Eye (2002) 16, 132-135
`© 2002 Nature Publishing Group All rights reserved 0950-222X/02 $25.00
`
`www.nature.com/eye
`
`P Watts & N Hawksworth
`
`Delayed
`
`hypersensitivity to
`
`brimonidine tartrate
`
`0.2 % associated with
`high intraocular
`pressure
`
`Abstract
`
`IOP. Though this is a small cohort of
`patients, it is not unreasonable to suggest
`that patients on brimonidine eye drops
`should be instructed to report promptly to
`their ophthalmologist the onset of redness of
`their eyes so that their glaucoma control may
`be reassessed.
`Eye (2002) 16, 132-135. DOI: 10.1038/
`
`
`sj/EYE/ 6700053
`
`Keywords: allergy; brimonidine; intraocular
`
`
`
`pressure
`
`Introduction
`
`Department of
`Ophthalmology
`East Glamorgan General
`Hospital
`Church Village
`Mid Glamorgan CF 38 1 AB
`South Wales, UK
`
`Correspondence:
`P Watts
`49 St Agatha Road
`Cardiff CF14 4EA
`South Wales, UK
`Tel: 029 20620591
`Fax: 029 20610746
`E-mail: patrickowatts@
`hotmail.com
`
`Received: 18 June 2001
`Accepted: 21 September
`2001
`
`
`
`Purpose To report the late presentation of
`an allergic reaction to brimonidine tartrate
`0.2% associated with an elevation of
`intraocular pressure.
`Methods During a 6-month period six
`Caucasian patients (three were male), with
`primary open angle glaucoma (POAG) or
`ocular hypertension, with an allergic reaction
`to brimonidine tartrate eye drops were
`identified. Brimonidine was initiated as
`additional medical therapy in four patients
`and monotherapy in two patients. The
`median age of the patients was 67 years
`(range 57-73 years).
`Results There were nine eyes with a
`Brimonidine tartrate is a highly selective alpha
`
`
`
`follicular conjunctivitis; three patients
`
`2 adrenoreceptor agonist.
`
`
`1 Clinical trials have
`received brimonidine in one eye only. In two
`
`proved it to be an effective drug for treating
`patients an additional redness of the
`
`
`chronically elevated IOP and the prophylactic
`periocular skin was present. The median
`2 Its
`
`
`treatment of acute pressure rises.
`duration on brimonidine therapy before the
`
`
`
`
`hypotensive action is primarily attributed to
`onset of the allergic reaction was 12 months
`
`
`aqueous suppression, though an uveoscleral
`(range 5-15 months). The median intraocular
`
`outflow has also been suggested.3 Its long­
`pressure (IOP) before the onset of the allergy
`
`
`
`term efficacy in lowering intraocular pressure
`was 18 mmHg (range 16-21 mmHg). There
`
`
`is comparable to that of timolol eye drops4 but
`was a significant elevation of IOP at the time
`
`of the allergy with a median IOP of
`
`
`without the adverse cardiopulmonary side
`
`
`effects associated with the latter.
`5 Brimonidine
`
`28 mmHg (range 20-44 mmHg) (P = 0.007,
`
`is increasingly being used as a first line drug
`
`
`
`Wilcoxon sign rank test). The cessation of
`
`
`
`brimonidine allowed the resolution of the
`
`
`in primary open angle glaucoma,6 especially
`
`
`
`allergic reaction. The intraocular pressure
`
`when beta-blockers are contraindicated.
`
`
`
`
`Topical therapy with brimonidine tartrate is
`
`was then controlled with alternative
`
`
`medication in eight eyes. One patient went
`
`
`well tolerated; its adverse events are reported
`2 These
`
`on to have filtering surgery.
`
`to be mild to moderate in nature.
`Conclusions A delayed hypersensitivity
`dry ness of the mouth, fatigue­
`include
`
`
`drowsiness, headache and an allergic
`
`
`
`reaction to brimonidine tartrate eye drops
`
`
`
`resembles a viral follicular conjunctivitis. It
`
`
`
`reaction.4 Apart from ocular allergy the above
`
`
`adverse events are not statistically different
`
`
`is imperative that it is recognised as such, as
`it may occur many months after brimonidine
`
`from those patents on beta blockers.
`
`
`Ocular allergy associated with conjunctiva!
`
`
`is initiated. This allergy has been found to
`
`
`be associated with a loss of control of the
`
`
`
`follicles occurs in 4.8-9% of patients on
`
`4
`
`•7
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`Brimonidine tartrate treatment for high IOL
`P Watts and N Hawksworth
`
`133
`
`brimonidine tartrate and up to 15% of patients
`may discontinue the drug due to an allergic reaction.4
`'
`This allergic reaction has been reported to occur within
`the first 6--9 months.
