Cardiac safety of ophthalmic timolol

Expert Opinion on Drug Safety

Volumn 15, Issue 11, 2016, Pages 1549-1561

  Mäenpää, Jukka ^a   Pelkonen, Olavi ^b  

^a ASTRAZENECA R AND D   (Sweden)

^b UNIVERSITY OF OULU   (Finland)

Author keywords

Beta blocker; bradycardia; CYP2D6; eye drops; glaucoma; poor metabolizer; selective serotonin reuptake inhibitors; timolol

Indexed keywords

BETA ADRENERGIC RECEPTOR BLOCKING AGENT; CIMETIDINE; CYTOCHROME P450 2D6; DRUG METABOLITE; FLECAINIDE; QUINIDINE; SEROTONIN UPTAKE INHIBITOR; TIMOLOL; VERAPAMIL; ANTIHYPERTENSIVE AGENT; EYE DROPS;

ADVERSE DRUG REACTION; ARTICLE; BRADYCARDIA; CLINICAL TRIAL (TOPIC); DRUG BLOOD LEVEL; DRUG METABOLISM; DRUG SAFETY; FAINTNESS; FALLING; HUMAN; IN VITRO STUDY; IN VIVO STUDY; ORTHOSTATIC HYPOTENSION; PHASE 3 CLINICAL TRIAL (TOPIC); PREGNANCY; RANDOMIZED CONTROLLED TRIAL (TOPIC); SYSTEMIC CIRCULATION; CARDIOTOXICITY; DRUG INTERACTION; GENETICS; GLAUCOMA; INTRAOCULAR DRUG ADMINISTRATION; METABOLISM;

ADMINISTRATION, OPHTHALMIC; ADRENERGIC BETA-ANTAGONISTS; ANTIHYPERTENSIVE AGENTS; CARDIOTOXICITY; CYTOCHROME P-450 CYP2D6; DRUG INTERACTIONS; GLAUCOMA; HUMANS; OPHTHALMIC SOLUTIONS; TIMOLOL;

EID: 84992020815     PISSN: 14740338     EISSN: 1744764X     Source Type: Journal    
DOI: 10.1080/14740338.2016.1225718     Document Type: Article

References (93)

