REVIEW ARTICLE
`
`Drugs 2007; 67 (1): 75-93
`0012-6667/07/0001-0075/$49.95/0
`
`© 2007 Adis Data Information BV. All rights reserved.
`
`Ocular Adverse Effects Associated
`with Systemic Medications
`Recognition and Management
`
`Ricardo M. Santaella and Frederick W. Fraunfelder
`Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA
`
`Contents
`Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
`1. Categorising Adverse Drug-Related Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
`2. Medications and Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
`2.1 Bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
`2.2 Antiepileptic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
`2.2.1 Topiramate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
`2.2.2 Vigabatrin and Tiagabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
`2.3 Isotretinoin and Other Retinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
`2.4 Ethambutol and Isoniazid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
`2.5 Amiodarone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
`2.6 Hydroxychloroquine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
`2.7 Erectile Dysfunction Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
`2.8 Tamoxifen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
`2.9 Cyclo-Oxygenase-2 Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
`2.10 Nicotinic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
`2.11 Herbal Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
`2.11.1 Canthaxanthine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
`2.11.2 Chamomile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
`2.11.3 Datura . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
`2.11.4 Echinacea purpurea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
`2.11.5 Ginkgo biloba . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
`2.11.6 Liquorice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
`2.11.7 Vitamin A (Retinol) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
`2.11.8 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
`3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
`
`Abstract
`
`This article reviews several retrospective case series and reported adverse
`events regarding common ocular adverse effects related to systemic therapy. It is
`not intended as a comprehensive summary of these well described adverse drug
`reactions, nor is it intended to cover the complete spectrum of all ocular adverse
`effects of systemic therapy. Many systemic drugs may produce ocular toxicity,
`including bisphosphonates, topiramate, vigabatrin, isotretinoin and other reti-
`noids, amiodarone, ethambutol, chloroquine and hydroxychloroquine, tamoxifen,
`quetiapine, cyclo-oxygenase (COX)-2 inhibitors, erectile dysfunction agents and
`some herbal medications. For this review, the certainty of the adverse effect
`
`Novartis Exhibit 2296.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`76
`
`Santaella & Fraunfelder
`
`profile of each medication was evaluated according to the WHO Causality
`Assessment Guide.
`A certain relationship has been established for pamidronate and alendronate as
`causes of scleritis, uveitis, conjunctivitis and blurred vision. Topiramate has been
`established as adversely causing symptoms consistent with acute angle-closure
`glaucoma, typically bilateral. Vigabatrin has been shown to cause bilateral irre-
`versible visual field defects attributed to underlying medication-induced retinal
`pathology. Isotretinoin should be considered in the differential diagnosis of any
`patient with pseudotumour cerebri. Patients taking amiodarone and hydroxy-
`chloroquine should be monitored and screened regularly for development of optic
`neuropathy and maculopathy, respectively. Sildenafil has been reported to cause
`several changes in visual perception and is a possible, not yet certain, cause of
`anterior ischaemic optic neuropathy. Patients taking tamoxifen should also be
`monitored for development of dose-dependent maculopathy and decreased colour
`vision. COX-2 inhibitors should be included in the differential diagnosis of
`reversible conjunctivitis. Several herbal medications including canthaxanthine,
`chamomile, datura, Echinacea purpurea, Ginkgo biloba and liquorice have also
`been associated with several ocular adverse effects.
`It is the role of all healthcare professionals to detect, treat and educate the
`public about adverse reactions to medications as they are an important health
`problem.
`
`er, if undetected, toxic effects may progress and
`The term ‘side effect’ usually refers to an unde-
`cause irreversible ocular damage often with an asso-
`sired or negative effect of medication that is extrane-
`ciated reduction in visual function.[3,4]
`ous to the intended therapy. When the effect is
`negative, the term ‘adverse effect’ is used. Drug-
`For ophthalmic drugs to be effective, they must
`induced ocular adverse effects are the second most
`reach ocular tissue in relatively high concentrations.
