Low Adverse Reaction Risk Seen In Oral, Topical Carbonic Anhydrase Inhibitors


Oral CAIS had a slightly higher, but small risk of severe adverse reaction compared to topical CAIS, which may help the reluctance to prescribe.

Donald A. Redelmeier, MD

Donald A. Redelmeier, MD

New research found the risk of serious adverse reaction following prescription of an oral or topical carbonic anhydrase inhibitor (CAI) was low and similar between agents, in contrast to a known reluctance in CAI prescriptions due to the potential risk of life-threatening complications.

Led by Donald A. Redelmeier, MD, Sunnybrook Health Sciences Centre, the team examined the safety of CAIs in a universal health care system in Canada by comparing adverse event rates of patients prescribed an oral CAI with matched controls in those prescribed a topical CAID.

“In comparison with topical CAIs, there was a modest difference in the risk of a SCAR event and no increased risk of a general adverse drug reaction,” wrote investigators.

The Study

A matched longitudinal cohort study identified consecutive patients older than 65 years old who were prescribed an oral or topical CAI in Ontario between January 1995 - January 2020. Exclusions included a lack of valid health care insurance or younger than 66 years.

Oral CAI were defined as either acetazolamide or methazolamide, while a topical CAI was defined as dorzolamide, brinzolamide, or a combination agent. Included baseline demographic data were age, sex, socioeconomic status, and home location, while data on race or ethnicity were not available.

Patients were matched 1:1 based on age, sex, and diabetes status identified, wherein 1 patient was prescribed an oral CAI and 1 patient was prescribed a topical CAI.

The primary endpoint was considered a severe complicated adverse reaction (SCAR), representing a physician diagnosis of at least 1 of 3 idiosyncratic adverse events, including Stevens-Johnson syndrome, toxic epidermal necrolysis, or aplastic anemia.

Investigators defined time zero as the date of the first prescription for an oral or topical CAI. The analysis examined the risk of SCAR events in the 120 days following initial treatment using conditional logistic regression.


A total of 64,477 patients were prescribed an oral CAI and 111,598 were prescribed a topical CAI during the 25-years of the study. After matching, investigators obtained a cohort of 128,942 total patients, which consisted of 64,471 patients prescribed an oral CAI and 64,471 prescribed a topical CAI.

They noted differences between groups because of the proportion of patients with glaucoma, repeated visual field tests, recent eye surgery, and hospital admissions. Data show the mean age of 75 years, 71,958 (55.8%) were women, and 25,058 (19.4%) had a diagnosis of diabetes.

The most common oral agent was acetazolamide (n = 59,554; 92.4%) and the most common topical CAI was dorzolamide or combination agents (n = 45,505; 70.6%).

Data show patients prescribed an oral CAI accounted for 187 SCAR events (absolute risk, 2.90 per 1000 patients), whereas patients prescribed a topical CAI accounted for 134 SCAR events (absolute risk, 2.08 per 1000 patients). Investigators found the difference was equivalent to a risk ratio of 1.40, with a number needed to harm of 1 in 1220 patients (95% CI, 1.12 - 1.74, P = .003).

Additionally, the risk of a SCAR event was consistent regardless of age, sex, and socioeconomic status, while living in a rural location and patients diagnosed with diabetes was associated with marginally lower risk in multivariable analysis.


Redelmeier and colleagues noted oral CAIs should not be initiated casually, so informed consent discussions should be held with patients initiating the agents.

“At the same time, this population-level analysis supports reconsidering the reluctance toward prescribing oral CAIs, given the low risk of severe adverse events,” investigators concluded.

The study, “Serious Adverse Events of Oral and Topical Carbonic Anhydrase Inhibitors,” was published in JAMA Ophthalmology.

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