1. H.A.Quigley Glaucoma. Lancet. 2011;377:1367–1377.
2. D.Schmidl, L.Schmetterer, G.Garhofer, et al. Pharmacotherapy of glaucoma. J Ocul Pharmacol Ther. 2015;31:63–77.
3. M.J.Reiter. Cardiovascular drug class specificity:beta-blockers. Prog Cardiovasc Dis. 2004;47:11–33.
4. A.Brayfield, editor. Timolol maleate. Martindale:The Complete Drug Reference. London:Pharmaceutical Press; [cited 2016 Apr 16]. Available from:http://www.medicinescomplete.com/
5. B.G.Craiglow, R.J.Antaya. Management of infantile hemangiomas:current and potential pharmacotherapeutic approaches. Pediatr Drugs. 2013;15:133–138.
6. M.F.Raphael, J.M.Breur, F.A.Vlasveld, et al. Treatment of infantile hemangiomas:therapeutic options in regard to side effects and adverse events - a review of the literature. Expert Opin Drug Saf. 2016;15:199–214.
7. M.C.Grieshaber, J.Flammer. Is the medication used to achieve the target intraocular pressure in glaucoma therapy of relevance?–an exemplary analysis on the basis of two beta-blockers. Prog Retin Eye Res. 2010;29:79–93.
8. European Glaucoma Society (EGS). Terminology and guidelines for glaucoma. 4th ed. Savona:Publicomm S.r.l.; 2014 [cited 2016 Apr10]. Chapter 3.3, Antiglaucoma drugs; p. 140–158. Available from: http://www.eugs.org/eng/egs_guidelines_reg.asp?l=1
9. W.L.Nelson, F.T.Fraunfelder, J.M.Sills, et al. Adverse respiratory and cardiovascular events attributed to timolol ophthalmic solution, 1978–1985. Am J Ophthalmol. 1986;102:606–611.
10. European Medicines Agency. Pharmacovigilance Working Party (PhVWP), monthly report. Annex 1:summary assessment report; beta-blockers for ophthalmic use – risk of systemic adverse reactions. 2011 Jun 30 [cited 2016 Apr16]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/06/WC500108098.pdf?_sm_au_=ikV30Vt5QQDN1Stc• European Medicines Agency’s concern and recommendation of cardiac and bronchial safety labeling information of ophthalmic timolol products in the European Union.
11. M.Sharifi, J.M.Koch, R.J.Steele, et al. Third degree AV block due to ophthalmic timolol solution. Int J Cardiol. 2001;80:257–259.
12. T.Minish, A.Herd. Symptomatic bradycardia secondary to interaction between topical timolol maleate, verapamil, and flecainide:a case report. J Emerg Med. 2002;22:247–249.
13. N.van der Velde, G.Ziere, T.J.M.van der Cammen. Falls in three patients due to timolol eye drops, tolterodine, and flecainide. J Gerontol A Biol Sci Med Sci. 2004;59:1343–1344.
14. B.J.Carey. Atishoo! Atishoo! We all fall down!. Age Ageing. 2006;35:446–447.
15. M.E.Müller, N.van der Velde, J.W.Krulder, et al. Syncope and falls due to timolol eye drops. BMJ. 2006;332:960–961.• Three well-described case reports of serious adverse effects related to ophthalmic timolol.
16. E.Calenda, F.Tourrel. Sinoatrial block induced by timolol eyedrops. Can J Ophthalmol. 2007;42:149.
17. S.Patane’, F.Marte, G.Di Bella, et al. Atrial fibrillation, pharmacological cardioversion and topical ophthalmic beta-blocker use. Int J Cardiol. 2008;126:e43–e46.
18. H.S.Walia, S.S.Walia, M.E.Emanuel. Sick sinus syndrome associated with topical timolol maleate instillation. J Pharmacol Pharmacother. 2011;2:300–302.
19. U.Canpolat, K.M.Gurses, K.Aytemir, et al. Severe bradycardia and syncope due to topical ophthalmic timolol. Herz. 2013;38:556–557.
20. L.Lee, C.Turnbull, M.M.Akhtar, et al. Ganfort, a blinding drug to the physician. BMJ Case Reports. 2012 [cited 2012 Sep7]. doi:10.1136/bcr.01.2012.5648.• Interesting case report in which ophthalmic timolol in a combination glaucoma product was considered to delay the diagnosis of large pulmonary emboli.