`frequent reason for claims against ophthalmolo-
`There are several different administration routes for
`gists.[1,2] This may not be surprising given that pre-
`ophthalmic drugs, including the topical, oral, paren-
`scribing medications is the most common therapeu-
`teral, periocular, intracameral (intraocular adminis-
`tic service provided by physicians. According to the
`tration into the anterior segment) and intravitreal
`National Center for Health Statistics, new or contin-
`routes. Topical application is the most common
`ued medications are ordered or provided at 41% of
`route of administration because it is simple, less
`visits to an ophthalmologist’s office. Because seri-
`invasive and does not involve the passage of drugs
`ous injury can occur, drug-related adverse effects
`through the blood-aqueous barrier. However, some
`can be costly to defend, indemnify or settle.[2]
`disorders require systemic drug administration to
`achieve adequate therapeutic levels of the drug in
`The rich blood supply and relatively small mass
`and around the ocular tissues.
`of the eye make it particularly susceptible to drug-
`Certain factors increase the probability of an
`induced adverse reactions. Adverse ocular reactions
`adverse ocular reaction. One such factor is use of a
`to drugs are diverse. Drug molecules present in the
`system may become selectively deposited in specif- medication over long periods of time, for example,
`ic ocular tissues such as the cornea, lens and retina,
`in cases of arthritic and cardiovascular diseases. In
`causing varied symptoms of drug toxicity. Fortu-
`some patients, it may be difficult to establish wheth-
`nately, most adverse reactions induced by systemic
`er ocular pathology is caused by the condition being
`medications are reversible if detected early. Howev-
`treated or by a drug used to treat the condition.
`
`© 2007 Adis Data Information BV. All rights reserved.
`
`Drugs 2007; 67 (1)
`
`Novartis Exhibit 2296.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Ocular Adverse Effects Associated with Systemic Medications
`
`77
`
`We performed a MEDLINE literature search us-
`Patient age is also a significant factor in the preva-
`ing the following keywords: ‘ocular’, ‘visual’, ‘eye’,
`lence of ocular drug reactions. Older patients are
`‘side effects’, ‘adverse effects’, ‘medication’ and
`more likely to have used medications for protracted
`‘treatment’. Some of the medication adverse effects
`periods. Also, the metabolism and excretion of a
`obtained through this search are summarised below;
`drug can be affected by decreased efficiency of the
`these were selected at the authors’ discretion, taking
`kidney and liver secondary to the patient’s age, or by
`into account some of the more recent published
`conditions adversely affecting these organs.[3,4]
`medication adverse effects, and are not presented in
`Some drug responses cannot be predicted from any particular order. This brief review is not intend-
`the drug’s pharmacological mode of action. A ge-
`ed as a comprehensive summary of these well de-
`netic basis may underlie many of these unpredict-
`scribed adverse drug reactions, nor is it intended to
`able responses, as observed in the rapid rise in
`cover the complete spectrum of all ocular adverse
`intraocular pressure reported with topical corticoste-
`effects of systemic therapy. Interested readers are
`encouraged to refer to textbooks cited within the
`roids.[5]
`references.
`The prevalence of adverse reactions is closely
`associated with drug dosage. Most reported ocular
`reactions occur when the dose is beyond the thera-
`peutic range. It is essential that clinicians try to
`establish whether the ocular problem coincided with
`the start of drug therapy or with a change in drug
`dosage. A useful marker is seen when the onset of
`the reaction coincides with commencement of the
`medication, but reactions can occur at any time
`during or after a course of medication, and can
`continue for years after cessation.
`
`The WHO Causality Assessment Guide of Sus-
`pected Adverse Reactions was used to classify the
`reported adverse drug-related events into the follow-
`ing categories: certain, probable/likely, possible, un-
`likely, conditional/unclassified and unassessable/
`unclassifiable.[6] The ‘certain’ category includes
`plausible time relationship to drug administration
`
`1. Categorising Adverse
`Drug-Related Events
`
`Table I. WHO definitions: causality assessment of suspected adverse reactions (reproduced from Brick,[2] with permission)
`
`Certain
`A clinical event, including a 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 which 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 is essential for a proper
`assessment or the additional data are under examination
`Unassessable/Unclassifiable
`A report suggesting an adverse reaction which cannot be judged because information is insufficient or contradictory, and which cannot
`be supplemented or verified
`
`© 2007 Adis Data Information BV. All rights reserved.
