Adverse Ocular Drug Reactions Recently

Identified by the National Registry of

Drug-Induced Ocular Side Effects
F. W. Fraunfelder, MD, F. T. Fraunfelder, MD

Purpose: To report recent ocular adverse drug reactions identified by the National Registry of Drug-Induced
Ocular Side Effects.
Methods: 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.
Results: 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.
Conclusion: 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
bisphosphonates, cetirizine, retinoids, and topiramate are
described. Conclusions are made after reviewing case re-
ports from national and international databases and from a
review of the literature.
Materials and Methods
Case reports from the National Registry of Drug-Induced Ocular
Side Effects (Casey Eye Institute, Portland, Oregon), the Food and
Drug Administration (Rockville, Maryland), the World Health
Organization (WHO; Uppsala, Sweden), and the literature were
reviewed to determine the relationship between the drug and the
adverse ocular side effects. The WHO’s Causality Assessment
Guide was used to categorize adverse drug reactions (Table 1).
Results
Bisphosphonates
Bisphosphonates are used to inhibit bone resorption in postmeno-
pausal women, in the management of hypercalcemia of osteolytic
Originally received: August 12, 2003.
Accepted: December 12, 2003. Manuscript no. 230531.
From the Casey Eye Institute, Oregon Health & Science University,
Portland, Oregon.
This study was supported in part by an unrestricted grant from Research to
Prevent Blindness, New York, New York.
The authors have no proprietary interest in these materials.
Presented at: American Academy of Ophthalmology Annual Meeting,
November 15–18, 2003; Anaheim, California.
Reprint requests to F. W. Fraunfelder, MD, Casey Eye Institute, 3375 SW
Terwilliger Boulevard, Portland, OR 97239-4197. E-mail: eyedrug@
ohsu.edu.
Table 1. World Health Organization Definitions—Causality
Assessment of Suspected Adverse Reactions
● Certain: a clinical event, including laboratory test abnormality,
occurring in a plausible time relationship to drug administration, and
which cannot be explained by concurrent disease or other drugs or
chemicals. The response to withdrawal of the drug (dechallenge)
should be clinically plausible. The event must be definitive
pharmacologically or phenomenologically, using a satisfactory
rechallenge procedure if necessary.
● Probable/likely: a clinical event, including laboratory test
abnormality, with a reasonable time sequence to administration of
the drug, unlikely to be attributed to concurrent disease or other
drugs or chemicals, and which follows a clinically reasonable response
on withdrawal (dechallenge). Rechallenge information is not required
to fulfill this definition.
● Possible: a clinical event, including laboratory test abnormality, with
a reasonable time sequence to administration of the drug, but which
could also be explained by concurrent disease or other drugs or
chemicals. Information on drug withdrawal may be lacking or
unclear.
● Unlikely: 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, or
underlying disease provide plausible explanations.
● Conditional/unclassified: a clinical event, including laboratory test
abnormality, reported as an adverse reaction, about which more data
are essential for a proper assessment or the additional data are under
examination.
● Unassessible/unclassifiable: a report suggesting an adverse reaction
that cannot be judged because information is insufficient or
contradictory, and which cannot be supplemented or verified.
bone cancer, and to treat metastases of breast cancer, multiple
myeloma, and Paget’s disease of the bone. Four hundred thirty-
eight ocular side effects have been reported to the National Reg-
istry due to bisphosphonate therapy. The majority of adverse
reactions are inflammatory (i.e., conjunctivitis, uveitis, and
episcleritis), with symptoms of eye pain and photophobia fre-
quently reported as well (Table 2). Scleritis in particular was

© 2004 by the American Academy of Ophthalmology ISSN 0161-6420/04/$–see front matter 1275
Published by Elsevier Inc. doi:10.1016/j.ophtha.2003.12.052
 Ophthalmology Volume 111, Number 7, July 2004

