Betaxolol Ophthalmic Solution As Alternative Treatment for Patients with Timolol Allergy: a Case Report

Case Report Betaxolol Ophthalmic Solution as Alternative Treatment for Patients with Timolol Allergy: A Case Report

Olivia Müllertz 1,*, Jette Jacobsen 2, Jacob P. Thyssen 3, Anna Horwitz 1,4 and Miriam Kolko 1,4,*

1 Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark; [email protected] 2 Department of Pharmacy, University of Copenhagen, 2100 Copenhagen, Denmark; [email protected] 3 Department of Dermatology and Allergy, Herlev-Gentofte Hospital, 2900 Hellerup, Denmark; [email protected] 4 Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, 2600 Glostrup, Denmark * Correspondence: [email protected] (O.M.); [email protected] (M.K.)

Received: 24 March 2020; Accepted: 25 June 2020; Published: 30 July 2020

Abstract: Background: To establish if an allergy towards all β-blockers, as a group, should be assumed, if an allergic reaction is observed while using one speciﬁc β-blocking agent. Case presentation: The non-selective β-blocker timolol caused a severe allergic ocular reaction in a non-atopic patient with advanced primary open-angle glaucoma. Results: A patch test conﬁrmed timolol allergy. No allergic reaction to other anti-glaucomatous topical drugs was observed, and treatment with the selective β-blocker betaxolol was successfully initiated. Conclusion: Allergy to the non-selective β-blocker timolol does not necessarily predict allergy to the selective β-blocker betaxolol, and betaxolol should therefore not be excluded as an alternative treatment.

Keywords: betaxolol; timolol; β-blocker; allergy

1. Introduction Drug allergies are a class of unpredictable adverse reactions that are not related to the pharmacological eﬀect of a drug, and can occur at subtherapeutic doses. Drug allergies encompasses a variety of immuno-modulated hypersensitive reactions, which can be stimulated by the administration of drug compounds, such as timolol [1] (Figure1). Most clinically relevant unpredictable adverse drug reactions are type I and type IV allergies. Type I allergy, mediated by immunoglobulin E (IgE) antibodies, occurs rapidly within minutes to hours. Type IV allergy, mediated by T-lymphocytes is delayed, and appears up to several hours or days after exposure [2]. Drug allergies are structure-speciﬁc, which means that an allergic reaction to a drug does not necessarily cause cross-reactivity with another similar drug, even if they derive from the same class and share the same functional groups. Topical β-blockers exert their ocular hypotensive action by blockade of the sympathetic nerve endings in the ciliary body, causing a decrease in the production of aqueous humor. They can be either non-selective or selective for β1-adreneric receptors [3]. Timolol is a non-selective β-blocker, inhibiting both β1- and β2-adrenergic receptors, while betaxolol is a β1-selective β-blocker. Common to all β-blockers is that they all contain an aryl-oxy-isopropanol-amine chain (Figure1).

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Reports 2020, 3, 21 2 of 4 Reports Figure2020, 3, x1. FOR Chemical PEER REVIEW structure of timolol and betaxolol, illustrated by ChemDraw professional 19.0. 2 of 4