`
`Drugs 2007; 67 (1)
`
`Novartis Exhibit 2296.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`78
`
`Santaella & Fraunfelder
`
`Table II. Classification of adverse ocular effects associated with medication usage
`
`Medication
`Pamidronate
`
`Alendronate
`
`Risedronate
`
`Etidronate
`
`Topiramate
`
`Isotretinoin
`
`Amiodarone
`
`Certain
`Blurred vision
`Pain
`Photophobia
`Ocular irritation
`Nonspecific conjunctivitis
`Anterior uveitis (rare posterior)
`Anterior scleritis (rare posterior)
`Episcleritis
`
`Blurred vision
`Pain
`Conjunctivitis
`Uveitis
`Scleritis
`
`No effects
`
`Blurred vision
`
`Acute glaucoma (mainly bilateral)
`Anterior chamber shallowing
`Increased ocular pressure
`Mydriasis
`Suprachoroidal effusions
`
`Abnormal meibomian gland secretion
`Blepharoconjunctivitis
`Corneal opacities
`Decreased dark adaptation
`Decreased tolerance for contact lens wear
`Decreased vision
`Increased tear osmolarity
`Keratitis
`Meibomian gland atrophy
`Myopia
`Ocular sicca
`Ocular discomfort
`Photophobia
`Pseudotumour cerebri
`Teratogenic ocular abnormalities
`
`Aggravated sicca (drug in tears)
`Blepharoconjunctivitis
`Bright lights
`Coloured haloes around lights
`Corneal microdeposits
`Glare
`Hazy vision
`Photosensitivity
`Periocular skin pigmentation
`Thyroid eye disease
`Visual sensations
`
`Possible
`Probable
`Periocular, lid, and/or orbital Diplopia
`oedema
`Visual hallucinations
`Yellow vision
`Retrobulbar neuritis
`Cranial nerve palsy
`
`Diplopia
`
`Glaucoma
`
`Conjunctivitis
`Pain
`Scleritis
`Uveitis
`Blurred vision
`
`Conjunctivitis
`
`Blepharospasm
`Oculogyric crisis
`Retinal bleeds
`Uveitis
`
`Decreased colour vision
`Permanent loss of dark
`adaptation
`
`Diplopia
`Papilloedema
`Episcleritis
`
`Diplopia
`
`Scleritis
`Teratogenic effects, including
`ocular malformations
`
`Corneal ulcers
`Diplopia
`Eyelid oedema
`Optic neuritis
`Idiopathic intracranial
`hypertension with optic disc
`oedema
`Permanent sicca-like syndrome
`Subconjunctival haemorrhage
`
`Autoimmune reaction (dry mouth,
`dry eyes, peripheral neuropathy
`and pneumonitis)
`
`Anterior subcapsular lens
`opacities
`Corneal ulceration
`Loss of eyelashes or
`eyebrows
`Non-arteritic ischaemic optic
`neuropathy
`Pseudotumour cerebri
`
`Continued next page
`
`© 2007 Adis Data Information BV. All rights reserved.
`
`Drugs 2007; 67 (1)
`
`Novartis Exhibit 2296.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Ocular Adverse Effects Associated with Systemic Medications
`
`79
`
`Table II. Contd
`
`Medication
`Sildenafil
`
`Tamoxifen
`
`COX-2 inhibitors
`
`Nicotinic acid
`
`Certain
`Changes in colour perception
`coloured tinge
`decreased colour vision
`dark colours appear darker
`Blurred vision
`central haze
`transitory decreased vision
`Changes in light perception
`increased perception of brightness
`flashing lights, especially when blinking
`ERG changes
`Conjunctival hyperaemia
`Ocular pain
`Photophobia
`Corneal opacities
`Retinal opacities, degeneration, pigmentary
`changes, haemorrhage
`Loss of visual acuity
`Conjunctivitis
`Blurred vision
`No effects
`
`Canthaxanthine
`Chamomile
`Datura
`Echinacea purpurea
`Ginkgo biloba
`
`Crystalline retinopathy
`Allergic conjunctivitis
`Mydriasis
`No effects
`No effects
`
`Liquorice
`
`No effects
`
`Vitamin A
`
`Intracranial hypertension (when taken in
`large doses)
`COX = cyclo-oxygenase; ERG = electroretinogram.
