse ocular reaction abated after drug discontinuation.
†The adverse ocular reaction abated after drug discontinuation and reappeared with reinstitution of therapy with the same medication.
Table 5. Adverse Ocular Effects in Patients Taking
Isotretinoin: World Health Organization Classification
In ophthalmology we rarely have scientific data as to the
causation of an adverse ocular drug-related event. Unfortu-
nately, much of our clinical ophthalmic toxicology relies on
voluntary postmarketing surveillance systems and case re-
ports. These, however, may provide information as to a
Decreased dark adaptationDecreased tolerance to contact lens
temporal relationship, a pattern of presentation, dechallenge
data, and, most importantly, rechallenge When
analyzed with the WHO Causality Assessment Guide
data may provide guidance for clinicians. Using the WHO
system, the likelihood of causation of adverse ocular side
effects can be classified for easy recognition by clinicians.
From the 4 classes of medications described here, general-
izations can be deduced and guidelines for clinical care
The mechanism behind the development of ocular inflam-
mation in some patients taking bisphosphonates is un-
known. Pamidronate stimulates the production of a distinct
subgroup of T cells to inhibit bone resorption. As analogs of
pyrophosphate, the bisphosphonates share several homolo-
gies with nonpeptide (␥, ⌬) T cell ligands that activate
antigenic receptor (␥, ⌬) T cells, whose activation releases
cytokines. These cytokines may contribute to an immuno-
logic or toxic reaction in patients who develop uveitis
Suggestions for treatment of bisphosphonate-induced oc-
ular side effects are as follows: if there is a persistent
decrease in vision or if ocular pain occurs, examination by
an ophthalmologist is necessary. Nonspecific conjunctivitis
seldom requires treatment and usually decreases in intensity
Cortical blindnessDecreased accommodation
or may be absent on subsequent treatments. In rare in-
stances, a nonsteroidal anti-inflammatory eyedrop may be
needed. More than one ocular side effect could occur at the
same time (i.e., episcleritis with uveitis). Rarely, bilateral
anterior uveitis or posterior unilateral uveitis may occur and
can vary markedly in severity. Many cases require intensive
Table 6. Intracranial Hypertension from Retinoids
Time to Onset
F ϭ female; M ϭ male; U ϭ unknown.
*ϩ, positive; Ϫ, negative.
†Schroeter T, Lanvers C, Herding H, Suttorp M. Pseudotumor cerebri induced by all-trans-retinoic acid in a child treated for acute promyelocyticleukemia. Med Pediatr Oncol 2000;34:284 – 6.
‡Sano F, Tsuji K, Kunika N, et al. Pseudotumor cerebri in a patient with acute promyelocytic leukemia during treatment with all-trans-retinoic acid. InternMed 1998;37:546 –9.
§Tiamkao S, Sirijirachai C. Pseudotumor cerebri caused by all-trans-retinoic acid: a case report. J Med Assoc Thai 2000;83:1420 –3.
Drugs reported to cause intracranial hypertension.
¶Bonnetblanc JM, Hugon J, Dumas M, Rupin D. Intracranial hypertension with etretinate [letter]. Lancet 1983;2(8356):974.
#Viraben R, Mathieu C, Fontan B. Benign intracranial hypertension during etretinate therapy for mycosis fungoides [letter]. J Am Acad Dermatol1985;13:515–7.
Table 7. Adverse Ocular Side Effects Associated with
Topiramate Use: World Health Organization Classification
topical ocular or systemic medication. In some instances,the drug may need to be discontinued for uveitis to resolve.
Episcleritis may require topical ocular medication; how-
ever, the bisphosphonate may be continued. In all patients
Acute intraocular pressure elevationAcute myopia (up to 8.75 diopters)
studied, in this series, the bisphosphonate had to be discon-
tinued for the scleritis to resolve, even on full medical
Shallow anterior chamber with angle closure
The mechanism whereby cetirizine causes oculogyric crisis
is still a subject of speculation. This antihistamine has a
weak anticholinergic effect, and this may lead to an oculo-
Congenital ocular abnormalitiesPeriorbital edema
gyric crisis. As with phenothiazine toxicity, in which it is
recognized that the dystonic side effect is due to an acute
Fraunfelder and Fraunfelder
⅐ Adverse Ocular Drug Reactions
Table 8. Management of Topiramate-Associated Acute,
topical ␤-blockers and oral pressure-lowering agents
Bilateral, Secondary Angle-Closure Glaucoma
Consult the prescribing physician. Topiramate should be discontinued
as soon as possible. Decreasing the dosage more than 50 mg/day maycause other, systemic adverse effects. In most cases, intraocular
pressure decreases rapidly after the drug is stopped.
Institute maximum medical therapy, including oral medications and
1. Macarol V, Fraunfelder FT. Pamidronate disodium and pos-
Laser iridotomy or peripheral iridectomy probably is not beneficial if the
sible ocular adverse drug reactions. Am J Ophthalmol 1994;
glaucoma is only associated with topiramate therapy.
