Out of the 4,641,636 participants in 2015 UR-BMI and UE-BMI database, a total of 57,612 participants with XYP prescriptions were identified. After excluding 42,969 (74.6%) who had no anti-allergic marker drug prescription, we identified 12,288 (21.3%) as incident cases. Among incident cases, 11,339 (19.7%) were excluded, who had anti-allergic drugs prescribed before, more than 3 days after, or on the same day of XYP. We finally included 949 (7.7%) as cases for primary analyses, with 949 controls one-on-one matched from the same study cohort. An additional 1,489 cases were included with matched controls obtained from the study cohort for the sensitivity analysis. This expanded sample ended up with 2,438 cases matched with 2,438 controls. (Figure 1)
3.1 Characteristics of Cases and Controls
For the cases and controls of primary analyses, the average age ± standard deviation (SD) of the cases was 34.0 ± 29.6 years, 504 (53.1%) were male, 231 (24.3%) received the first administration of XYP in the outpatient services while 718 (75.7%) received it during inpatient services. Secondary hospitals were the most frequently visited (n = 496, 52.3%), followed by primary health-care institution (n = 207, 21.8%), and tertiary hospitals (n = 246, 25.9%) were the least visited. As expected, the matched controls shared approximately the same distribution for baseline characteristics as the cases. Table 2 shows the baseline characteristics results.
Table 2 Baseline characteristics of patients with suspected allergic reactions and matched controls
|
Cases
(N = 949)
|
Controls
(N = 949)
|
Age(x̄ ± SD)
|
34.0 ± 29.6
|
34.0 ± 29.6
|
Gender (n, %)
|
Male
|
504 (53.1)
|
505 (53.2)
|
Female
|
445 (46.0)
|
444 (46.8)
|
Type of Hospital Visits (n, %)
|
Outpatient
|
231 (24.3)
|
231 (24.3)
|
Inpatient
|
718 (75.7)
|
718 (75.7)
|
Hospital Level (n, %)
|
Tertiary hospital
|
246 (25.9)
|
246 (25.9)
|
Secondary hospital
|
496 (52.3)
|
496 (52.3)
|
Primary health-care institution
|
207 (21.8)
|
207 1.8)
|
Abbreviations: SD, Standard Deviation.
3.2 Univariate Analyses
Table 3 presents the univariate analyses results of for 25 target concomitant medications in cases and controls respectively. In summary, the combined use with a total of 9 concomitant medications including vitamin C, potassium chloride, ribavirin, lidocaine, pantoprazole, gentamicin, aminophylline, amoxicillin-clavulanate, and cefoperazone-sulbactam were associated with the increased risk of allergic reactions. The combined use with 14 medications were found independent with the risk of allergic reactions, including ambroxol, vitamin B6, levofloxacin, azithromycin, penicillin, heparin, bromhexine, cefuroxime, sodium bicarbonate, cefazolin, ceftazidime, ceftriaxone, amikacin, and moxifloxacin. And the concomitant use of cefathiamidine was associated with decreased risk of allergic reactions.
Table 3 Univariate analyses results
Concomitant Medication
|
Cases with Exposure
(N = 949)
|
Controls with Exposure
(N = 949)
|
OR
|
95% CI
|
P value
|
Ambroxol
|
274
|
242
|
1.2
|
1.0, 1.5
|
0.1
|
Vitamin C
|
268
|
203
|
1.5
|
1.2, 1.9
|
<0.01
|
Potassium Chloride
|
209
|
159
|
1.4
|
1.1, 1.8
|
<0.01
|
Ribavirin
|
159
|
105
|
1.8
|
1.3, 2.3