`
`and inability to explain the adverse effect by concur-
`rent disease or other drugs or chemicals. Dechal-
`lenge data are necessary and rechallenge should be
`positive. ‘Probable’ is the same as ‘certain’ without
`positive rechallenge data. ‘Possible’ is an adverse
`event in a reasonable time sequence to administra-
`tion of the drug, but could also be explained by
`concurrent disease or other drugs or chemicals. Pos-
`itive dechallenge data are lacking or unclear in this
`category (table I).
`
`Probable
`No effects
`
`Possible
`Mydriasis (emotional effect?)
`Retinal vascular accidents
`(secondary to exertion?)
`Subconjunctival haemorrhage
`Anterior ischaemic optic
`neuropathy
`
`No effects
`
`No effects
`
`No effects
`
`No effects
`
`Cystoid macular oedema
`
`No effects
`No effects
`No effects
`Conjunctivitis
`No effects
`
`No effects
`
`No effects
`
`Decreased vision, dry eyes,
`discoloration of the eyelids,
`eyelid oedema,
`Proptosis
`Loss of eyebrows and eyelashes,
`and superficial punctate keratitis
`No effects
`No effects
`No effects
`No effects
`Spontaneous hyphema
`Retinal haemorrhage
`Vasospasm, visual loss
`associated with migraine-like
`symptoms
`No effects
`
`2. Medications and Adverse Effects
`
`2.1 Bisphosphonates
`
`Bisphosphonates inhibit bone resorption by bind-
`ing to hydroxyapatite crystals and inhibiting their
`dissolution.[7] Different bisphosphonates vary great-
`ly in their efficacy and their adverse-effect profiles
`depending on the structure of the individual drug.
`These medications are associated with ocular ad-
`verse effects that are mainly inflammatory, i.e. con-
`junctivitis, uveitis and episcleritis.[8,9] Recent studies
`
`© 2007 Adis Data Information BV. All rights reserved.
`
`Drugs 2007; 67 (1)
`
`Novartis Exhibit 2296.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`80
`
`Santaella & Fraunfelder
`
`have proved that pamidronate can cause scleri-
`tis.[10,11]
`Pamidronate disodium, an intravenous bisphos-
`phate, has been reported to cause anterior uveitis and
`nonspecific conjunctivitis.[9-12] Its most striking as-
`sociation is that of being the first medication report-
`ed to cause scleritis.[10] Case reports have also asso-
`ciated pamidronate with episcleritis,[13] nerve pal-
`sy,[14] ptosis[14] and retrobulbar neuritis[15] (table II).
`Pamidronate bears a ‘certain’ relationship to uve-
`itis, conjunctivitis, episcleritis and scleritis when
`taken at standard doses between 30 and 90mg intra-
`venously. The onset of ocular signs and symptoms
`was usually noted within 48 hours.
`Alendronate is an oral bisphosphonate widely
`prescribed for the treatment and prevention of osteo-
`porosis, in particular postmenopausal osteoporosis,
`and for the treatment of Paget’s disease of the
`bone.[16] This bisphosphonate has been associated
`with a ‘certain’ relationship to blurred vision, ocular
`pain, conjunctivitis, uveitis and scleritis when taken
`in dosages ranging from 5 to 40mg daily (table II).
`Onset of ocular signs and symptoms was noted an
`average of 2 days to 2 weeks (range 1 day to 1 year)
`after starting therapy[11] (table II).
`Risedronate is taken orally and is indicated in the
`treatment of Paget’s disease of the bone.[16] The data
`are not sufficiently complete to classify any ocular
`adverse effect as ‘certain’. However, there are posi-
`tive rechallenge data on a single report of scleritis
`associated with this medication, which indicates
`there could be a cause and effect relationship.[10]
`Etidronate is an oral medication indicated in the
`treatment of symptomatic Paget’s disease, or for
`heterotopic ossification in hip replacement and spi-
`nal cord injury patients. This medication has been
`associated with conjunctivitis and blurred vision[11]
`(table II).