2. Case Presentation A 58-year-old non-atopic male experienced visual impairment on the right eye. Severe visual field losses (MD values of 25.5/24.5 db), total glaucomatous excavation of both optic nerve heads, severe loss of nerve fibers and retinal ganglion cells using Heidelberg OCT and intraocular pressure (IOP) of 38/40 mmHg were observed. Visual acuity was 0.2/0.6 and gonioscopy revealed open angles. The patient was diagnosed with advanced primary open angle glaucoma and immediate treatment with preservative free (PF) latanoprost (50 µm/mL) was initiated. The pressure was reduced to 25/25 mmHg. Due to insufficient IOP-lowering effect of PF latanoprost (50 µm/mL), a combined treatment of timololFigure (5 1. mgChemical/mL)/dorzolamide structure of timolol (20 mg and/mL) betaxolol, and PF illustrated latanoprost by ChemDraw (50µg/mL) professional was initiated. 19.0. This combinationFigure 1.lead Chemical to a satisfactory structure of IOPtimolol of and14/14 betaxolol, mmHg, illustrated without byfluctuations. ChemDraw At professio a controlnal 19.0visit. after four months,Here, we no report significant a severe progression allergic ocular in lowering reactionto IOP timolol was observed. in a patient After where six subsequent months, the treatment patient β withexperienced2. Case the Presentation1-selective increasingly blocking red agent, and irritated betaxolol, conjunctiva was successful as well and as presented periorbital no allergic dermatitis. reaction. Due to suspected2. CaseA 58 Presentation- yearpreservative-old non -allergy,atopic male the patient experienced was changed visual impairment to PF timolol/dorzolamide. on the right eye. As Severe the redness visual andfield irritation losses (MD remained values unchanged, of 25.5/24.5 PF db), timolol/dorzolamide total glaucomatous was excavation discontinued. of both Her opticeafter, nerve timolol heads, gel A 58-year-old non-atopic male experienced visual impairment on the right eye. Severe visual field losses (1mgsevere/mL) loss was of nerve initiated fibers, while and retinalPF latanoprost ganglion (50 cells µm using/mL) Heidelberg was continued. OCT Fewand intraoculardays after initiationpressure (MD values of 25.5/24.5 db), total glaucomatous excavation of both optic nerve heads, severe loss of nerve of(IOP) timolol of 38/40 gel mmHg(1mg/mL) were, the observed. patient Visualwent to acuity the emergency was 0.2/0.6 roomand gonioscopy with severe revealed allergic open symptoms, angles. fibers and retinal ganglion cells using Heidelberg OCT and intraocular pressure (IOP) of 38/40 mmHg were includingThe patient angioedema was diagnosed (Figure with 2A). advanced Timolol primary gel was open discontinued angle glaucoma and the and IOP immediate increased treatme to 22/24nt observed. Visual acuity was 0.2/0.6 and gonioscopy revealed open angles. The patient was diagnosed with mmHg.with preservative free (PF) latanoprost (50 µm/mL) was initiated. The pressure was reduced to 25/25 advanced primary open angle glaucoma and immediate treatment with preservative free (PF) latanoprost mmHg.An Dueacute to patch insufficient test was IOP performed-lowering to effect establish of PF that latanoprost the cause (50 of µmthe /mL)allergic, a combined reaction was treatment due to (50 µm/mL) was initiated. The pressure was reduced to 25/25 mmHg. Due to insufficient IOP-lowering effect timololof timolol, and (5 to mg rule/mL) out/dorzolamide any cross-reactivity (20 mg/mL) with and other PF glaucomatous latanoprost (50µg/mL) drugs. A waspositive initiated. patch Thistest of PF latanoprost (50 µm/mL), a combined treatment of timolol (5 mg/mL)/dorzolamide (20 mg/mL) and PF reacombinationction to timolollead to a wassatisfactory observed IOP (Figure of 14/14 2B) mmHg,, while without no allergic fluctuations. reaction At a wascontrol observed visit after to latanoprost (50µg/mL) was initiated. This combination lead to a satisfactory IOP of 14/14 mmHg, without prostaglandinfour months, no analogues significant (latanoprost) progression carbon in lowering anhydrase IOP wasinhibitors observed. (dorzolamide After six months,and brinzolamide), the patient fluctuations. At a control visit after four months, no significant progression in lowering IOP was observed. sympathomimeticsexperienced increa singly(brimonidine red and tartrate irritated and