Oral Carbonic Anhydrase Inhibitors Show Low Risk in Large Study

Plenty vitamins pills on a table.
The findings suggest clinicians reconsidering their reluctance toward prescribing oral carbonic anhydrase inhibitors.

Ophthalmologists can be averse to prescribing oral carbonic anhydrase inhibitors (CAIs) due to rare but severe adverse reactions “sometimes worse than the disease itself,” according to a report published in JAMA Ophthalmology. Side effects can include nausea, tingling and numbness, or hypokalemia. Alternately, clinicians are less hesitant with topical CAIs — but investigators are now asking ‘how much greater are risks with the oral version?’

Scarce proof exists for the magnitude of serious risk, though, that is dissuading physicians from prescribing oral CAIs, suggests the research team. They conducted a longitudinal, population-based analysis using validated health services databases of patient records for those who were prescribed oral or topical CAIs in Ontario between January 1, 1995 and January 1, 2020. The total was narrowed to individuals matched 1:1 by sex, age, and diabetes diagnosis (related to kidney function), to form 2 cohorts; 64,471 prescribed an oral CAI and 64,471 given the drug as a topical. Nearly half, 49.9% had a diagnosis of glaucoma ≤1 year before starting a CAI.

The analysis first contrasted rates of oral and topical CAI-associated severe complicated adverse reactions (SCARs) — defined as 1 or more of 3 disorders including aplastic anemia, Stevens-Johnson syndrome, or toxic epidermal necrolysis. Results for the population sample, mean age 75±6.6 years, comprised a total of 187 SCAR events among the oral medication group, and 134 of these reactions in the topical drug set. 

Participants who took an oral CAI had an absolute risk for SCAR of 2.90 per 1000, slightly higher than those who used a topical CAI at 2.08 per 1000 individuals. For the difference in events between oral and topical agents, the number needed to harm was 1 in 1220 patients. “Adjustment for all measured covariates suggested a 51% relative increased risk of a SCAR event for patients prescribed oral compared with topical CAIs (95% CI, 15-98; P =.003),” the study explains. Further, investigators found no meaningful differences between topical or oral CAI use for total adverse drug reaction or other conditions including delirium or kidney stones.

Overall, risk did not change based on subgroups, including participants of varying age; sex; socioeconomic status; diagnoses such as hypertension or glaucoma; or by year treated. In multivariable analysis, individuals with diabetes had a slightly lower risk for a SCAR event, and those with greater Charlson Comorbidity Index scores or more clinic contact had a higher risk. The chance for SCAR was also connected with time from prescription for a 120-day period in both cohorts, which contrasts with prior belief that events happen shortly after starting CAIs. 

This investigation is the first to compare SCAR events from CAI, and a strength was the diversity in disease diagnoses within the sample. However, inclusion was limited to those more than 65 years of age. Other limitations included a number of unavailable specific ICD-9 codes, no comparison of SCAR rate with that in the general population, and missing data for confounders such as doses prescribed, or if CAIs are already avoided for patients at most risk for adverse events. 

Careful consideration must be taken when prescribing CAIs and patients should be well-informed, the study notes, adding “this population-level analysis supports reconsidering the reluctance toward prescribing oral CAIs, given the low risk of severe adverse events.”

Disclosures: Multiple authors declared affiliations with the biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Popovic MM, Schlenker MB, Thiruchelvam D, Redelmeier DA. Serious adverse events of oral and topical carbonic anhydrase inhibitors. JAMA Ophthalmol. Published online January 27, 2022. doi:10.1001/jamaophthalmol.2021.5977