`Clodronate is used in Europe and Canada for
`tumour-induced bone disease.[7] It has not been ap-
`proved by the US FDA. This medication is also used
`by some to prolong survival in breast cancer pa-
`tients. Although some studies indicate there are few-
`er metastases with clodronate therapy, there is no
`evidence of prolonged survival in patients taking
`
`clodronate.[17] Reports of clodronate-induced uveitis
`have a ‘probable’ association and blurred vision is
`classified as having a ‘possible’ association[18] (table
`II).
`Pamidronate is the first medication ever reported
`to cause scleritis. Bisphosphonates are high molecu-
`lar weight drugs that have been described as poten-
`tially causing immune complex formation and pos-
`sibly being secreted by the lacrimal gland, thus
`causing transient irritation to mucus membranes.[3]
`Pamidronate stimulates the production of a distinct
`subgroup of T cells to inhibit bone resorption. As
`analogues of pyrophosphate, they can activate re-
`ceptors in T cells leading to cytokine release.[18,19]
`This may contribute to an immunological reaction in
`patients who develop uveitis and/or scleritis. Some
`authors have contended that the nitrogen-containing
`bisphosphonates (alendronate, pamidronate, rise-
`dronate) are more likely to cause uveitis.[20-23] Nitro-
`gen-containing bisphosphonates are known to cause
`transient pyrexia, a flu-like syndrome and serologi-
`cal changes resembling a typical acute phase re-
`sponse.[3,18,19] The cytokines released with this acute
`phase response could act as adjuvants in an immune
`reaction with the uvea of the eye as the target organ.
`However, a non-nitrogen-containing bisphospho-
`nate, clodronate, has also been reported as inducing
`uveitis.[18] Still, there are many more reports of
`uveitis associated with nitrogen-containing bisphos-
`phonates than there are for the bisphosphonates that
`do not contain nitrogen (etidronate, clodronate,
`tiludronate).
`In summary, bisphosphonates are associated with
`ocular inflammation. Ocular pain, photophobia,
`blurred vision, periorbital changes and glaucoma
`can be due to uveitis, scleritis and other types of
`ocular inflammation. Ocular inflammation, espe-
`cially scleritis and uveitis, is of the greatest concern
`in the eye care of patients taking bisphosphonates.
`Scleritis causes a severe deep eye pain, and can lead
`to structural damage of the globe and loss of vision.
`Patients typically present with a piercing ocular pain
`that is worse at night and awakens them from sleep.
`The sclera assumes a violaceous hue in natural sun-
`light and scleral vessels become inflamed and can
`
`© 2007 Adis Data Information BV. All rights reserved.
`
`Drugs 2007; 67 (1)
`
`Novartis Exhibit 2296.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Ocular Adverse Effects Associated with Systemic Medications
`
`81
`
`2.2 Antiepileptic Drugs
`
`the drug may need to be discontinued for uveitis to
`resolve. Episcleritis may require topical ocular med-
`ication; however, the bisphosphonate may be con-
`tinued. In all patients studied by Fraunfelder et
`al.,[11] the bisphosphonate had to be discontinued for
`the scleritis to resolve, even on full medical therapy.
`
`have a crisscross pattern. Scleral oedema develops
`acutely and scleral thinning can occur, along with
`vision loss, if necrotising scleritis persists or inflam-
`mation is left unchecked. Ocular complications from
`scleritis can include keratitis, cataract, uveitis and
`glaucoma.[12,24]
`In uveitis associated with bisphosphonate ther-
`apy, the early symptoms may be mild or severe,
`depending on which part of the uvea is affected and
`2.2.1 Topiramate
`on the amount of inflammation. Anterior uveitis
`Topiramate, a sulfamate-substituted monosac-
`usually has the most dramatic symptoms, typically
`charide, is structurally unrelated to any other
`presenting with severe pain in the eye, redness of the
`antiepileptic drug (AED). This AED is also used in
`conjunctiva, sensitivity to bright light and a decrease
`the management of migraine, depression and neuro-
`in vision. The examiner may see prominent blood
`pathic pain. Off label, it has gained popularity as a
`vessels on the conjunctiva near the edge of the iris,
`weight reduction agent, to treat migraine headaches
`white blood cells floating in the aqueous humour
`and to treat bipolar disorder.
