Expert Opinion on Drug Metabolism & Toxicology
`
`ISSN: 1742-5255 (Print) 1744-7607 (Online) Journal homepage: http://www.tandfonline.com/loi/iemt20
`
`Olopatadine 0.2% ophthalmic solution: the first
`ophthalmic antiallergy agent with once-daily
`dosing
`
`Mark B Abelson & Paul J Gomes
`
`To cite this article: Mark B Abelson & Paul J Gomes (2008) Olopatadine 0.2% ophthalmic solution:
`the first ophthalmic antiallergy agent with once-daily dosing, Expert Opinion on Drug Metabolism &
`Toxicology, 4:4, 453-461, DOI: 10.1517/17425255.4.4.453
`To link to this article: https://doi.org/10.1517/17425255.4.4.453
`
`Published online: 23 Apr 2008.
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`
`IPR2018-01020 and IPR2018-01021, Exhibit 108, Page 1
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`

`

`1.
`
`Introduction
`
`2. Overview of market
`
`3. Chemistry
`
`4. Ocular allergy: pathophysiology
`
`5. Pharmacology of olopatadine
`
`6. The conjunctival allergen
`challenge model in
`olopatadine studies
`
`7. Clinical effi cacy of olopatadine
`hydrochloride 0.1%
`ophthalmic solution
`
`8.
`
`Increased concentration
`of olopatadine
`
`9. Tolerability and safety
`
`10. Regulatory affairs
`
`11. Conclusion
`
`12. Expert opinion
`
`Drug Evaluation
`
` Olopatadine 0.2% ophthalmic
`solution: the fi rst ophthalmic
`antiallergy agent with
`once-daily dosing
` Mark B Abelson † & Paul J Gomes
` Schepens Eye Research Institute, Boston, Massachusetts, USA
`
`topical ophthalmic
`first
`the
`is
` Background : Olopatadine 0.2%
`antihistamine/mast cell stabilizer indicated for once-daily dosing. Objective :
`This review provides a comprehensive description of the pharmacology
`of the olopatadine molecule, as well as of the clinical efficacy, tolerability,
`and safety of olopatadine 0.2% ophthalmic solution. Methods : References
`cited
`in this review were obtained from the PubMed biomedical
`literature database. Also included were several posters presented at
`nationally renowned ophthalmology-related conferences. Results/conclusion :
`Olopatadine 0.2% was found to be a safe and effective medication for
`the reduction of itching with a duration of action of up to 24 h. The added
`convenience of a once-a-day dosing regimen is a major advancement in this
`drug class.
`
` Keywords: antiallergy , antihistamine , olopatadine , ophthalmic
`
`Expert Opin. Drug Metab. Toxicol. (2008) 4(4):453-461
`
` 1. Introduction
` Approximately 20% of Americans have ocular allergies [1] , and this prevalence is
`increasing worldwide [2] . The most common forms of ocular allergy include acute
`seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC),
`in which the primary sign and symptom is redness and itching, respectively.
`Rhinoconjunctivitis involves the manifestation of both ocular and nasal allergy
`symptoms. Ocular allergies can have a negative impact on sufferers, due to
`intense bouts of ocular itching and effects on their appearance (red and puffy
`eyes). Patients seek potent medications that will alleviate their allergies in a
`rapid, effective, and comfortable manner [3] . Olopatadine is the most commonly
`prescribed topical antihistamine/mast cell stabilizer, and provides relief from SAC
`and PAC. Multitudes of patients have used olopatadine, supporting its strong
`safety and efficacy profile, which spans more than a decade. Olopatadine 0.1%
`ophthalmic solution was developed for twice-daily dosing, and is indicated for
`the treatment of the signs and symptoms of allergic conjunctivitis. A new
`formulation – olopatadine 0.2% ophthalmic solution – has been recently
`developed and marketed. The double-strength formulation allows for once-a-day
`dosing and a duration of action of up to 24 h. As olopatadine 0.2% is
`relatively new to the ocular allergy market, a review of the pharmacology, clinical
`studies, and therapeutic use of the drug is warranted to highlight its efficacy,
`tolerability, and safety.