conjunctivaapraclonidine), as wellparasympathom as periorbitalimetic dermatitis. (pilocarpine), Due or to After six months, the patient experienced increasingly red and irritated conjunctiva as well as periorbital thesuspected selective preservative-1 β-blocking allergy, agent, the betaxolol. patient Treatmentwas changed with to betaxolol PF timolol/dorzolamide. (5 mg/mL) was initiated, As the redness with a dermatitis. Due to suspected preservative allergy,the patient was changed to PF timolol/dorzolamide. As the resultingand irritation IOP remained of 10/12 unchanged, mmHg, without PF timolol/dorzolamide significant fluctuations was discontinued. throughout Her theeafter, day. Combinedtimolol gel redness and irritation remained unchanged, PF timolol/dorzolamide was discontinued. Hereafter, timolol treatment(1mg/mL) withwas initiatedbetaxolol, whileadministered PF latanoprost twice daily (50 µm and/mL) PF waslatanoprost continued. (50 µmFew/mL) days on afterce a initiationday was gel (1mg/mL) was initiated, while PF latanoprost (50 µm/mL) was continued. Few days after initiation of wellof timolol tolerated gel (1mg (Figure/mL) 2C)., the Periorbital patient went dermatitis to the emergency was treated room successfully with severe with allergic topical symptoms, tacrolimus timolol gel (1mg/mL), the patient went to the emergency room with severe allergic symptoms, including 0.1%including twice angioedema daily for a week (Figure. The 2A). patient Timolol has gegivenl was his discontinued written informed and the consent IOP increasedfor publication to 22/24 of angioedema (Figure2A). Timolol gel was discontinued and the IOP increased to 22 /24 mmHg. thismmHg. case report and accompanying images. An acute patch test was performed to establish that the cause of the allergic reaction was due to timolol, and to rule out any cross-reactivity with other glaucomatous drugs. A positive patch test reaction to timolol was observed (Figure 2B), while no allergic reaction was observed to prostaglandin analogues (latanoprost) carbon anhydrase inhibitors (dorzolamide and brinzolamide), sympathomimetics (brimonidine tartrate and apraclonidine), parasympathomimetic (pilocarpine), or the selective-1 β-blocking agent, betaxolol. Treatment with betaxolol (5 mg/mL) was initiated, with a resultingFigure IOP 2. This of 10/12 illustration mmHg, represents without the significant subject after fluctuations ocular treatment throughout with timolol the day. (1 mg Combined/mL), Figure 2. This illustration represents the subject after ocular treatment with timolol (1 mg/mL), (A), treatment(A), the with subject betaxolol after a administered patch test with twice timolol daily (B) and and PF the latanoprost subject after (50 treatment µm/mL) with on betaxololce a day was the subject after a patch test with timolol (B) and the subject after treatment with betaxolol (5 mg/mL) well (5 tolerated mg/mL) ( (FigureC). 2C). Periorbital dermatitis was treated successfully with topical tacrolimus (C). 0.1% twice daily for a week. The patient has given his written informed consent for publication of this caseAn acutereport patchand accompanying test was performed images. to establish that the cause of the allergic reaction was 3. Discussion due to timolol, and to rule out any cross-reactivity with other glaucomatous drugs. A positive patch test reaction to timolol was observed (Figure2B), while no allergic reaction was observed to prostaglandin analogues (latanoprost) carbon anhydrase inhibitors (dorzolamide and brinzolamide), sympathomimetics (brimonidine tartrate and apraclonidine), parasympathomimetic (pilocarpine), or the selective-1 β-blocking agent, betaxolol. Treatment with betaxolol (5 mg/mL) was initiated, with a resulting IOP of 10/12 mmHg, without signiﬁcant ﬂuctuations throughout the day. Combined treatment with betaxolol administered twice daily and PF latanoprost (50 µm/mL) once a day was well toleratedFigure 2. This (Figure illustration2C). Periorbital represents dermatitis the subject was after treated ocular successfullytreatment with with timolol topical (1 mg tacrolimus/mL), (A),0.1% twicethe daily subject for after a week. a patch The test patient with timolol has given (B) and his writtenthe subject informed after treatment consent with for betaxolol publication (5 mg/mL) of this case report(C and). accompanying images.