Table 2. Bisphosphonates and Adverse Ocular Side Effects seasonal allergic rhinitis, perennial allergic rhinitis, and chronic
urticaria. Ocular side effects from this class of medicine include
No. of Cases pupillary changes, blurred vision, and keratoconjunctivitis sicca.
Reported Oculogyric crisis is a bilateral condition in which the eyes and
Pamidronate lids are tonically elevated and the neck is hyperextended, usually
Nonspecific conjunctivitis 72 without visual complaints. Oculogyric crisis is seen most com-
Uveitis 66 monly in association with phenothiazine toxicity and can also
Abnormal or blurred vision 24 occur after postencephalitic parkinsonism. Seventy-two drugs have
Scleritis 19 been reported as possibly causing oculogyric crisis.5 Nine cases of
Ocular pain 16 oculogyric crisis due to cetirizine therapy were reported to the
Photophobia 14 National Registry, with 8 occurring in the pediatric age group.7
Episcleritis 10
Alendronic acid Two patients in this series were using other antihistamines that
Abnormal or blurred vision 94 could have caused an additive effect. Dosage ranged from 5 to 10
Ocular pain 33 mg orally, and time to onset of symptoms ranged from 3 to 184
Nonspecific conjunctivitis 30 days. Six cases of oculogyric crisis had positive rechallenge data
Uveitis 19 (Table 4). Eight cases had complete neurologic consultation, in-
Scleritis 4 cluding radiographic studies.
Etidronate The WHO category of the relationship of cetirizine as a cause
Abnormal or blurred vision 18 of oculogyric crisis is “certain.”
Nonspecific conjunctivitis 3
Risedronate
Nonspecific conjunctivitis 7
Abnormal or blurred vision 2 Retinoids
Scleritis 1
Sodium clodronate Retinoids are used to treat severe recalcitrant nodular acne, acne
Abnormal or blurred vision 5 vulgaris, and severe recalcitrant psoriasis, and to induce remission
Photophobia 1
of leukemia. The National Registry received 327 case reports of
ocular side effects associated with retinoids, and these have been
classified for isotretinoin, a retinoid, in previous publications5– 8
recently shown to have a cause-and-effect relationship with (Table 5). 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 doses9 –13 (also Fraun-
effect attributed to this class of drugs.1– 6 The time to onset of felder and Fraunfelder, unpublished data) (Table 6). 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
the patients (14/17).3 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.
Table 3. In 6 reports, patients were taking a tetracycline, a drug associated
with intracranial hypertension. It is possible that the combination
Cetirizine of a retinoid and a tetracycline may lead to a higher incidence of
intracranial 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 H1 receptors indicated for treatment of intracranial hypertension is “certain.”

Table 3. World Health Organization Classification of

Bisphosphonates and Ocular Side Effects Topiramate
Certain Topiramate is used to treat refractory epilepsy and off label to treat
Blurred vision migraine headaches and as a weight loss medication. Eighty-six
Ocular irritation cases of acute onset glaucoma (83 bilateral and 3 unilateral), 17
Nonspecific conjunctivitis cases of acute bilateral myopia (up to 8.75 diopters), 9 cases of
Pain suprachoroidal effusions, 3 cases of periorbital edema, and 4 cases
Epiphoria of scleritis were reported to the National Registry due to topira-
Photophobia
Conjunctivitis
mate therapy. Onset of angle-closure glaucoma was acute, and
Uveitis ranged from 1 to 49 days, with a mean of 7 days from the onset of
Scleritis therapy. Eighty-five percent of cases occurred in the first 2 weeks
Episcleritis of treatment with topiramate. In those cases for which management
Probable was reported, 38% had laser or surgical peripheral iridectomy (21
Periocular lid and/or orbital edema cases).14
Possible In the “certain” category of the WHO classification system, the
Retrobulbar neuritis following are caused by topiramate therapy: abnormal vision,
Yellow vision
acute secondary angle-closure glaucoma, acute myopia, and supra-
Diplopia
Cranial nerve palsy choroidal effusions (Table 7). All findings are reversible if recog-
Ptosis nized early and if the drug is discontinued. The first presenting
Visual hallucinations symptom of acute secondary angle-closure glaucoma in many
patients was blurred vision.14 –17

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 Fraunfelder and Fraunfelder 䡠 Adverse Ocular Drug Reactions

Table 4. Case Reports of Cetirizine and Oculogyric Crisis

Case Time to Positive Positive

No. Age Gender Dose Onset Other Medications Dechallenge* Rechallenge†
1 7 mos M 10 mg 14 days Chlorpheniramine Yes Yes
(nursing)
2 9 yrs M 5 mg 3 days Cromolyn, aspirin Yes Yes
3 30 mos M 5 mg 184 days Folic acid, ascorbic acid, Yes ?
ergocalciferol
4 6 yrs M 5 mg 22 days Mometasone, dextromethorphan Yes Yes
5 10 yrs F 10 mg 21 days Loratadine, fluticasone Yes Yes
6 6 yrs M ? 12 days Albuterol, montelukast Yes Yes
7 54 yrs F 10 mg 1 mo Digoxin, estradiol, Yes ?
medroxyprogesterone
8 12 yrs M 10 mg 3 mos None Yes Yes
9 7 yrs M ? ? ? Yes ?