`
`
`
`10.1517/17425255.4.4.453 © 2008 Informa UK Ltd ISSN 1742-5255
`
`453
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`Olopatadine
`
` 2. Overview of market
`
` First-generation topical antihistamines include antazoline
`and pheniramine, which have been
`formulated with
`naphazoline, a vasoconstrictor that reduces redness. These
`over-the-counter (OTC) medications are available for q.i.d.
`dosing. The presently available mast cell stabilizers include
`nedocromil
`sodium and pemirolast, which are both
`indicated for
`itching due to ocular allergies. Topical
`antihistamine/mast cell stabilizers comprise of olopatadine,
`ketotifen, epinastine, and azelastine. Ketotifen has recently
`been introduced to the OTC market as the first non-
`prescription
`topical
`antihistamine/mast
`cell
`stabilizer.
`Olopatadine 0.1% is indicated for signs and symptoms of
`allergic conjunctivitis, whereas the other members of this
`drug class are indicated for itching only. Olopatadine 0.2%
`is
`the
`first
`topical antiallergy agent approved
`for
`once-daily dosing.
`
` 3. Chemistry
`
` Olopatadine hydrochloride is a selective histamine (H 1 )
`receptor antagonist and mast cell stabilizer. It inhibits
`the activity of released histamine on its receptors and
`suppresses further release of histamine and other allergic
`and proinflammatory mediators. The chemical name for
`olopatadine is 11-[(Z)-3-(dimethylamino)propylidene]-6-11-
`dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride. It is a
`white, crystalline, water-soluble powder and has a molecular
`weight of 373.88.
` Olopatadine hydrochloride is the active ingredient in
`olopatadine hydrochloride 0.2% ophthalmic solution, which
`contains 2.22 mg of olopatadine hydrochloride, equivalent
`to olopatadine 2 mg. Olopatadine hydrochloride also
`contains the preservative benzalkonium chloride 0.01% and
`excipients povidone, dibasic sodium phosphate, sodium
`chloride, edetate disodium, hydrochloric acid/sodium
`hydroxide, and purified water [4] .
`
` 4. Ocular allergy: pathophysiology
`
` Ocular allergies are type I hypersensitivity reactions that first
`commence with allergic sensitization. The allergen binds to
`an antigen-presenting cell, such as a macrophage, which
`internalizes the allergen, processes it, and presents it as part
`of a MHC complex. The binding of T helper (T H ) cells to
`the MHC complex triggers IL production, secretion of
`T H 2-specific cytokines, and proliferation of B cells into
`plasma cells. Plasma cells then produce IgE molecules
`specific to the allergen, which bind to Fc receptors on
`conjunctival mast cells. The mast cells are thus sensitized,
`and subsequent exposure to the allergen will provoke the
`allergic response to specific IgE receptors [1] .
` When a sensitized individual is exposed to allergen again,
`the allergen degrades into antigens upon entry into the
`
`conjunctiva. Antigen then binds to IgE receptors on mast
`cells, causing IgE cross-linkage. This leads to mast cell
`degranulation, and within
`seconds
`the
`inflammatory
`mediator histamine is released. Histamine is the only
`mediator that reproduces all of the clinical signs and
`symptoms of the ocular allergic reaction, which include
`itching, redness, chemosis,
`tearing, and
`lid swelling.
`Of the four histamine receptors that have been identified
`in humans, only H 1 and H 2 have been detected in the eye.
`Histamine binding to H 1 receptors on nerve endings causes
`itching, while histamine binding to H 1 and H 2 receptors
`on endothelial vascular smooth muscle tissue leads to
`vasodilation and increased vascular permeability (redness), as
`well as endothelial gaping (swelling). Selective antagonists
`block these receptors, which results in diminished itching
`and redness [1] .