3. Discussion

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OphthalmicOphthalmic β-adrenergic-adrenergic antagonistic agents are commonly used in the treatment of glaucoma glaucoma,, becausebecause of theirtheir eeffectivenessﬀectiveness inin reducingreducing IOPIOP [[3].3]. Although the majority of published data suggests similarsimilar IOP IOP reduction reduction between between betaxolol betaxolol and and timolol timolol [ [44––66],], the use of of betaxolol betaxolol in in Denmark Denmark is is uncommon.uncommon. We investigated the number of betaxolol prescriptions based on thethe numbernumber ofof timololtimolol prescriptionsprescriptions per yearyear inin DenmarkDenmark in thethe periodperiod 19961996 to 20182018 (Figure(Figure3 3)) andand foundfound thatthat betaxololbetaxolol isis usedused atat anan increasinglyincreasingly lowerlower raterate thanthan timololtimolol (Figure(Figure3 3)). .

FigureFigure 3.3. ((AA)) The The figure figure shows shows the the evolution evolution of ofthe the indexed indexed number number of prescriptions of prescriptions of betaxolol of betaxolol (red (redline) line) and andtimolol timolol (blue (blue line) line) per per years years in inDenmark Denmark in inthe the period period 1996 1996 to to 2018, 2018, with with 1996 1996 as as the the index year,year, inin whichwhich thethe valuesvalues areare normalizednormalized toto 100.100. ((BB)) DepictsDepicts thethe evolutionevolution ofof thethe relativerelative numbernumber ofof prescriptionsprescriptions ofof betaxololbetaxolol to timololtimolol per yearyear inin DenmarkDenmark inin thethe periodperiod fromfrom 19961996 toto 2018.2018. The blackblack dotsdots represent thethe exactexact ratiosratios and the blue line andand grey area represents the best linear fitfit (using OLS) andand thethe 95% confidenceconfidence intervals, respectively. TheThe figurefigure establishesestablishes aa significantlysignificantly negativenegative trendtrend inin the ratio with a negative slope of 0.0083 per year, p < 0.001 (blue line). All data is drawn from the the ratio with a negative slope of −−0.0083 per year, p < 0.001 (blue line). All data is drawn from the DanishDanish RegistryRegistry ofof MedicinalMedicinal ProductsProducts Statistics,Statistics, whichwhich containscontains datadata onon allall prescriptionsprescriptions dispenseddispensed inin DenmarkDenmark sincesince 1995.1995. ForFor methodsmethods seesee [[7].7]. AnatomicalAnatomical Therapeutic Chemical system codes used: betaxolol:betaxolol: S01ED02; timolol: S01ED01.

PreviousPrevious reports [[77––1414]] havehave extensively described the detrimental effects effects of ophthalmic timolol. timolol. InIn accordanceaccordance with with our our case case report, report, a previousa previous study study based based on aon study a study population population of 448 of patients, 448 patients, have shownhave shown that 2.6 that % 2.6 of patients% of patients treated treated with timololwith timolol presented presented with allergicwith allergic reactions reactions [8]. However, [8]. However, most studiesmost studies reporting reporting allergic dermatitis allergic dermatitis in response in to response timolol treatment,to timolol also treatment, report cross-sensitivity also report cross with- β othersensitivity known with-blockers other known such β as-blockers betaxolol such or as other betaxolol glaucoma or other eye dropsglaucoma [9–14 eye]. Indrops the present[9–14]. In case, the β allergypresent was case, only allergy present was after only treatment present with after timolol. treatment Comparing with the timolol. structural Comparing elements the of structural-blockers β timololelements and of betaxololβ-blocker withs timolol other knownand betaxolol anti-glaucomatous with other known-blockers anti (levobunolol,-glaucomatous metipranolol, β-blockers carteolol),(levobunolol, none metipranolol, other than timolol carteolol), contains none a morpholin-4-yl-1,2,5-thiadiazol other than timolol contains a scamorpholinffold, which-4-yl is-1,2,5 why- thatthiadiazol the allergic scaffold, reaction which observed is why that in the the present allergic patient reaction is caused observed by thisin the sca presentffold. patient is caused 4.by Conclusions this scaffold.

4. ConclusionsOur findings emphasize that physicians should not assume allergy towards all β-blockers as a group, if an allergic reaction is only observed while using one specific β-blocking agent. Therefore, Our findings emphasize that physicians should not assume allergy towards all β-blockers as a further evaluation of a patient showing signs of drug allergies, should be conducted to determine if group, if an allergic reaction is only observed while using one specific β-blocking agent. Therefore, the allergy is limited to a specific β-blocker. further evaluation of a patient showing signs of drug allergies, should be conducted to determine if Authorthe allergy Contributions: is limited to Conceptualization,a specific β-blocker. J.J., J.P.T. and M.K.; methodology, O.M., A.H., and M.K.; writing—original draft preparation, O.M., A.H.; writing—review and editing, O.M., J.J., J.P.T., A.H. and M.K.; visualization,Author Contributions: O.M.; supervision, Conceptualization, M.K.; project J.J., J. administration,P.T. and M.K.; methodology, M.K. All authors O.M., have A.H., read and and M. agreedK.; writing to the— publishedoriginal draft version preparation, of the manuscript. O.M., A.H.; writing—review and editing, O.M., J.J., J.P.T., A.H. and M.K.; visualization, O.M.; supervision, M.K.; project administration, M.K. All authors have read and agreed to the Funding: This research received no external funding. published version of the manuscript. Conflicts of Interest: The authors declare no conflict of interest. Funding: This research received no external funding.

Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

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Abbreviations

IOP Intra Ocular pressure PF Preservative free

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