Topical miotics are probably contraindicated in this condition because
2. Fraunfelder FW, Fraunfelder FT. Bisphosphonates and ocular
their use may precipitate a relative pupillary block.
inflammation [letter]. N Engl J Med 2003;348:1187– 8.
3. Fraunfelder FW, Fraunfelder FT, Jensvold B. Scleritis and
other ocular side effects associated with pamidronate diso-
imbalance between dopaminergic and cholinergic block-
dium. Am J Ophthalmol 2003;135:219 –22.
ades, cetirizine toxicity may create the same condition.
4. Fraunfelder FW. Ocular side effects associated with bisphos-
It is hoped that clinicians will recognize this ocular side
phonates. Drugs Today (Barc) 2003;39:829 –35.
effect when it occurs in conjunction with cetirizine therapy.
5. Fraunfelder FT, Fraunfelder FW, Randall JA, eds. Drug-In-
An oculogyric crisis will resolve rapidly upon discontinua-
duced Ocular Side Effects. 5th ed. Boston: Butterworth-Heine-
tion of cetirizine. In the presence of a normal neurologic
examination, further evaluation, including neuroimaging,
6. Mbekeani JN, Slamovits TL, Schwartz BH, Sauder HL. Oc-
may be unnecessary because the vast majority of cases are
ular inflammation associated with alendronate therapy. ArchOphthalmol 1999;117:837– 8.
7. Fraunfelder FW, Fraunfelder FT. Oculogyric crisis in patients
taking cetirizine. Am J Ophthalmol 2004;137:355–7.
8. Fraunfelder FT, Fraunfelder FW, Edwards R. Ocular side
effects possibly associated with isotretinoin usage. Am J Oph-
For patients receiving retinoids, we suggest the following
guidelines: first, consider discontinuation of retinoid ther-
9. Schroeter T, Lanvers C, Herding H, Suttorp M. Pseudotumor
apy in patients who develop otherwise unexplained head-
cerebri induced by all-trans-retinoic acid in a child treated for
aches or blurred vision, and evaluate them for intracranial
acute promyelocytic leukemia. Med Pediatr Oncol 2000;34:
hypertension. Second, avoid concomitant use of tetracy-
clines, retinoids, and other drugs causing intracranial hyper-
10. Sano F, Tsuji K, Kunika N, et al. Pseudotumor cerebri in a
patient with acute promyelocytic leukemia during treatment
tension, as there are many reported cases of intracranial
with all-trans-retinoic acid. Intern Med 1998;37:546 –9.
hypertension occurring when certain classes of medicines
11. Tiamkao S, Sirijirachai C. Pseudotumor cerebri caused by
are used simultaneously. Third, patients taking retinoids
all-trans-retinoic acid: a case report. J Med Assoc Thai 2000;
should avoid vitamin A, a known contributor to intracranial
hypertension, due to the possibility of additive toxic effects.
12. Bonnetblanc JM, Hugon J, Dumas M, Rupin D. Intracranial
It is hoped that clinicians will recognize the possible
hypertension with etretinate [letter]. Lancet 1983;2(8356):
association between retinoids and intracranial hypertension
and stop treatment when indicated, as this adverse event
13. Viraben R, Mathieu C, Fontan B. Benign intracranial hyper-
resolves in the majority of cases when this class of medi-
tension during etretinate therapy for mycosis fungoides [let-
ter]. J Am Acad Dermatol 1985;13:515–7.
14. Fraunfelder FW, Fraunfelder FT, Keates EU. Topiramate-
associated acute, bilateral, secondary angle-closure glaucoma.
15. Banta JT, Hoffman K, Budenz DL, et al. Presumed topira-
Sulfa-containing medications, such as topiramate, are
mate-induced bilateral acute angle-closure glaucoma. Am J
known to cause transient myopia. The mechanism behind
this occurrence is not fully understood, but could include
16. U.S. Food and Drug Administration. Topamax (topiramate)
lenticular swelling, forward rotation of the lens–iris dia-
tablets prescribing information. Available at: http://www.fda.
phragm, ciliary body swelling causing increased curvature
gov/medwatch/SAFETY/2003/tpamax.pdf. Accessed August
The management of topiramate-related acute pressure
17. Thambi L, Kapcala LP, Chambers W, et al. Topiramate-
associated secondary angle-closure glaucoma: a case series
elevation requires stopping the drug in concert with the
[letter]. Arch Ophthalmol 2002;120:1108.
prescribing physician, because decreasing the dosage as
18. Rhee DJ, Goldberg MJ, Parrish RK. Bilateral angle-closure
little as 50 mg may exacerbate pre-existing systemic con-
glaucoma and ciliary body swelling from topiramate. Arch
ditions. Topical cyclopegic agents are effective and proba-
bly lower intraocular pressure by retracting the ciliary pro-
19. Edwards R, Biriell C. Harmonisation in pharmacovigilance.
cesses. Clinicians should also consider treatment with
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