` During mast cell degranulation, de novo proinflammatory
`mediators are generated and released. These include cytokines,
`chemokines, and growth factor. TNF- α , a cytokine, increases
`the expression of intercellular adhesion molecule-1 (ICAM-1)
`and triggers histamine release. The arachidonic acid cascade
`is also activated upon mast cell degranulation; this mecha-
`nism ultimately leads to the recruitment of inflammatory
`cells and the formation of prostaglandins and leukotrienes,
`whose combined effects contribute to redness, chemosis, and
`mucous discharge [1] . Since the mechanism of the ocular
`allergic reaction is so complex and involves a variety of
`mediators, antihistamine/mast cell stabilizer medications
`such as olopatadine provide a dual action that is valuable in
`the treatment of allergies.
`
` 5. Pharmacology of olopatadine
`
` The specificity and strong binding affinity of olopatadine
`to H 1 receptors distinguishes this molecule from other
`antihistamines. One study demonstrated that olopatadine
`blocks the binding of histamine to receptors and has
`a stronger affinity for H 1 receptors than for H 2 and
`H 3 receptors [5] . A unique binding pocket containing an
`aspartate residue within the H 1 receptor might be the reason
`for olopatadine’s high selectivity for H 1 receptors [6] .
` The capacity of olopatadine to effectively suppress
`allergen- and histamine-induced conjunctivitis was displayed
`in the oral and topical administration of the compound in
`rats and guinea-pigs [7] . Olopatadine also exhibited its
`antiallergic effect – namely, the inhibition of mast cell and
`basophil degranulation – in an in vitro study of human
`conjunctival mast cells and rat basophilic leukemia cells.
`This
`study
`specifically
`showed
`the dose-dependent
`inhibition of histamine release. Olopatadine, when tested at
`10 times the maximally effective dose, successfully inhibited
`more than 90% of histamine release without demonstrating
`any mast cell cytotoxicity [8] . Olopatadine has also been
`shown to counteract histamine-induced phosphoinositide
`turnover in cultured human conjunctival epithelial cells,
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`human corneal fibroblasts, and transformed human trabecular
`meshwork cells [5] . Furthermore, olopatadine inhibited the
`release of leukotrienes and thromboxanes (TX), as well as
`the formation of platelet-activating factors, which are all
`lipid mediators that contribute to the allergic reaction [9] .
` The
`functional consequences of the
`interaction of
`olopatadine and various antihistamines with natural cell
`membranes were investigated in various comparative studies.
`Olopatadine, in comparison to other antihistamines, displayed
`restricted membrane perturbation and subsequent limited
`release of hemoglobin, lactate dehydrogenase, and histamine;
`these effects might contribute to the ocular comfort of the
`drug [10,11] . High concentrations of olopatadine have also
`demonstrated superiority over nedocromil, pemirolast, and
`cromolyn sodium in the reduction of histamine release from
`human conjunctival mast cells [12] . Olopatadine’s ability to
`maintain its stabilizing effect at high concentrations implicates
`its efficacy in a stronger concentration formulation.
` Several in vitro studies demonstrated that olopatadine
`also successfully blocks the release of other inflammatory
`mediators. The drug was more potent than pheniramine and
`antazoline in the inhibition of IL-6 and -8 (proinflammatory
`mediators) secretion from human conjunctival epithelial
`cells [13] . When human conjunctival mast cells were incu-
`bated with olopatadine and then challenged with anti-IgE
`antibody, olopatadine inhibited the release of TNF- α in a
`dose-respondent fashion [14] . A subsequent study indicated
`that olopatadine can also
`inhibit the upregulation of
`ICAM-1, whose expression is elevated by TNF- α . In this
`study, olopatadine significantly blocked the anti-IgE mast
`cell supernate-mediated upregulation of ICAM-1 on human
`conjunctival epithelial cells [15] . Another study similarly
`demonstrated that olopatadine inhibits IgE-activated human
`conjunctival mast cell supernates from stimulating eosinophil-
` derived neurotoxin release [16] . The abilities of olopatadine
`to suppress the release of inflammatory mediators and
`to inhibit inflammatory cell recruitment are thought to
`contribute to the drug’s long duration of action.