21. J.Mäenpää Pharmacology of ophthalmic drugs. In:O.Pelkonen, H.Ruskoaho, J.Hakkola, editors. Medical pharmacology and toxicology. Helsinki:Duodecim Medical Publications Ltd.; 2014. p. 973–984. Finnish
22. A.J.Lee, J.J.Wang, A.Kifley, et al. Open-angle glaucoma and cardiovascular mortality:the Blue Mountains Eye Study. Ophthalmology. 2006;113:1069–1076.• In this population-based cohort study, it was suggested that in previously diagnosed glaucoma patients, topical timolol may increase the risk of cardiovascular mortality.
23. S.-Y.Wu, B.Nemesure, A.Hennis, et al. Open-angle glaucoma and mortality:the barbados eye studies. Arch Ophthalmol. 2008;126:365–370.• In this population-based cohort study, it was suggested that in previously diagnosed glaucoma patients, topical timolol may increase the risk of cardiovascular mortality.
24. P.J.Lama. Topical β-adrenergic blockers and glaucoma:a heart-stopping association? Ophthalmology. 2006;113:1067–1068.
25. J.Vogler, G.Breithardt, L.Eckardt. Bradyarrhythmias and conduction blocks. Rev Esp Cardiol (Engl Ed). 2012;65:656–667.
26. K.Dickstein, R.Hapnes, T.Aarsland. Comparison of aqueous and gellan ophthalmic timolol with placebo on the 24-hour heart rate response in patients on treatment for glaucoma. Am J Ophthalmol. 2001;132:626–632.• Ophthalmic timolol significantly decreased heart rate versus placebo in 43 glaucoma patients especially during daytime period, when glaucoma patients were Holter monitored for 24 h.
27. Y.Dinai, M.Sharir, N.Naveh, et al. Bradycardia induced by interaction between quinidine and ophthalmic timolol. Ann Intern Med. 1985;103:890–891.• The first report to show the serious effect of CYP2D6 inhibitor on cardiac safety in the patient receiving ophthalmic timolol.
28. S.D.Pringle, C.J.MacEwen. Severe bradycardia due to interaction of timolol eye drops and verapamil. Br Med J (Clin Res Ed). 1987;294:155–156.
29. C.Tattersall, S.Vernon, R.Singh. Resting pulse rates in a glaucoma clinic:the effect of topical and systemic beta-blocker usage. Eye (Lond). 2006;20:221–225.
30. H.Uusitalo, M.Kähönen, A.Ropo, et al. Improved systemic safety and risk-benefit ratio of topical 0.1% timolol hydrogel compared with 0.5% timolol aqueous solution in the treatment of glaucoma. Graefes Arch Clin Exp Ophthalmol. 2006;244:1491–1496.
31. H.Uusitalo, J.Niño, K.Tahvanainen, et al. Efficacy and systemic side-effects of topical 0.5% timolol aqueous solution and 0.1% timolol hydrogel. Acta Ophthalmol Scand. 2005;83:723–728.
32. N.L.Pratt, E.N.Ramsay, L.M.Kalisch Ellett, et al. Association between ophthalmic timolol and hospitalisation for bradycardia. J Ophthalmol. 2015 [cited 2015 Mar22]. doi:10.1155/2015/567387.•• In this retrospective study, ophthalmic timolol was shown to increase the risk of hospitalization due to bradycardia.
33. I.C.Logan, M.D.Witham. Efficacy of treatments for orthostatic hypotension:a systematic review. Age Ageing. 2012;41:587–594.
34. J.Niño, K.Tahvanainen, H.Uusitalo, et al. Cardiovascular effects of ophthalmic 0.5% timolol aqueous solution and 0.1% timolol hydrogel. Clin Physiol Funct Imaging. 2002;22:271–278.
35. P.Kannus, H.Sievänen, M.Palvanen, et al. Prevention of falls and consequent injuries in elderly people. Lancet. 2005;366:1885–1893.
36. R.J.Glynn, J.M.Seddon, J.H.Krug, et al. Falls in elderly patients with glaucoma. Arch Ophthalmol. 1991;109:205–210.• In this 1-year retrospective follow-up study, ophthalmic beta-blockers increased the risk of falls in glaucoma patients.
