Serious Adverse Events of Oral and Topical Carbonic Anhydrase Inhibitors

Abstract

laucoma is a progressive optic neuropathy that affects more than 60 million patients worldwide. 1 Carbonic anhydrase inhibitors (CAIs) decrease aqueous humor production, thus lowering intraocular pressure. 2 Topical CAIs are associated with a 20% intraocular pressure reduction, whereas oral CAIs are associated with a 30% intraocular pressure reduction. 3,4 When there are concerns about efficacy or patient adherence, oral CAIs are sometimes preferred over topical agents.Topical CAIs are often prescribed early in glaucoma treatment, whereas oral CAIs are reserved as a temporizing measure for acute, significant intraocular pressure elevation or for patients who are refractory to topical medications and laser trabeculoplasty. A reluctance to prescribe oral CAIs is attributed to the risk of life-threatening complications, systemic adverse events, and cross-reactivity in patients with a sulfonamide allergy. 2,[5][6][7][8][9] CAIs can cause systemic adverse reactions, including fatigue, paresthesias, nausea, dizziness, hypokalemia, kidney stones, and weight loss. 2,[9][10][11] Rare but serious complications include Stevens-Johnson syndrome (SJS), toxic-epidermal necrolysis (TEN), and aplastic anemia. The symptoms from CAIs have been described as intolerable, debilitating, serious, and sometimes worse than the disease itself. A prior report has noted that oral CAIs have fallen into disfavor because of the concern for serious adverse events. 9 The same reluctance is not found with topical CAIs. Some patients may not tolerate oral CAIs; however, the risk of serious adverse reactions is unclear. Given the paucity of evidence and the potential benefits, a critical analysis can support or refute prevailing concerns associated with oral CAIs. To examine the safety of CAIs in a universal health care system in Canada, we identified patients prescribed an oral CAI IMPORTANCE Some ophthalmologists may be reluctant to prescribe oral carbonic anhydrase inhibitors, given the potential for life-threatening systemic adverse reactions. OBJECTIVE To conduct a population-based analysis of the safety of oral or topical carbonic anhydrase inhibitors in clinical care. DESIGN, SETTING, AND PARTICIPANTSThis matched longitudinal cohort study took place in Ontario, Canada. Consecutive patients older than 65 years who were prescribed an oral or topical carbonic anhydrase inhibitor in Ontario, Canada, between January 1, 1995, and January 1, 2020, were identified. Patients were matched 1-to-1 based on age, sex, and diabetes status. Time zero was defined as the date of the first identified prescription for the medication, and the primary analysis focused on the first 120 days of follow-up. MAIN OUTCOMES AND MEASURESThe primary end point was a severe complicated adverse event of either Stevens-Johnson syndrome, toxic epidermal necrolysis, or aplastic anemia.RESULTS Overall, 128 942 matched patients initiated an oral or topical carbonic anhydrase inhibitor during the 25-year study period. The mean (SD) age was 75 (6.6) years, 71 958 (55.8%) were women...

Reevaluating the Risk of Serious Adverse Events of Carbonic Anhydrase Inhibitors—Reply

“…In Reply We thank Bleicher et al for their comments. We found that carbonic anhydrase inhibitors have a low risk of severe adverse reactions regardless of whether prescribed as oral or topical formulations . Moreover, our study was designed in a manner slanted against this conclusion; namely, the risk of Stevens-Johnson syndrome, toxic epidermal necrolysis, or aplastic anemia could be even lower if estimated by different analytic methods.…”

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“…The treatment of glaucoma requires a high dose of sulfonamide drugs to effectively reduce intraocular pressure. Those drugs have shown poor specificity for the targeted isozyme, therefore causing a wide range of undesirable side effects, including altered taste, malaise, fatigue, depression, and anorexia [ 25 , 26 ]. In addition, some of the marketed sulfonamide drugs cause allergies in a significant number of people [ 27 , 28 ].…”

Reevaluating the Risk of Serious Adverse Events of Carbonic Anhydrase Inhibitors

“…To the Editor We read with great interest the article by Popovic et al and we appreciate the opportunity to comment. The authors compare the risk of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and aplastic anemia after exposure with topical vs oral carbonic anhydrase inhibitors (CAIs).…”

“…There are some potential contributors to a seemingly elevated rate. The authors did not report data on how representative the database is of the general population. What is the overall rate of SJS/TEN in their database?…”

“…Third, the use of International Classification of Diseases, Ninth Revision (ICD-9) code 659.1 to identify rates of SJS/TEN can overestimate the true rate. The authors reference a study where only 14.8% of cases with this code were found to be true SJS/TEN after detailed medical record review. Could the authors individually review their cases to verify?…”