` Olopatadine has also demonstrated its ability to affect
`allergic mechanisms other than those of the eye. Studies
`showed that the nasal lavage fluid of guinea-pigs with
`allergic rhinitis had high concentrations of histamine,
`peptide leukotrienes, and TXB 2 . The oral administration
`of olopatadine decreased the levels of these inflammatory
` [17,18] . Olopatadine also
`mediators
`inhibited the early
`phase reaction and the late phase reaction of antigen-
`induced nasal obstruction (blockage) [19] . These results
`represent the suppressive effect olopatadine can have on
`nasal obstruction.
`
` 6. The conjunctival allergen challenge
`model in olopatadine studies
`
` The conjunctival allergen challenge (CAC) model is a
`validated clinical method that has been accepted for the
`
`Abelson & Gomes
`
`including
`evaluation of ocular antiallergic medications,
`olopatadine, in the US, Europe, and Japan. The CAC design
`involves two screening visits, during which patients who
`have positive skin tests for specific environmental or
`perennial allergens receive bilateral ocular challenges. At the
`first visit, increasing doses of allergen are administered to
`each eye until a moderate ocular allergic reaction occurs.
`The second visit challenges subjects with the final dose
`determined at the first visit. Onset and duration of action,
`as well as comfort, of the test medication can be evaluated
`at subsequent visits. This methodology provides a controlled,
`safe, reproducible, and standardized way to evaluate ocular
`itching, redness, chemosis, tearing, and eyelid swelling.
`In the CAC model, the contralateral eye can also be
`used as an internal control to limit variability within
`an individual [20] .
`
` 7. Clinical effi cacy of olopatadine
`hydrochloride 0.1% ophthalmic solution
`
` The clinical efficacy and safety of olopatadine hydrochloride
`0.1% ophthalmic solution was first established by several
`double-masked, placebo-controlled, contralateral eye, CAC
`studies that compared solutions of different olopatadine
`concentrations. Results revealed that olopatadine concen-
`trations of 0.05% and 0.1% effectively diminished itching
`and redness with an onset of 27 min and an 8-h duration of
`action [21] . Another similar study confirmed the 27-min
`onset and 8-h duration and found that olopatadine 0.1%
`was the most effective concentration (in comparison to
`0.01%, 0.05%, 0.1%, and 0.15% formulations) for the
`reduction of itching and redness [22] .
` Olopatadine has also effectively and safely reduced eyelid
`swelling and chemosis associated with allergic conjunctivitis.
`In one CAC study, eyelid swelling was evaluated by assess-
`ments provided by the participants and three-dimensional
`objective scanning and imaging technology. Analysis of both
`the subjective and objective assessments revealed that
`olopatadine significantly reduced eyelid swelling [23] . Another
`CAC study revealed that olopatadine significantly decreased
`chemosis, which was assessed by the investigator at 3, 10
`and 20 min postchallenge [24] .
` In a CAC study that included clinical assessments and
`tear cytology, olopatadine 0.1% significantly reduced itching
`and redness at 30 min and 5 h postchallenge. Olopatadine
`reduced ICAM-1 expression, tear histamine levels, and
`numbers of leukocytes at 30 min and 5 h postchallenge,
`suggesting that the drug inhibited the release of mast
`cell-derived mediators [25] .
`
` 7.1 Comparative studies
` Several comparative studies of olopatadine with other anti-
`allergy agents indicated olopatadine’s superior efficacy and
`tolerability. Olopatadine significantly reduced ocular itching
`more effectively than nedocromil [26] and diminished both
`
`
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`Olopatadine
`
`than cromolyn
`redness more effectively
`itching and
`sodium and levocabastine [27,28] . In a comparative study
`of olopatadine, cromolyn, and levocabastine, olopatadine
`was the most effective agent to inhibit ocular allergy
`symptoms in children as young as 4 years of age [29] .