`and deposits of white blood cells on the inside
`Topiramate has been associated with acute angle-
`surface of the cornea. Intermediate uveitis is typical-
`closure glaucoma. Findings associated with topira-
`ly painless. Vision may be decreased and the patient
`mate-associated acute, bilateral, secondary angle-
`may see floaters (irregular floating black spots).
`closure glaucoma syndrome include blurred vision,
`Posterior uveitis typically produces decreased vision
`conjunctival hyperaemia, corneal oedema, shallow
`with or without floaters. There may also be retinal
`anterior chamber, cataracts, pupil changes, elevated
`detachment and inflammation of the optic nerve
`intraocular pressure, visual field defects and blind-
`(symptoms include loss of vision, which may vary
`ness. Topiramate has also been associated with
`from a small blind spot to total blindness). Diffuse
`causing bilateral myopia, bilateral suprachoroidal
`uveitis may produce any or all of these symptoms.
`effusions, blepharospasm, myokymia, nystagmus
`Uveitis can rapidly damage the eye and can produce
`and diplopia. Scleritis has also been reported.[25]
`long-term, vision-threatening complications, such as
`Topiramate-associated visual adverse effects and
`swelling of the macula, glaucoma and cataracts.
`their WHO classifications are listed in table II. The
`Those affected may have only one episode or peri-
`entity described as topiramate-associated acute, bi-
`odic recurrences over months to years.
`lateral, secondary angle-closure glaucoma[26,27] can
`Suggestions for treatment of bisphosphonate-in-
`present in the same manner as an acute angle closure
`duced ocular adverse effects are as follows. If there
`glaucoma attack. All the findings of acute glaucoma,
`is a persistent decrease in vision or if ocular pain
`such as ocular pain, headache, nausea and vomiting,
`occurs, examination by an ophthalmologist is neces-
`pupillary changes, hyperaemia, corneal oedema,
`sary. Nonspecific conjunctivitis seldom requires
`cataracts, retinal and vascular accidents, visual field
`treatment and usually decreases in intensity or may
`defects and blindness have been reported.[25] In most
`be absent on subsequent treatments. In rare in-
`patients, this is a bilateral process. If not recognised
`stances, a nonsteroidal anti-inflammatory eye drop
`as a drug-related event, this condition can easily be
`may be needed. More than one ocular adverse effect
`confused with acute, pupillary block, narrow angle
`can occur at the same time, i.e. episcleritis with
`glaucoma for which a peripheral iridectomy is indi-
`uveitis. Bilateral anterior uveitis or, rarely, posterior
`cated. However, if the drug is stopped and medical
`or bilateral uveitis may occur and can vary markedly management instituted, pressure may return to nor-
`in severity. Many patients require intensive topical mal in hours to days without the need for an iridecto-
`ocular or systemic medication. In some instances, my. The acute pressure elevation usually occurs
`
`© 2007 Adis Data Information BV. All rights reserved.
`
`Drugs 2007; 67 (1)
`
`Novartis Exhibit 2296.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`82
`
`Santaella & Fraunfelder
`
`the last decade, the marked efficacy of this medica-
`within the first 2 weeks after starting topiramate
`therapy, but it has been reported within hours after
`tion and its low toxic effects prompted widespread
`doubling the dose. If pressure elevation goes un-
`use in Europe. The manufacturers of vigabatrin
`treated, serious outcomes are possible, including
`(Hoechst Marion Roussel) had received 28 reports
`blindness.