37. A.C.Ham, K.M.A.Swart, A.W.Enneman, et al. Medication-related fall incidents in an older, ambulant population:the B-PROOF study. Drugs Aging. 2014;31:917–927.
38. DuoTrav 40 micrograms/mL + 5 mg/mL eye drops, solution. Summary of product characteristics (UK). [cited 2016 Apr 17]. Available from: https://www.medicines.org.uk/emc/medicine/17774
39. E.J.Higginbotham. Considerations in glaucoma therapy:fixed combinations versus their component medications. Clin Ophthalmol. 2010;4:1–9.
40. G.Holló, J.Vuorinen, J.Tuominen, et al. Fixed-dose combination of tafluprost and timolol in the treatment of open-angle glaucoma and ocular hypertension:comparison with other fixed-combination products. Adv Ther. 2014;31:932–944.
41. K.Kaarniranta, K.Ikäheimo, E.Mannermaa, et al. Pharmacokinetics, efficacy, and safety of the preservative-free fixed combination of tafluprost 0.0015% and timolol 0.5% in healthy volunteers:a phase I comparison vs. the corresponding preservative-free monotherapies. Clin Pharmacokinet. 2016;55:485–494.
42. P.Saini, Y.K.Loke, C.Gamble, et al. Selective reporting bias of harm outcomes within studies:findings from a cohort of systematic reviews. BMJ. 2014 [cited 2014 Nov21]. doi:10.1136/bmj.g6501.
43. E.J.Higginbotham. Topical beta-adrenergic antagonists and quinidine. A risky interaction. Arch Ophthalmol. 1996;114:745–746.
44. A.Spratt, L.Ogunbowale, R.Wormald, et al. What’s in a name? New glaucoma drugs. Lancet. 2006;368:826–827.• Critical comment regarding the ‘blinding feature of cardiac safety’ in new combination glaucoma ophthalmic products containing both timolol and prostaglandin analog.
45. T.Nieminen, H.Uusitalo, V.Turjanmaa, et al. Association between low plasma levels of ophthalmic timolol and haemodynamics in glaucoma patients. Eur J Clin Pharmacol. 2005;61:369–374.• Plasma timolol levels were correlated with the decrease in heart rate in exercise test in glaucoma patients.
46. J.Mäenpää, M.Volotinen-Maja, H.Kautiainen, et al. Paroxetine markedly increases plasma concentrations of ophthalmic timolol; CYP2D6 inhibitors may increase the risk of cardiovascular adverse effects of 0.5% timolol eye drops. Drug Metab Dispos. 2014;42:2068–2076.• A clinic–pharmacological interaction study demonstrating that simultaneously used paroxetine increase timolol plasma concentration and may increase CV adversities.
47. D.Ghate, H.F.Edelhauser. Barriers to glaucoma drug delivery. J Glaucoma. 2008;17:147–156.
48. K.Sakanaka, K.Kawazu, K.Nishida, et al. Transport of timolol and tilisolol in rabbit corneal epithelium. Biol Pharm Bull. 2006;29:2143–2147.
49. M.Volotinen, J.Mäenpää, K.Kautiainen, et al. Ophthalmic timolol in a hydrogel vehicle leads to minor inter-individual variation in timolol concentration in aqueous humor. Eur J Pharm Sci. 2009;36:292–296.
50. M.Volotinen, M.Turpeinen, A.Tolonen, et al. Timolol metabolism in human liver microsomes is mediated principally by CYP2D6. Drug Metab Dispos. 2007;35:1135–1141.
51. T.Zhang, C.D.Xiang, D.Gale, et al. Drug transporter and cytochrome P450 mRNA expression in human ocular barriers:implications for ocular drug disposition. Drug Metab Dispos. 2008;36:1300–1307.
52. M.Volotinen, J.Mäenpää, E.Kankuri, et al. Expression of cytochrome P450 (CYP) enzymes in human nonpigmented ciliary epithelial cells:induction of CYP1B1 expression by TCDD. Invest Ophthalmol Vis Sci. 2009;50:3099–3105.
53. M.Volotinen, J.Hakkola, O.Pelkonen, et al. Metabolism of ophthalmic timolol:new aspects of an old drug. Basic Clin Pharmacol Toxicol. 2011;108:297–303.