`Various studies comparing olopatadine to the combination
`antihistamine/mast cell stabilizers ketotifen fumarate and
`azelastine
`indicated the superiority of olopatadine
`in
`terms of comfort and the reduction of itching [30-34] .
`Olopatadine was significantly more effective than the anti-
`allergy agent epinastine in the relief of itching, conjunctival
`and episcleral redness, and chemosis [35,36] . Olopatadine also
`demonstrated superior efficacy and tolerability over the
`corticosteroid loteprednol in the treatment of seasonal
`allergic conjunctivitis [37] . Finally, in comparison to non-
`steroidal anti-inflammatory drug ketorolac, olopatadine yielded
`significantly less ocular itching and redness [38] . These results
`support olopatadine as a preferable treatment for ocular
`allergy over other topical antiallergy medications.
`
` 7.2 Olopatadine and other ocular conditions:
`contact lenses and dry eye
` Contact lens wearers can safely treat ocular allergy with
`olopatadine, as
`long as they ensure that their eyes
`are not red before using the solution and that they wait
`10 min after drug
`instillation before
`inserting their
` [4,39] . Several
`lenses
`studies have demonstrated
`the
`advantages olopatadine 0.1% can have for contact lens
`wearers who follow the dosing directions. Olopatadine
`successfully inhibited the symptoms of allergic conjunctivitis
`in contact lens wearers to the same degree that it did in
`non-contact lens wearers [40] , and the drug is also more
`effective and comfortable than placebo in suppressing ocular
`allergy [41] . Contact lens use can induce signs and symptoms
`of dry eye such as tear deficiency and rapid tear film
`break-up time (TBUT) [42] ; however, a study indicating that
`olopatadine 0.1% improves tear function and maintains the
`strength of the tear film barrier suggested that the medica-
`tion is suitable for contact lens wearers as well as dry eye
`patients [43] . Indeed, a study comparing the effects of
`olopatadine 0.2% to those of saline solution showed that
`both agents yielded comparable changes in dry eye signs and
`symptoms, as well as similar tolerability ratings among
`patients suffering from ocular allergy and dry eye [44] .
`Another study also demonstrated that the incidence of dry
`eye after the use of either olopatadine 0.1% and olopatadine
`0.2% was less than or equal to that of placebo [45] .
`
` 7.3 Olopatadine and systemic drugs
` Systemic oral antihistamines, through nonspecific interactions
`with G protein–coupled receptors (GPCR), have been
`shown to induce ocular drying. Histamine and muscarinic
`receptors are both GPCRs, and M 3 receptors are involved
`in regulation of lacrimal gland function. Antagonists to the
`M 3 receptor – such as nonselective antihistamines – cause
`
`diminished lacrimal gland secretion, which in turn leads
`to ocular surface drying. This desiccated tear film means
`decreased barrier protection: allergens can more easily pene-
`trate the ocular surface [46-48] , which may in turn exacerbate
`the allergic reaction. The antiallergic effects of olopatadine
`were replicated with the concomitant treatment of oral
`antihistamines. Olopatadine, in comparison to loratadine,
`significantly reduced ocular itching [46,49] , and has not been
`shown to elicit significant ocular drying [48] . These findings
`suggest that the combined use of oral antihistamines (for
`rhinitis) and olopatadine (for ocular allergies) is safe and
`effectively decreases allergic signs and symptoms without
`drying the ocular surface.
`
` 7.4 Olopatadine and rhinitis/rhinoconjunctivitis
` The comorbidity of seasonal allergic conjunctivitis and
`rhinitis manifests itself as allergic rhinoconjunctivitis, of
`which
`the primary
`symptoms
`include nasal
`itching,
`irritation, sneezing, rhinorrhea, and congestion, as well as
`the ocular characteristics of itching, tearing, and swelling.