`We report the late presentation of ocular allergy with
`the use of brimonidine tartrate associated with an
`elevated intraocular pressure in six patients.
`
`8
`
`Patients and methods
`
`During a 6-month period six patients with an allergic
`reaction to brimonidine tartrate were identified. Five
`patents had POAG and one had ocular hypertension.
`Three patients presented acutely before their next
`follow-up appointment and three patients were seen at
`their routine follow-up appointment. The patients who
`presented acutely were treated with brimonidine in
`one eye only and had a unilateral allergic response.
`Patients reviewed at their routine follow-up had a
`bilateral allergic reaction to brimonidine instilled in
`both eyes. The median age of the patients was 67 years
`(range 57-73 years). There were three male and three
`female patients with a diagnosis of primary open angle
`glaucoma (POAG). Brimonidine tartrate 0.2%
`(Alphagan) twice a day was used as monotherapy in
`two patients. It was used in addition to betaxolol 0.5%
`twice a day in three patients and in addition to
`betaxolol 0.5% twice a day with dorzolamide 2% twice
`a day in one patient. Visual fields were performed
`with a Humphrey Field Analyser, program 24-2.
`
`Results
`
`The allergic reaction consisted of a follicular
`conjunctivitis, which was unilateral in three patients
`who instilled brimonidine in one eye only. Three
`patients had an additional swelling and redness of the
`periocular skin. The median IOP, before brimonidine
`was started, in the eyes that developed an allergic
`reaction was 28 mmHg (range 23-30 mmHg). The
`median IOP of the eyes while on brimonidine before
`the development of the allergic reaction was 18 mmHg
`(range 16-21 mmHg). The median IOP in the eyes
`(nine eyes) at the time of the allergic reaction was
`28 mmHg (range 20-44 mmHg). This difference was
`statistically significant (P = 0.007, Wilcoxon sign rank
`test). All the patients had continued to use all their
`ocular hypotensive medication, including brimonidine,
`until the diagnosis of the allergic reaction was
`established (Table 1).
`When brimonidine was stopped, the intraocular
`pressure was controlled with a combination of
`betaxolol 0.5% twice a day, latanoprost 0.005% once a
`day in two patients, latanoprost 0.005% alone in one
`
`Table 1 Details of patients with an elevation of IOP associated
`to brimonidine
`with a delayed hypersensitivity
`tartrate
`(M = male, F = female)
`
`Case Age/Sex
`
`Eye Duration on IOP before
`involved brimonidine
`the onset
`of allergy
`
`IOP at the
`time of
`allergy
`
`1
`2
`3
`4
`
`5
`
`6
`
`62 M
`68 M
`71 F
`57 F
`
`73 M
`
`66 F
`
`R 8 months
`17mmHg 28mmHg
`18mmHg
`44mmHg
`R 15 months
`L 12 months 20mmHg 28mmHg
`32mmHg
`R 12 months 21 mmHg
`L 12 months 20mmHg 28mmHg
`18mmHg
`41 mmHg
`R 5 months
`30mmHg
`18mmHg
`L 5 months
`16mmHg 24mmHg
`R 12 months
`16mmHg 20mmHg
`L 12 months
`
`patient, dorzolamide 2% three times a day in one
`patient and betaxolol 0.5% and dorzolamide 2% twice
`a day in one patient. One patient had a trabeculectomy
`due to failure of control of IOP with alternative
`medical therapy. The allergic reaction resolved within
`a week of cessation of brimonidine eye drops. Three
`representative cases are presented.
`
`Case 2
`
`A 68-year-old Caucasian male was referred from his
`optician with high IOP. His visual acuity was 6/6 with
`an IOP of 30 mmHg in his right and left eye. He had
`open angles on gonioscopy. He had a CDR of 0.8 on
`the right and 0.9 on the left with a left relative afferent
`pupillary defect. He was started on brimonidine in
`both eyes. His left eye underwent a trabeculectomy as
`a target IOP was not achieved with medical therapy.
`The intraocular pressure was controlled with
`brimonidine in the right eye with an average IOP of
`18 mmHg and stable visual fields. His left eye was on
`no medication with an IOP of 18 mmHg and a
`functioning filtering bleb. He presented 15 months later
`with a 2-week history of an acute red right eye. On
`examination his right eye had a follicular conjunctivitis
`(Figure 1) with an IOP of 44 mmHg in his right eye
`and 18 mmHg in his left eye with quiet anterior
`chambers. The follicular conjunctivitis resolved within
`a week of cessation of brimonidine eye drops. The IOP
`was subsequently controlled in the right eye with
`betaxolol 0.5% twice a day and latanoprost 0.005%
`once a day.