`of visual field abnormalities worldwide by January
`1997 in an estimated 140 000 patients treated.[38]
`Acute myopia up to 8.75 diopters may occur in a
`matter of hours after starting topiramate use, but
`This information appears to have not been released
`may take weeks to fully resolve on or off medica-
`during that time. Since 1997, numerous reports have
`tion. Sulfa-containing medications, such as topira-
`appeared of visual field abnormalities in adults and
`mate, are known to cause transient myopia. Lenticu-
`children treated with this AED. In most documented
`lar swelling, forward rotation of the lens-iris dia-
`cases, the visual field defect seems to be a specific,
`phragm, ciliary body swelling causing increased
`bilateral, symmetrical and irreversible peripheral
`curvature of the lens surfaces, and spasm of accom-
`constriction.[38-40] The fact that most patients are
`modation have all been proposed as the mechanism asymptomatic with normal visual acuity may have
`behind this occurrence.[3,25,28-31]
`contributed to the late recognition of these visual
`field defects that apparently occur in more than 30%
`The management of topiramate-related acute
`of patients but were initially estimated to affect
`pressure elevation requires stopping the drug in con-
`fewer than 0.1%.[41-44]
`sultation with the prescribing physician, since de-
`creasing the dosage as little as 50mg may exacerbate
`The site of toxicity is proposed to be the retina,
`pre-existing systemic conditions. Instituting maxi- where GABA is an important modulatory neuro-
`mal medical therapy, including oral and topical
`transmitter. Vigabatrin increases GABA levels by
`aqueous suppressants, is indicated. Laser iridotomy
`inhibiting the GABA transaminase enzyme. GABA
`or peripheral iridectomy may not be beneficial if the
`is an inhibitory neurotransmitter in bipolar cells and
`glaucoma is only associated with topiramate ther-
`some amacrine cells and may have a role in the
`apy, but would be considered adequate in the setting modulation of phototransduction from the retinal
`of angle closure if one is not certain that it is
`photoreceptor cells to the ganglion cells.[45] System-
`completely medication-induced. Topical miotics are
`ic vigabatrin has been shown to cross the blood-
`probably contraindicated, as these could precipitate
`retinal barrier and can be detected immuno-
`a relative pupillary block that would exacerbate the
`cytochemically in the retina.[46] Vigabatrin causes
`condition.
`white matter microvacuolation and intramyelinic
`oedema in the brains of rodents and dogs but not in
`monkeys and humans.[47] It also has been shown to
`cause accumulation of GABA in the retinal Muller
`cells.[48] How an increase in retinal GABA levels
`may produce visual field constriction is not clear,
`but the lower density of ganglion cells in the periph-
`eral retina or a toxic effect on the retinal Muller cells
`has been suggested as being possibly related.[49]
`Thus far, the understanding of the role played by
`GABA in retinal transmission is not sufficient to
`allow for a mechanistic explanation of the adverse
`effects of vigabatrin.
`There is no consensus regarding screening visual
`field examinations for patients taking vigabatrin.[49]
`The incidence, higher than previously estimated, of
`
`2.2.2 Vigabatrin and Tiagabine
`Vigabatrin is a selective, enzyme-activated, irre-
`versible GABA aminotransferase inhibitor.[32] It is a
`custom-made AED that is particularly useful in the
`management of drug-resistant partial seizures and
`infantile spasms, especially those secondary to tu-
`berous sclerosis.[33-36] The antiepileptic effect is pre-
`sumably mediated by elevation of GABA levels of
`the brain caused by inhibition of GABA metabo-
`lism.[36]
`Initially, only relatively minor adverse effects
`were attributed to vigabatrin use.[37] It was first
`introduced into clinical practice in the UK on a trial
`basis in the mid 1980s and granted licence in 1989.
`The FDA has not approved its use in the US. Over
`
`© 2007 Adis Data Information BV. All rights reserved.
`
`Drugs 2007; 67 (1)
`
`Novartis Exhibit 2296.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Ocular Adverse Effects Associated with Systemic Medications
`
`83
`
`acitretin and etretinate have been reported as having
`this complication, particularly in asymptomatic pa-
`a ‘probable’ causal relationship to IH.[59]
`tients, suggests that screening visual field examina-
`tions may be necessary. Daneshvar et al.[49] have
`The mechanism of how retinoids cause IH has
`recommended visual field examinations covering
`been postulated as being through a common path-
`the peripheral 60° of the visual field for all patients way.[61] It is possible that high doses of this class of
`taking vigabatrin, before or soon a