`When inhaled, airborne allergens can result in the develop-
`ment of a nasal allergic response; they can also enter the
`eye and leak through the nasolacrimal duct into the nose,
`leading to the presentation of ocular and nasal allergy signs
`and symptoms. Likewise, topically administered ophthalmic
`solutions can also drain into the nasal cavity, and olopatadine
`can have an effect on nasal allergic symptoms [50] . Studies
`have shown that olopatadine is significantly more effective
`than placebo in the reduction of nasal allergic symptoms.
`The combined therapy of olopatadine and a nasal spray
`reduced ocular
`itching and redness significantly more
`than the combined use of the nasal spray and a systemic
`antihistamine [49] . Another study indicated that among
`olopatadine, a nasal spray, and a systemic antihistamine, the
`former was the most effective in the reduction of ocular
`allergic signs and symptoms [50] . Furthermore, the added
`treatment of olopatadine in allergic rhinitis patients who
`were already using a nasal spray or systemic drug signi-
`ficantly improved their quality of life scores [51] . These
`studies demonstrate that the local treatment of site-specific
`allergies
`is
`important and that olopatadine can even
`contribute to the reduction of nasal allergy symptoms.
`
` 8. Increased concentration of olopatadine
`
` As reviewed, many studies have established the efficacy
`and safety of the twice-daily treatment of olopatadine 0.1%
`ophthalmic solution. A preclinical study provided evidence
`of detectable drug
`levels of a single 30-µl drop of
`olopatadine 0.2% ophthalmic solution that had been instilled
`in the conjunctiva 24 h earlier. It has also been shown that
`after a single 1-mg/kg bilateral dose of olopatadine, 50%
`H 1 -receptor occupancy remained for 24 h. These findings
`collectively suggested that a higher-concentration formulation
`of olopatadine could be developed for a once-daily dosing
`
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`regimen. In a guinea-pig model, formulations containing
`various concentrations of olopatadine (in the range of
`0.175 – 0.75%) were all found to be significantly superior
`to olopatadine 0.1% in the reduction of histamine-induced
`conjunctival vascular permeability. The 0.2% solution,
`chosen on the basis of drug aqueous solubility limits, was
`further investigated. Preclinically, olopatadine 0.2% was
`significantly more effective than olopatadine 0.1% after
`24 h of activity, and as effective as olopatadine 0.1% after
`5 min. A clinical CAC trial revealed that olopatadine 0.2%
`was statistically more effective than placebo in the reduction
`of itching and conjunctival redness, with an onset of
`5 min and duration of up to 24 h. The drug was also
`significantly more effective in the reduction of chemosis
`and tearing in comparison to placebo [52] . Other CAC
`studies demonstrated the efficacy and safety of the new
`formulation at 16 h postinstillation. Olopatadine 0.2%
`was statistically superior to placebo in the relief of ocular
`itching, redness, chemosis, and lid swelling associated with
`allergic conjunctivitis [53-55] .
` The use of olopatadine 0.2% has also been investigated in
`environmental studies conducted with patients suffering
`from allergic conjunctivitis or rhinoconjunctivitis. Patients
`self-administered olopatadine 0.2% or placebo bilaterally
`once a day during the spring allergy season (April to August
`2003). Olopatadine 0.2%-treated patients experienced signi-
`ficantly lower mean itching and redness scores than did
`placebo-treated patients, regardless of the level of pollen.
`Efficacy results for mean itching and redness during different
`periods of peak mean pollen counts also favored olopatadine
`0.2%. Only three minor ocular adverse events occurred
`that were related to olopatadine 0.2% treatment, and no
`participant discontinuation resulted from these events;
`overall, the medication was well tolerated [56] .
