Doi:10.1016/j.ophtha.2003.12.052

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 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 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- ● Certain: 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.
● Probable/likely: 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 ● Possible: a clinical event, including laboratory test abnormality, with
Guide 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.
● Unlikely: a clinical event, including laboratory test abnormality, with
a temporal relationship to drug administration that makes a causal Bisphosphonates
relationship improbable, and in which other drugs, chemicals, orunderlying disease provide plausible explanations.
Bisphosphonates are used to inhibit bone resorption in postmeno- ● Conditional/unclassified: 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.
● Unassessible/unclassifiable: 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.
Reported
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
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 Cetirizine
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
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 Positive
Positive
Other Medications
Dechallenge*
Rechallenge†
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 Discussion
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, these 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 Bisphosphonates
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 Other Medications
Time to Onset
Dechallenge*
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 Cetirizine
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 References
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.
Retinoids
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.
Topiramate
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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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