F ⫽ female; M ⫽ 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

Discussion Isotretinoin: World Health Organization Classification

Certain
In ophthalmology we rarely have scientific data as to the Abnormal meibomian gland secretion
causation of an adverse ocular drug-related event. Unfortu- Abnormal scotopic ERG
nately, much of our clinical ophthalmic toxicology relies on Blepharoconjunctivitis
voluntary postmarketing surveillance systems and case re- Corneal opacities
ports. These, however, may provide information as to a Decreased dark adaptation
Decreased tolerance to contact lens
temporal relationship, a pattern of presentation, dechallenge Decreased vision
data, and, most importantly, rechallenge data.17–19 When Increased tear osmolarity
analyzed with the WHO Causality Assessment Guide, these Keratitis
data may provide guidance for clinicians. Using the WHO Meibomian gland atrophy
Myopia
system, the likelihood of causation of adverse ocular side Ocular discomfort
effects can be classified for easy recognition by clinicians. Intracranial hypertension
From the 4 classes of medications described here, general- Photophobia
izations can be deduced and guidelines for clinical care Ocular sicca
provided as follows. Teratogenic ocular abnormalities
Probable/likely
Decreased color vision (reversible)
Bisphosphonates Permanent loss of dark adaptation
Possible
The mechanism behind the development of ocular inflam- Corneal ulcers
Diplopia
mation in some patients taking bisphosphonates is un- Eyelid edema
known. Pamidronate stimulates the production of a distinct Optic neuritis
subgroup of T cells to inhibit bone resorption. As analogs of Permanent siccalike syndrome
pyrophosphate, the bisphosphonates share several homolo- Subconjunctival hemorrhage
gies with nonpeptide (␥, ⌬) T cell ligands that activate Unlikely
Activation of herpes simplex virus
antigenic receptor (␥, ⌬) T cells, whose activation releases Corneal vascularization
cytokines. These cytokines may contribute to an immuno- Exophthalmos
logic or toxic reaction in patients who develop uveitis Glaucoma
and/or scleritis.3 Keratoconus
Limbal infiltrates
Suggestions for treatment of bisphosphonate-induced oc- Pupil abnormalities
ular side effects are as follows: if there is a persistent Vitreous disturbance
decrease in vision or if ocular pain occurs, examination by Conditional/unclassifiable
an ophthalmologist is necessary. Nonspecific conjunctivitis Cataracts
seldom requires treatment and usually decreases in intensity Cortical blindness
Decreased accommodation
or may be absent on subsequent treatments. In rare in- Iritis
stances, a nonsteroidal anti-inflammatory eyedrop may be Peripheral field loss
needed. More than one ocular side effect could occur at the Retinal findings
same time (i.e., episcleritis with uveitis). Rarely, bilateral Scleritis
anterior uveitis or posterior unilateral uveitis may occur and ERG ⫽ electroretinogram.
can vary markedly in severity. Many cases require intensive

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Table 6. Intracranial Hypertension from Retinoids

Age
Drug (yrs) Gender Other Medications Dose Time to Onset Dechallenge*
All-trans 19 F Arsenic trioxide, plaquenil 45 mg/day 540 days ⫺
retinoic acid
(vitamin A)
8† F Cytarabine, etoposide, 25 mg/m2/day 65 days ⫹
idarubicin
18‡ M Daunorubicin, cytosine 45 mg/m2/day 23 days ⫹
arabinoside
35§
F None 60 mg/day 14 days ⫹
Acitretin U U None 50 mg/day U U
40 F None 50 mg/day 515 days ⫹
30 M None 50 mg/day U ⫹
Tretinoin 24 M Zidovudine 45 mg/m2/day 53 days ⫺
29 F Trazodone pyridoxine 45 mg/m2/day 45 days ⫺
hydrochloride epoetin
alfa insulin
U F None 45 mg/m2/day 257 days U
19 F Minocycline㛳 45 mg/m2/day U U
U F Minocycline㛳 45 mg/m2/day U U
25 F Tetracycline,㛳 imipramine, 45 mg/m2/day U ⫹
naproxen, lorazepam
30 F Tetracycline,㛳 lorazepam 45 mg/m2/day 82 days U
31 F Oral contraceptive 45 mg/m2/day 730 days U
14 U Tetracycline㛳 45 mg/m2/day U U
14 F Sulfamethoxazole, 45 mg/m2/day U U
fluconazole, oral
contraceptive
27 F None 45 mg/m2/day U ⫹
Etretinate 36 F None 0.75–1 mg/kg/day 5 days ⫹
44 F Furosemide 0.75–1 mg/kg/day 90 days U
11 M None 0.75–1 mg/kg/day Same day ⫹
U F None 0.75–1 mg/kg/day U ⫹
33¶ F Floctafenine 0.50–1 mg/kg/day 90 days ⫹
67# F None 1.0 mg/kg/day 30 days ⫹
75# F Minocycline㛳 1.0 mg/kg/day 180 days ⫹

F ⫽ female; M ⫽ male; U ⫽ unknown.