` The effects of olopatadine 0.2% on nasal symptoms in
`seasonal allergic conjunctivitis or rhinoconjunctivitis patients
`were examined in two hybrid environmental, placebo-
`controlled studies. During a 12-week fall trial (July to
`December 2001) and a 10-week spring trial (April to August
`2003), patients visited the clinic weekly to receive a CAC
`administration and to report weekly nasal symptoms.
`In the fall study, olopatadine 0.2% effectively reduced the
`frequencies of sneezing and itchy nose, as well as the
`severities of sneezing, runny nose, and itchy nose. In the
`spring study, olopatadine 0.2% significantly reduced the
`frequency of sneezing and runny nose. Ocular dryness, the
`most commonly occurring adverse event related to therapy,
`was experienced equally by olopatadine 0.2%- and placebo-
`treated patients in the fall study (incidence of 1.7%). Only
`three ocular adverse events related to olopatadine treatment
`occurred during the spring study. These studies provide
`support for the safe and tolerable use of olopatadine 0.2%
`in patients with nasal allergy symptoms [57] .
` In a 5-min onset-of-action challenge comparison study
`between olopatadine 0.2% and epinastine, both drugs
`
`Abelson & Gomes
`
`demonstrated efficacy in the reduction of ocular itching and
`redness. Olopatadine 0.2% demonstrated superior efficacy
`and tolerability over epinastine 0.05%. Olopatadine 0.2%
`yielded significantly
`lower mean
`itching and redness
`scores than epinastine. Patients of both treatment groups
`reported comparable comfort scores at all time points
`except at the 1-min time point postchallenge, when
`olopatadine 0.2% was found to be statistically more
`comfortable than epinastine [3] .
`
` 9. Tolerability and safety
`
` Both olopatadine 0.1% and 0.2% ophthalmic solutions have
`been shown to be well tolerated in the eye [3,20,52-55] .
`Comparative studies revealed that olopatadine is more
`comfortable and tolerable than nedocromil [26] , cromolyn [28] ,
` [27] ,
` [37] ,
` [38] ,
`levocabastine
`loteprednol
`ketorolac
`ketotifen [30-33] , and epinastine [58] . The high tolerability of
`olopatadine is of significant note, as ocular allergy symptoms
`can be very irritating. Instillation of first-generation anti-
`histamines such as antazoline and pheniramine are known
`to cause ocular discomfort and also have limited efficacy
`and a short duration of action [27] . The excellent comfort
`profile of olopatadine makes it a preferable treatment
`option. No serious adverse events have occurred in relation
`to olopatadine treatment, and very rarely have
`local
`adverse events occurred. Patients as young as 3 years old
`can use olopatadine 0.2% [59] , and 4 years old, 0.1% [29] ;
`neither formulation increases ocular drying, as do some
`systemic antihistamines [46-49] .
`
` 10. Regulatory affairs
`
` Olopatadine 0.2% ophthalmic solution (Pataday ™ , Alcon)
`received approval from the US FDA on 22 December 2004.
`Olopatadine 0.2% (Patanol ® S, Alcon) is also approved
`for use in Latin America.
`
` 11. Conclusion
`
` The safety and efficacy profile of olopatadine as an anti-
`allergy medication has been firmly established. In vitro and
`preclinical studies initially investigated the molecule’s mecha-
`nism of action, namely, its capabilities of H 1 inhibition,
`mast cell stabilization, and suppression of inflammatory
`mediators. Clinical trials have confirmed the effectiveness
`of olopatadine, as well as revealed its rapid onset and
`long duration of action; furthermore, comparative studies
`between olopatadine and other antiallergic agents have
`displayed the former’s superiority in terms of efficacy
`and comfort. Other benefits of olopatadine
`include
`its capacity to reduce nasal allergy manifestations and its
`safe utilization among contact lens wearers, dry eye patients,
`and children. A new formulation of increased potency
`(olopatadine 0.2%) enables patients to dose once a day,
`
`
`
`Expert Opin. Drug Metab. Toxicol. (2008) 4(4)
`
`457
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 108, Page 6
`
`

`

`Olopatadine
`
`allowing for improved compliance and thus better control of
`ocular allergies.