`
`Case 3
`
`A 71-year-old Caucasian female was referred to the eye
`clinic from her optician with a high IOP in her left eye.
`On examination her visual acuity was 6/5 in the right
`
`Eye
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`134
`
`Brimonidine tartrate treatment for high IOL
`P Watts and N Hawksworth
`
`and left eye respectively. Brimonidine eye drops were
`started, which brought the IOP down to 16 rnrnHg in
`both eyes. At a routine follow-up appointment 12
`months from the initiation of the above drops, she had
`a redness of the periocular skin (Figure 2) with a
`bilateral follicular conjunctivitis. She volunteered that
`her eyes had been red over the preceding 2 months
`and that there had been no response to the sodium
`fusidate prescribed by the general practitioner. Her
`IOP measured 24 mmHg in the right eye and
`20 mmHg in the left eye. The anterior chambers were
`quiet. The follicular conjunctivitis resolved a week after
`the brimonidine eye drops were stopped. Her IOP was
`controlled with dorzolamide eye drops three times a
`day.
`
`Figure 1 Case 2: Allergic follicular conjunctivitis in the right
`
`
`
`
`
`
`eye. Duration on brimonidine tartrate before the onset of the
`Discussion
`
`
`allergic reaction: 15 months. IOP prior to onset of allergy
`
`18 mmHg and 44 mmHg at the time of allergic reaction.
`Six patients developed an allergic reaction to
`brimonidine tartrate 0.2% eye drops instilled twice a
`day, this consisted of a follicular conjunctivitis and a
`swelling and redness of the periocular skin. The
`patients were diagnosed as having an infective
`conjunctivitis by their general practitioners and were
`treated with antibacterial drugs. When there was no
`response to treatment they were referred to the eye
`department. Hence there was a delay, which ranged
`from 2 to 8 weeks (median 6 weeks) before a diagnosis
`of an allergic conjunctivitis was established. This
`delayed hypersensitivity response occurred up to 15
`months (range 5-15 months, median 12 months) after
`the drops were started. At the time of the allergic
`reaction while the patients were still using the drops,
`the IOP was found to be significantly elevated with a
`
`eye and 6/6 in the left eye. Her IOP was 20 mmHg in
`the right eye and 30 mmHg in the left eye, with wide­
`open angles on gonioscopy. The right eye had a CDR
`of 0.1 and the left a CDR of 0.8 with a normal right
`visual field. The IOP was controlled with tirnolol 0.25%
`and dipivefrin 0.1 % twice a day in her left eye. This
`was substituted with brimonidine as the patient
`experienced breathlessness on the above medication.
`The IOP was an average of 16 mmHg on brirnonidine
`eye drops.
`In between her routine 6-monthly appointments she
`visited her general practitioner with an acute redness
`of her left eye, this was treated with sodium fusidate,
`however when the redness failed to resolve she was
`referred to the eye clinic 4 weeks later. On examination
`she had a puffy left lower lid with a follicular
`conjunctivitis. The IOP was 28 mmHg with a quiet
`anterior chamber. The conjunctivitis resolved with the
`cessation of brirnonidine. The intraocular pressure was
`26 mmHg and she was rechallenged with brimonidine
`when the allergy recurred with an elevated intraocular
`pressure of 30 mmHg. The left eye underwent a
`trabeculectomy and achieved good IOP control with a
`functioning filtering bleb at 3 months follow-up.
`
`Case 6
`
`A 66-year-old female was referred to the eye clinic
`from her optician with high IOP. She had chronic
`obstructive airways disease. Her visual acuity was 6/ 6
`in her right and left eye, with presenting IOP of
`30 mmHg in the right eye and 28 rnrnHg in the left
`eye, the anterior chamber angles were wide open
`gonioscopy. She had a 0.5 and 0.3 CDR in the right
`
`Eye
`
`Figure 2 Case 6: Skin erythema, especially below the medial
`
`
`
`
`
`and lateral ends of the lower lid. Duration on brimonidine tar­
`
`
`
`trate before the onset of the allergic reaction: 12 months. IOP
`
`prior to onset of allergy 12 mmHg (R) 16 mmHg (L), and
`
`24 mmHg (R) 20 mmHg (L) at the time of the allergic reaction.
`
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`

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`Brimonidine tartrate treatment for high IOL
`P Watts and N Hawksworth
`
`135
`
`allergic reaction will develop a high IOP. A
`prospective study is now underway to identify all
`patients with a delayed hypersensitivity to brimonidine
`tartrate eye drops who may also have a high IOP.