|
<0.01
|
Vitamin B6
|
114
|
118
|
1.0
|
0.7, 1.3
|
0.78
|
Levofloxacin
|
97
|
75
|
1.3
|
1.0, 1.9
|
0.07
|
Lidocaine
|
93
|
38
|
2.8
|
1.9, 4.3
|
<0.01
|
Pantoprazole
|
90
|
67
|
1.4
|
1.0, 2.0
|
0.05
|
Azithromycin
|
86
|
75
|
1.2
|
0.8, 1.6
|
0.36
|
Gentamicin
|
84
|
20
|
4.6
|
2.7, 7.6
|
<0.01
|
Penicillin
|
77
|
85
|
0.9
|
0.7, 1.2
|
0.52
|
Heparin
|
72
|
64
|
1.1
|
0.8, 1.6
|
0.46
|
Bromhexine
|
65
|
74
|
0.9
|
0.6, 1.2
|
0.44
|
Cefuroxime
|
60
|
55
|
1.1
|
0.7, 1.6
|
0.62
|
Aminophylline
|
56
|
33
|
1.9
|
1.2, 3.0
|
0.01
|
Sodium Bicarbonate
|
45
|
52
|
0.9
|
0.6, 1.3
|
0.85
|
Cefazolin
|
44
|
32
|
1.4
|
0.9, 2.2
|
0.16
|
Amoxicillin-Clavulanate
|
43
|
24
|
1.8
|
1.1, 3.0
|
0.02
|
Ceftazidime
|
30
|
23
|
1.3
|
0.8, 2.3
|
0.33
|
Ceftriaxone
|
23
|
17
|
1.4
|
0.7, 2.5
|
0.34
|
Cefathiamidine
|
18
|
52
|
0.3
|
0.2, 0.6
|
<0.01
|
Cefoperazone-Sulbactam
|
17
|
4
|
4.3
|
1.4, 12.6
|
<0.01
|
Meropenem
|
10
|
0
|
-
|
-
|
-
|
Amikacin
|
9
|
4
|
2.2
|
0.7, 7.3
|
0.07
|
Moxifloxacin
|
9
|
13
|
0.7
|
0. 3, 1.6
|
0.37
|
Abbreviations: OR, Odds ratio; CI, Confidence Interval.
3.3 Multivariable Conditional Logistic Regression Analysis
The results of multivariable conditional logistic regression on 25 target concomitant medications showed that the combined use of XYP with 7 medications were associated with increased risk of allergic reactions, including gentamicin (OR = 4.3; 95% CI [2.5, 7.3]), cefoperazone-sulbactam (OR = 4.3; 95% CI [1.4, 13.0]), lidocaine (OR = 2.8; 95% CI [1.8 , 4.2]), aminophylline (OR = 1.7; 95% CI [1.1, 2.9]), ribavirin (OR = 1.5; 95% CI [1.1, 2.1]), potassium chloride (OR = 1.4; 95% CI [1.1, 1.9]), and vitamin C (OR = 1.3; 95% CI [1.0, 1.7]), while the concomitant use with cefathiamidine (OR = 0.3; 95% CI [0.2, 0.5]) was the only one found associated with reduced risk of allergic reactions (Table 4).
Table 4 Multivariable conditional logistic regression analysis results
Concomitant Medication
|
OR
|
95% CI
|
P value
|
Gentamicin
|
4.3
|
2.5, 7.3
|
<0.01
|
Cefoperazone-Sulbactam
|
4.3
|
1.4, 13.0
|
0.01
|
Lidocaine
|
2.8
|
1.8, 4.2
|
<0.01
|
Aminophylline
|
1.7
|
1.1, 2.9
|
0.03
|
Ribavirin
|
1.5
|
1.1, 2.1
|
0.01
|
Potassium Chloride
|
1.4
|
1.1, 1.9
|
0.01
|
Vitamin C
|
1.3
|
1.0, 1.7
|
0.03
|
Cefathiamidine
|
0.3
|
0.2, 0.5
|
<0.01
|
Abbreviations: OR, Odds ratio; CI, Confidence interval.
3.4 Sensitivity Analysis
After further including cases with anti-allergic marker drugs and XYP prescribed on the same day, and stopped using XYP on the next day, the sample for analysis was expanded to 2,438 cases matched with 2,438 controls, yielded a total of 4,876 for sensitivity analyses. Overall, sensitivity analysis results were consistent with the primary analyses. When concomitantly used with XYP, 6 medications remained associated with increased risk of allergic reactions, including gentamicin (OR = 6.3; 95% CI [4.2, 9.6]), lidocaine (OR = 4.5; 95% CI [3.3, 6.0]), aminophylline (OR = 2.5; 95% CI [1.8, 3.6]), ribavirin (OR = 1.8; 95% CI [1.4, 2.2]), vitamin C (OR = 1.5; 95% CI [1.3, 1.8]), and potassium chloride (OR = 1.4; 95% CI [1.1, 1.7]). Cefathiamidine (OR = 0.6; 95% CI [0.4, 0.9]) remained associated with reduced risk (Appendices Tables 5-7).