54. J.M.Korte, T.Kaila, K.M.Saari. Systemic bioavailability and cardiopulmonary effects of 0.5% timolol eyedrops. Graefes Arch Clin Exp Ophthalmol. 2002;240:430–435.•• The first study to estimate the systemic bioavailability of ophthalmic timolol, in which its absorption resembled intravenous timolol.
55. I.Goldberg, G.Moloney, P.McCluskey. Topical ophthalmic medications:what potential for systemic side effects and interactions with other medications? Med J Aust. 2008;189:356–357.
56. T.Nieminen, T.Lehtimäki, J.Mäenpää, et al. Ophthalmic timolol:plasma concentration and systemic cardiopulmonary effects. Scand J Clin Lab Invest. 2007;67:237–245.
57. D.J.Tocco, A.E.Duncan, F.A.deLuna, et al. Timolol metabolism in man and laboratory anamals. Drug Metab Dispos. 1980;8:236–240.
58. J.B.Fourtillan, P.Courtois, M.A.Lefebvre, et al. Pharmacokinetics of oral timolol studied by mass fragmentography. Eur J Clin Pharmacol. 1981;19:193–196.
59. M.Volotinen, T.Korjamo, A.Tolonen, et al. Effects of selective serotonin reuptake inhibitors on timolol metabolism in human liver microsomes and cryo-preserved hepatocytes. Basic Clin Pharmacol Toxicol. 2010;106:302–309.
60. K.M.Bertelsen, K.Venkatakrishnan, L.L.Von Moltke, et al. Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine:comparison with fluoxetine and quinidine. Drug Metab Dispos. 2003;31:289–293.
61. X.-L.Liu, Q.-J.Jia, L.-N.Wang, et al. Roles of CYP2C19 gene polymorphisms in susceptibility to POAG and individual differences in drug treatment response. Med Sci Monit. 2016;22:310–315.
62. T.Yamamoto, A.Suzuki, Y.Kohno. High-throughput screening to estimate single or multiple enzymes involved in drug metabolism:microtitre plate assay using a combination of recombinant CYP2D6 and human liver microsomes. Xenobiotica. 2003;33:823–839.
63. O.Pelkonen, M.Turpeinen, J.Hakkola, et al. Inhibition and induction of human cytochrome P450 enzymes:current status. Arch Toxicol. 2008;82:667–715.
64. O.Pelkonen, J.Mäenpää, P.Taavitsainen, et al. Inhibition and induction of human cytochrome P450 (CYP) enzymes. Xenobiotica. 1998;28:1203–1253.
65. S.F.Zhou. Polymorphism of human cytochrome P450 2D6 and its clinical significance:part I. Clin Pharmacokinet. 2009;48:689–723.
66. G.Alvan, C.von Bahr, P.Seidemann, et al. High plasma concentrations of beta-receptor blocking drugs and deficient debrisoquine hydroxylation. Lancet. 1982;1:333.
67. R.V.Lewis, M.S.Lennard, P.R.Jackson, et al. Timolol and atenolol:relationships between oxidation phenotype, pharmacokinetics and pharmacodynamics. Br J Clin Pharmacol. 1985;19:329–333.
68. J.C.McGourty, J.H.Silas, J.J.Fleming, et al. Pharmacokinetics and beta-blocking effects of timolol in poor and extensive metabolizers of debrisoquin. Clin Pharmacol Ther. 1985;38:409–413.
69. G.Alvan, B.Calissendorff, P.Seideman, et al. Absorption of ocular timolol. Clin Pharmacokinet. 1980;5:95–100.
70. T.I.Edeki, H.He, A.J.Wood. Pharmacogenetic explanation for excessive beta-blockade following timolol eye drops. Potential for oral-ophthalmic drug interaction. JAMA. 1995;274:1611–1613.•• Well-designed study, in which the role of CYP2D6 in cardiac safety of topically applied timolol was shown both in PMs of CYP2D6 and in EM volunteers receiving a potent CYP2D6 inhibitor quinidine concomitantly.
71. T.Nieminen, H.Uusitalo, J.Mäenpää, et al. Polymorphisms of genes CYP2D6, ADRB1 and GNAS1 in pharmacokinetics and systemic effects of ophthalmic timolol. A pilot study. Eur J Clin Pharmacol. 2005;61:811–819.
72. J.S.Leeder, A.Gaedigk. CYP2D6 and pharmacogenomics:where does future research need to focus? Part 2:clinical aspects. Pharmacogenomics. 2014;15:1055–1058.• Editorial discussing about the cost effectiveness and the benefits of genotyping individuals regarding CYP2D6 gene.