*⫹, positive; ⫺, negative.
†
Schroeter T, Lanvers C, Herding H, Suttorp M. Pseudotumor cerebri induced by all-trans-retinoic acid in a child treated for acute promyelocytic
leukemia. 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. Intern
Med 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.
㛳
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 Dermatol
1985;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. Certain
Episcleritis may require topical ocular medication; how- Abnormal vision
Acute intraocular pressure elevation
ever, the bisphosphonate may be continued. In all patients Acute myopia (up to 8.75 diopters)
studied, in this series, the bisphosphonate had to be discon- Diplopia (at high doses)
tinued for the scleritis to resolve, even on full medical Nystagmus (at high doses)
therapy.4 Shallow anterior chamber with angle closure
Probable/likely
Blepharospasm
Cetirizine Myokymia
Oculogyric crisis
The mechanism whereby cetirizine causes oculogyric crisis Suprachoroidal effusions
is still a subject of speculation. This antihistamine has a Possible
Congenital ocular abnormalities
weak anticholinergic effect, and this may lead to an oculo- Periorbital edema
gyric crisis. As with phenothiazine toxicity, in which it is Scleritis
recognized that the dystonic side effect is due to an acute

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 Fraunfelder and Fraunfelder 䡠 Adverse Ocular Drug Reactions
Table 8. Management of Topiramate-Associated Acute,
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 may
cause other, systemic adverse effects. In most cases, intraocular
pressure decreases rapidly after the drug is stopped.
Institute maximum medical therapy, including oral medications and
aqueous suppressants.
Laser iridotomy or peripheral iridectomy probably is not beneficial if the
glaucoma is only associated with topiramate therapy.
Topical miotics are probably contraindicated in this condition because
their use may precipitate a relative pupillary block.
imbalance between dopaminergic and cholinergic block-
ades, cetirizine toxicity may create the same condition.
It is hoped that clinicians will recognize this ocular side
effect when it occurs in conjunction with cetirizine therapy.
An oculogyric crisis will resolve rapidly upon discontinua-
tion of cetirizine. In the presence of a normal neurologic
examination, further evaluation, including neuroimaging,
may be unnecessary because the vast majority of cases are
drug related.7
Retinoids
For patients receiving retinoids, we suggest the following
guidelines: first, consider discontinuation of retinoid ther-
apy in patients who develop otherwise unexplained head-
aches or blurred vision, and evaluate them for intracranial
hypertension. Second, avoid concomitant use of tetracy-
clines, retinoids, and other drugs causing intracranial hyper-
tension, as there are many reported cases of intracranial
hypertension occurring when certain classes of medicines
are used simultaneously. Third, patients taking retinoids
should avoid vitamin A, a known contributor to intracranial
hypertension, due to the possibility of additive toxic effects.
It is hoped that clinicians will recognize the possible
association between retinoids and intracranial hypertension
and stop treatment when indicated, as this adverse event
resolves in the majority of cases when this class of medi-
cation is discontinued.
Topiramate
Sulfa-containing medications, such as topiramate, are
known to cause transient myopia. The mechanism behind
this occurrence is not fully understood, but could include
lenticular swelling, forward rotation of the lens–iris dia-
phragm, ciliary body swelling causing increased curvature
of the lens surfaces, and a spasm of accommodation.5
The management of topiramate-related acute pressure
elevation requires stopping the drug in concert with the
prescribing physician, because decreasing the dosage as
little as 50 mg may exacerbate pre-existing systemic con-
ditions. Topical cyclopegic agents are effective and proba-
bly lower intraocular pressure by retracting the ciliary pro-
cesses. Clinicians should also consider treatment with
topical ␤-blockers and oral pressure-lowering agents (Table
8).
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cerebri induced by all-trans-retinoic acid in a child treated for
acute promyelocytic leukemia. Med Pediatr Oncol 2000;34:
284 – 6.
10. Sano F, Tsuji K, Kunika N, et al. Pseudotumor cerebri in a
patient with acute promyelocytic leukemia during treatment
with all-trans-retinoic acid. Intern Med 1998;37:546 –9.
11. Tiamkao S, Sirijirachai C. Pseudotumor cerebri caused by
all-trans-retinoic acid: a case report. J Med Assoc Thai 2000;
83:1420 –3.
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hypertension with etretinate [letter]. Lancet 1983;2(8356):
974.
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tension during etretinate therapy for mycosis fungoides [let-
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