`
`Conclusions
`
`An allergic reaction to brimonidine tartrate 0.2% eye
`drops resembles a viral conjunctivitis (without corneal
`involvement) and may delayed up to 15 months after
`treatment is started. This may be associated with a
`high IOP. It is imperative therefore that an allergic
`reaction to the drug is recognised promptly and the
`IOP is assessed. Failure to do so may allow an
`uncontrolled IOP to jeopardise an already
`compromised optic disc.
`
`References
`
`1 Burke J, Schwartz M. Preclinical evaluation of
`
`
`
`
`
`1): S9-S18. brimonidine. Surv Ophthalmol 1996; 41 (suppl
`
`
`
`
`2 Walters TR. Development and use of brimonidine in
`
`
`
`
`treating acute and chronic elevations of intraocular
`
`
`
`
`pressure: a review of safety, efficacy, dose response, and
`
`
`
`1): S19-dosing studies. Surv Ophthalmol 1996; 41 (Suppl
`S26.
`3 Toris CB, Gleason ML, Camras CB. Effects of brimonidine
`
`
`
`
`on aqueous humour dynamics in human eyes. Arch
`
`Ophthalmol 1995; 113: 1514-1517.
`
`
`4 LeBlanc RP, for the Brimonidine Study Group 2. Twelve­
`
`
`
`month results of an ongoing randomized trial comparing
`
`
`
`brimonidine tartrate 0.2% and timolol 0.5% given twice
`
`
`
`daily in patients with glaucoma or ocular hypertension.
`Ophthalmology 1998; 105: 1960-1967.
`
`
`5 Stewart WC, Garrison PM. B-Blocker-induced
`
`
`complications and the patient with glaucoma. Newer
`
`
`
`treatments to help reduce systemic adverse events.
`Arch
`Intern Med 1998; 158: 221-226.
`
`6 Wilensky JT. The role of brimonidine in the treatment of
`
`
`
`1): open angle glaucoma. Surv Ophthalmol 1996; 41 (Suppl
`
`
`
`S3-S7.
`7 Serie JB and the Brimonidine Study Group III. A
`
`
`
`
`
`comparison of the safety and efficacy of twice daily
`
`
`
`brimonidine 0.2% versus betaxolol 0.25% in subjects with
`
`
`
`elevated intraocular pressure. Surv Ophthalmol 1996;
`41
`(Suppl 1): S39-S47.
`8 Schuman JS, Horwitz B, Choplin NT, David R, Albracht
`
`
`
`D, Chen K and the Chronic Brimonidine Study Group. A
`
`
`1-year study of brimonidine twice daily in glaucoma
`and
`
`
`
`ocular hypertension. Arch Ophthalmol 1997; 115: 847-852.
`
`median of pressure of 28 mmHg (range 20--44 mmHg)
`(P = 0.007).
`The allergic reaction resembles a viral conjunctivitis
`without corneal involvement; hence a high index of
`suspicion should be entertained when a patient with
`glaucoma on brimonidine presents with a follicular
`conjunctivitis. The patients with an allergic reaction do
`not develop a keratitis as seen with viral disease. It has
`been reported that this allergic reaction which occurs
`in 4.8--9% of patients on brimonidine eye drops is
`usually seen within the first 9 months.4
`8 In our series
`•
`of patients a much later presentation was seen in four
`of the six patients. This may be due to the fact that the
`studies reporting the delayed hypersensitivity reaction
`were followed up for 12 months.4
` It is possible that
`with a longer duration of follow-up we may uncover
`more cases developing an allergic reaction to
`brimonidine.
`The fact that the allergic response may be associated
`with an elevated IOP or loss of a previously controlled
`IOP is of more serious consequence. The median IOP
`elevation was 28 mmHg, with two patients with an
`IOP above 40 mmHg. Patients with an allergic reaction
`may wait till their next appointment before advice is
`sought, and this may jeopardise an already
`compromised optic disc. We are unaware of previous
`studies reporting this association.
`The mechanism of pressure elevation may simply
`represent a failure of the ocular hypotensive effect with
`the onset of the allergic reaction, however this will not
`account for the IOP being higher than the presenting
`IOP. There was no evidence of an iritis at the time of
`the allergic reaction; hence a hypertensive uveitis is
`discounted. None of the patients received steroids as
`part of the treatment of the conjunctivitis, which would
`eliminate a steroid related elevated intraocular
`pressure. The possibility of an increased episcleral
`pressure associated with the vascular congestion is a
`plausible explanation, which is supported by the fact
`that the IOP is controlled with alternative medication
`when the conjunctivitis resolves without the use of
`topical steroids.
`This study suffers from the small number of patients
`presented. It is not known how many patients with an
`
`•8
`•7
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`Eye
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