A Pharmacovigilance Study of Drug-Induced Glaucoma Utilizing the Japanese Adverse Event Reporting System

Figures & data

Table 1 Characteristics of Study Patients

Variables	Glaucoma, n (%)	Angle-closure Glaucoma, n (%)
Sex
Men	329 (54.0)	29 (14.0)
Women	280 (46.0)	178 (86.0)
Age
<10	13 (2.1)	3 (1.4)
10s	27 (4.4)	0 (0)
20s	30 (4.9)	0 (0)
30s	62 (10.2)	2 (1.0)
40s	96 (15.8)	5 (2.4)
50s	119 (19.5)	28 (13.5)
60s	120 (19.7)	79 (38.3)
70s	90 (14.8)	80 (38.6)
80s	46 (7.6)	10 (4.8)
90s	6 (1.0)	0 (0)
Outcome
Remission	125 (20.5)	56 (27.1)
Recovery	82 (13.5)	71 (34.3)
No recovery	117 (19.2)	24 (11.6)
Death	0 (0)	0 (0)
After affects	45 (7.4)	32 (15.5)
Unknown	240 (39.4)	24 (11.5)

Table 2 Most Frequently Reported Drugs That Induce Glaucoma

Drug	n	Route of Administration
Prednisolone	61	Oral (n = 50)
		Unknown (n =11)
Pregabalin	37	Oral (n =36)
		Unknown (n =1)
Ranibizumab	31	Eye drops (n =31)
Betamethasone sodium phosphate	17	Eye drops (n = 10)
		Unknown (n = 6)
		Nasal (n = 1)
Crizotinib	14	Oral (n = 14)
Triamcinolone acetonide	14	Eye drops (n = 13)
		Unknown (n = 1)
Tacrolimus hydrate	13	Eye drops (n = 1)
		Oral (n = 12)
Darbepoetin alfa	13	Intravenous (n =13)
Fluorometholone	12	Eye drops (n = 12)
Foscarnet sodium hydrate	10	Intravenous (n =10)

Table 3 Most Frequently Reported Drugs That Induce Angle-Closure Glaucoma

Drug	n	Route of Administration
Atropine sulfate hydrate	7	Intravenous (n = 7)
Scopolamine butylbromide	6	Intramuscular (n = 1)
		Oral (n = 1)
		Intravenous (n = 2)
		Unknown (n = 2)
Fluvoxamine maleate	6	Oral (n = 6)
Bromazepam	6	Oral (n = 6)
Aflibercept	5	Eye drops (n = 5)
Aripiprazole	4	Oral (n = 4)
Quetiapine fumarate	4	Oral (n = 4)
Solifenacin succinate	4	Oral (n = 3)
		Unknown (n = 1)
Tiotropium bromide hydrate	4	Inhalation (n = 4)
Nicorandil	4	Oral (n = 2)
		Intravenous (n = 2)
Paroxetine hydrochloride hydrate	4	Oral (n = 4)
Fentanyl citrate	4	Intravenous (n = 4)
Brotizolam	4	Oral (n = 4)
Milnacipran hydrochloride	4	Oral (n = 4)
Combination drug of levodopa and carbidopa hydrate	4	Oral (n = 4)

Table 4 Most Frequently Reported Drugs That Induce Glaucoma, focusing on the administration route

Drug, Route	n	Unadjusted			Adjusted^a
		ROR	95% CI	P value	ROR	95% CI	P value
Prednisolone, oral	50	4.59	3.04–6.92*	<0.001	4.39	2.91–6.64*	<0.001
Pregabalin, oral	36	13.5	9.65–19.0*	<0.001	15.6	11.1–21.9*	<0.001
Ranibizumab, eye drops	31	35.5	24.67–51.0*	<0.001	46.4	32.0–67.3*	<0.001
Betamethasone sodium phosphate, eye drops	10	467.4	239.5–912.1*	<0.001	464.4	237.2–909.5*	<0.001
Crizotinib, oral	14	17.1	10.08–29.2*	<0.001	18.5	10.9–31.6*	<0.001
Triamcinolone acetonide, eye drops	13	201.6	114.4–355.1*	<0.001	212.4	120.4–374.8*	<0.001
Tacrolimus hydrate, oral	12	2.1	1.18–3.71*	0.011	1.81	1.02–3.21*	0.043
Darbepoetin alfa, intravenous	13	6.8	3.91–11.7*	<0.001	8.3	4.77–14.5*	<0.001
Fluorometholone, eye drops	12	227.8	126.1–411.4*	<0.001	231.1	127.7–418.2*	<0.001
Foscarnet sodium hydrate, intravenous	10	57.5	30.6–107.9*	<0.001	46.6	24.8–87.8*	<0.001

Notes: *Signal detected. ^aAdjusted for age (< 60s vs ≥ 60s) and sex (female vs male).