`
` 12. Expert opinion
`
` The recent development of olopatadine 0.2% provides
`clinicians and patients with a longer-acting agent for the
`prevention of itching associated with allergic conjunctivitis.
`This topical ophthalmic solution has also demonstrated
`an effect in reducing redness, chemosis, tearing, and lid
`swelling associated with ocular allergy [52,53] , as well as
`rhinoconjunctivitis symptoms [57] . Olopatadine 0.2% is safe
`and well tolerated among its users, which include children
`as young as 3 years old [59] . The increased concentration of the
`active ingredient did not significantly increase ocular drying
`or irritation, as it had with ketotifen fumarate 0.05% (from
`0.025%) ophthalmic solution [30,31] . Olopatadine 0.2% has
`successfully maintained the strong efficacy and safety profile
`of its predecessor. As olopatadine 0.2% has demonstrated
`excellent efficacy, comfort, and tolerability, this treatment
`option will prove to be an important one for years to come.
` Olopatadine 0.2% also offers a number of conveniences
`that make
`it an appealing treatment option. Patient
`compliance can improve with the use of olopatadine 0.2%,
`since it is indicated for once-daily dosing. A number of
`previous studies show that the switch from a twice-daily
`
`dosing drug to a once-daily drug enhances compliance,
`which allows for the maximum benefit from treatment [60,61] .
`Less frequent dosing has been shown to determine medi-
`cation preference [62] ; thus, as all other topical ophthalmic
`antiallergic agents require regimens of twice-daily dosing
`to
`four-times-daily dosing, olopatadine 0.2% has an
`advantage over its competitors. Olopatadine 0.2% will also
`be preferred among contact lens wearers, who can apply the
`medication before inserting their lenses and do not have to
`interrupt their day by removing the lenses for a second
`instillation. Additionally, olopatadine 0.2% is a preferable
`treatment option for children, who would otherwise have to
`receive a second dose during school hours. Not only is the
`dosing regimen of olopatadine 0.2% more convenient than
`that of olopatadine 0.1%, but both medications are also
`comparable in price, making the newer formulation a more
`cost-effective option. Olopatadine 0.2%, whose efficacy and
`convenient dosing can improve the quality of life of patients
`suffering from allergic conjunctivitis, is a valuable and novel
`addition to the ocular allergy market.
`
` Declaration of interest
`
`interest to declare
` The authors have no conflict of
`and no payment has been received for preparation of
`this manuscript.
`
` 5.
`
`(cid:127)
`
` 6.
`
` 7.
`
` Bibliography
` Papers of special note have been highlighted
`as either of interest ((cid:127)) or of considerable
`interest ((cid:127)(cid:127)) to readers.
`
` 1.
`
`(cid:127)
`
` 2.
`
` Abelson MB, Smith L, Chapin M.
`Ocular allergic disease: mechanisms,
`disease sub-types, treatment. Ocul Surf
` 2003 ; 1 : 127 -49
`Discusses the current understanding of
`ocular allergic disease and its therapies.
`
` Majkowska-Wojciechowska B, Pelka J,
`Korzon L, et al. Prevalence of allergy,
`patterns of allergic sensitization and allergy
`risk factors in rural and urban children.
` Allergy 2007 ; 62 : 1044 -50
`
` 3.
`
` Mah FS, Rosenwasser LJ, Townsend WD,
`et al. Effi cacy and comfort of olopatadine
`0.2% versus epinastine 0.05% ophthalmic
`solution for treating itching and redness
`induced by conjunctival allergen challenge.
` Curr Med Res Opin 2007 ; 23 : 1445 -52
`(cid:127)(cid:127) Clinical comparison of olopatadine 0.2%
`and epinastine, revealing superior effi cacy
`and tolerability of olopatadine 0.2%.
`
` 4.
`
` Alcon. Olopatadine hydrochloride