73. T.Kaila, R.Huupponen, S.Karhuvaara, et al. Beta-blocking effects of timolol at low plasma concentrations. Clin Pharmacol Ther. 1991;49:53–58.
74. W.E.Haefeli, M.J.Bargetzi, F.Follath, et al. Potent inhibition of cytochrome P450IID6 (debrisoquin 4-hydroxylase) by flecainide in vitro and in vivo. J Cardiovasc Pharmacol. 1990;15:776–779.
75. L.Labbe, G.O’Hara, M.Lefebvre, et al. Pharmacokinetic and pharmacodynamic interaction between mexiletine and propafenone in human beings. Clin Pharmacol Ther. 2000;68:44–57.
76. Y.Ishii, K.Nakamura, K.Tsutsumi, et al. Drug interaction between cimetidine and timolol ophthalmic solution:effect on heart rate and intraocular pressure in healthy Japanese volunteers. J Clin Pharmacol. 2000;40:193–199.
77. J.S.Almenoff, W.DuMouchel, L.A.Kindman, et al. Disproportionality analysis using empirical Bayes data mining:a tool for the evaluation of drug interactions in the post-marketing setting. Pharmacoepidemiol Drug Saf. 2003;12:517–521.
78. I.Goldberg, M.A.Adena. Co-prescribing of topical and systemic beta-blockers in patients with glaucoma:a quality use of medicine issue in Australian practice. Clin Experiment Ophthalmol. 2007;35:700–705.
79. S.C.Brauner, T.C.Chen, B.T.Hutchinson, et al. The course of glaucoma during pregnancy:a retrospective case series. Arch Ophthalmol. 2006;124:1089–1094.
80. C.Mendez-Hernandez, J.Garcia-Feijoo, F.Saenz-Frances, et al. Topical intraocular pressure therapy effects on pregnancy. Clin Ophthalmol. 2012;6:1629–1632.
81. A.M.Wagenvoort, J.M.Van Vugt, M.Sobotka, et al. Topical timolol therapy in pregnancy:is it safe for the fetus? Teratology. 1998;58:258–262.
82. J.Hakkola, M.Pasanen, R.Purkunen, et al. Expression of xenobiotic-metabolizing cytochrome P450 forms in human adult and fetal liver. Biochem Pharmacol. 1994;48:59–64.
83. J.C.Stevens, S.A.Marsh, M.J.Zaya, et al. Developmental changes in human liver CYP2D6 expression. Drug Metab Dispos. 2008;36:1587–1593.
84. S.M.Johnson, M.Martinez, S.Freedman. Management of glaucoma in pregnancy and lactation. Surv Ophthalmol. 2001;45:449–454.
85. J.-F.Bussières, R.Therrien, P.Hamel, et al. Retrospective cohort study of 163 pediatric glaucoma patients. Can J Ophthalmol. 2009;44:323–327.
86. M.Samant, A.Medsinge, K.K.Nischal. Pediatric glaucoma:pharmacotherapeutic options. Pediatr Drugs. 2016;18:209–219.
87. M.S.Passo, E.A.Palmer, E.M.Van Buskirk, et al. Plasma timolol in glaucoma patients. Ophthalmology. 1984;91:1361–1363.
88. N.K.Mungan, T.W.Wilson, K.K.Nischal, et al. Hypotension and bradycardia in infants after the use of topical brimonidine and beta-blockers. J AAPOS. 2003;7:69–70.
89. K.Kiryazov, M.Stefova, V.Iotova, et al. Can ophthalmic drops cause central nervous system depression and cardiogenic shock in infants? Pediatr Emerg Care. 2013;29:1207–1209.
90. L.Weibel, M.Barysch, H.S.Scheer, et al. Topical timolol:evidence for efficacy and degree of systemic absorption. Pediatr Dermatol. 2016;33:184–190.
91. M.Huber, M.Kölzsch, R.Stahlmann, et al. Ophthalmic drugs as part of polypharmacy in nursing home residents with glaucoma. Drugs Aging. 2013;30:31–38.• In this large study, ophthalmic timolol was shown to be the most prescribed glaucoma drug in elderly patients in Germany.
92. U.Klotz. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev. 2009;41:67–76.
93. Timoptol® 0.25%/0.5% w/v eye drops solution. Summary of product characteristics (UK). [cited 2016 Apr 17]. Available from: https://www.medicines.org.uk/emc/medicine/31332