Abbreviations: CI, confidence interval; ROR, reporting odds ratio.

Table 5 Most Frequently Reported Drugs That Induce Angle-Closure Glaucoma, focusing on the administration route

Drug	n	Unadjusted			Adjusted^a
		ROR	95% CI	P- value	ROR	95% CI	P- value
Atropine sulfate hydrate, intravenous	7	225.1	105.1–482.5*	<0.001	300.7	138.5–653.1*	<0.001
Fluvoxamine maleate, oral	6	23.8	10.6–53.7*	<0.001	29.2	12.9–66.2*	<0.001
Bromazepam, oral	6	69.7	30.9–157.5*	<0.001	110.4	48.0–253.8*	<0.001
Aflibercept, eye drops	5	23.9	9.83–58.1*	<0.001	25.0	10.2–61.1*	<0.001
Aripiprazole, oral	4	4.12	1.53–11.1*	0.005	7.03	2.6–19.0*	<0.001
Quetiapine fumarate, oral	4	7.69	2.86–20.7*	<0.001	9.83	3.65–26.5*	<0.001
Tiotropium bromide hydrate, inhalation	4	97.4	36.0–263.5*	<0.001	192.1	69.1–533.8*	<0.001
Paroxetine hydrochloride hydrate, oral	4	4.4	1.64–11.8*	0.003	4.49	1.67–12.1*	0.003
Fentanyl citrate, intravenous	4	15.9	5.89–42.7*	<0.001	18.3	6.79–49.4*	<0.001
Brotizolam, oral	4	16.6	6.18–44.8*	<0.001	22.3	8.25–60.0*	<0.001
Milnacipran hydrochloride, oral	4	22.8	8.46–61.4*	<0.001	36.2	13.4–97.8*	<0.001
Combination drug of levodopa and carbidopa hydrate, oral	4	26.7	9.9–71.8*	<0.001	21.4	7.93–57.8*	<0.001

Notes: *Signal detected. ^aAdjusted for age (< 60s vs ≥ 60s) and sex (female vs male).

Abbreviations: CI, confidence interval; ROR, reporting odds ratio.

Table 6 Comparison of Our Study with Previous Studies Regarding Glaucoma

Drug	Previous Studies
Prednisolone	The development for IOP ≥ 30 mmHg at a dose > 7.5 mg/day oral prednisolone (OR 4.4, P = 0.033)^Citation20
Pregabalin	A nested case-control study that pregabalin use is associated with incidence of glaucoma^Citation24
Ranibizumab	IOP elevations (more than 21 mmHg) at intravitreal ranibizumab (0.5 mg) (OR = 2.2, P = 0.015) reference to aflibercept-treated eyes (2 mg)^Citation26
Betamethasone sodium phosphate	IOP elevation ≥ 22 mmHg in 12% of patients treated with betamethasone (0.1%) drop after 6 weeks^Citation21
Crizotinib	None
Triamcinolone acetonide	IOP >24 mm Hg at 2 mg intravitreal triamcinolone (12.8%) after 3 months^Citation22
Tacrolimus hydrate	No significant difference in incidence of primary open-angle glaucoma between FK506-treated patients (15%) and non-FK506 group (22%)^Citation31
Darbepoetin Alfa	None
Fluorometholone	IOP elevation ≥ 22 mmHg, 2% of patients treated with fluorometholone (0.1%) drop after 6 weeks^Citation21
Foscarnet sodium hydrate	None

Abbreviations: IOP, intraocular pressure; OR, odds ratio.

Table 7 Comparison of Our Study with Previous Studies Regarding Angle-Closure Glaucoma

Drug	Previous Studies
Atropine sulfate hydrate	Case report: A 66-year-old man treated with systemic atropine (1.3 mg)^Citation34
Fluvoxamine maleate	Case report: A 66-year-old while woman treated fluvoxamine 50 mg/d^Citation36
Bromazepam	None
Aflibercept	Among 180 patients treated with aflibercept (2.0 mg), 4 patients developed intraocular pressure more than 10 mm Hg greater than baseline^Citation40
Aripiprazole	Case report: A 45-year-old white woman receiving aripiprazole 5 mg daily^Citation37
Quetiapine fumarate	Case report: A 63-year-old woman receiving quetiapine for more than 10 years^Citation39
Tiotropium bromide hydrate	Case report: A 46-year-old man treated tiotropium for 12 months once daily^Citation35
Paroxetine hydrochloride hydrate	Case report: A 53-year-old woman receiving paroxetine 20 mg once daily for 3 days^Citation38
Fentanyl citrate	Case report: A 60s women showing acute angle-closure glaucoma after general anesthesia with intravenous fentanyl (150 µg) for bone grafting^Citation41
Brotizolam	None
Milnacipran hydrochloride	None
Combination drug of levodopa and carbidopa hydrate	None

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