Disproportionality analysis of buprenorphine transdermal system and cardiac arrhythmia using FDA and WHO postmarketing reporting system data

Figures & data

Figure 1. Disproportionality analysis of cardiac arrythmia events reported to FDA between 1969 and December 2015. The figure displays Empirical Bayesian Geometric Mean (EBGM) Values and Upper (EB95) and Lower (EB05) limits of the 90% Confidence Intervals for cardiac arrhythmia events by opioid product grouping. A standard measure of an increase in disproportionality is an EB05 of ≥ 2.

Broad: includes 1 or more of 20 adverse event terms: electrocardiogram QT interval abnormal, electrocardiogram QT prolonged, long QT syndrome, long QT syndrome congenital, torsade de pointes, and ventricular tachycardia cardiac arrest, cardiac death, cardiac fibrillation, cardio-respiratory arrest, electrocardiogram repolarization abnormality, electrocardiogram U-wave abnormality, loss of consciousness, sudden cardiac death, sudden death, syncope, ventricular arrhythmia, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia.

Narrow: includes 1 or more of 6 adverse event terms: electrocardiogram QT interval abnormal, electrocardiogram QT prolonged, long QT syndrome, long QT syndrome congenital, torsade de pointes, and ventricular tachycardia.

Table 1. Cardiac arrhythmia disproportionality results, FAERS database, 1969-30 December 2015 (8,270,285 total cases).

	Buprenorphine								Methadone		Fentanyl
Opioid grouping	All formulations N = 32,067		Transdermal N = 22,454		BTDS 5–20 mcg/h N = 21,610		Tab/film with naloxone N = 11,206		All formulations N = 26,519		All formulations N = 88,335		Transdermal N = 39,976
Case characteristics	N	%	N	%	N	%	N	%	N	%	N	%	N	%
Arrhythmia (broad search)^1	467	1	124	<1%	85	<1%	411	4	3206	12%	4794	5	1132	3
Age (years)
0–17	29	6	1	1	1	1	17	4	133	4	272	6	13	1
18–64	225	48	39	31	24	28	309	75	2687	84	2780	58	573	51
65–109	97	21	25	20	10	12	14	3	90	3	973	20	229	20
Unspecified	116	25	59	48	50	59	71	17	296	9	769	16	317	28
Gender
Female	203	43	67	54	44	52	205	50	1071	33	2379	50	614	54
Male	240	51	52	42	38	45	189	46	1429	45	2153	45	474	42
Unspecified	24	5	5	4	3	4	17	4	706	22	262	5	44	4
Drug category
Primary suspect	432	93	124	100	85	100	411	100	3156	98	4367	91	1120	99
Disproportionality results	Count^2	EB05^3	Count	EB05	Count	EB05	Count	EB05	Count	EB05	Count	EB05	Count	EB05
Arrhythmia (broad search)^1	467	0.74	124	0.33	85	0.24	411	1.40	3206	3.26	4794	1.76	1132	0.95
-Gender
Males only	240	0.79	52	0.31	38	0.24	189	1.25	1429	3.21	2153	1.66	474	0.87
Females only	203	0.64	67	0.30	44	0.21	205	1.73	1071	3.57	2379	1.84	614	1.02
Not specified	24	0.66	5	0.70	3	0.43	17	0.35	706	2.69	262	1.53	44	0.49
-Age
<65 years	254	1.00	40	0.50	25	0.33	326	1.49	2820	3.40	3052	2.09	586	1.06
≥65 years	97	0.97	25	0.44	10	0.26	14	1.29	90	1.27	973	1.18	229	0.62
Not specified	116	0.37	59	0.22	50	0.18	71	0.92	296	2.93	769	1.58	317	1.01
-Arrhythmia (narrow search)^1	66	0.91	19	0.46	15	0.39	9	0.18	664	6.89	538	1.53	41	0.23
ECG QT interval abnormal	2	0.65	1	0.42	1	0.42	–	–	1	0.39	–	–	–	–
ECG QT prolonged	41	0.94	18	0.72	14	0.58	6	0.19	460	8.67	173	0.93	22	0.22
Long QT syndrome	2	0.45	–	–	–	–	1	0.28	15	3.28	17	1.48	–	–
Long QT syndrome congenital	–	–	–	–	–	–	–	–	–	–	1	0.45	–	–
Torsade de pointes	12	0.98	1	0.19	1	0.20	1	0.13	334	22.16	101	1.44	6	0.14
Ventricular tachycardia	22	0.67	–	–	–	–	3	0.16	150	3.38	331	2.03	14	0.17

BTDS: BUTRANS® – buprenorphine transdermal delivery system.

¹Broad: includes 1 or more of 20 adverse event terms: electrocardiogram QT interval abnormal, electrocardiogram QT prolonged, long QT syndrome, long QT syndrome congenital, torsade de pointes, and ventricular tachycardia cardiac arrest, cardiac death, cardiac fibrillation, cardio-respiratory arrest, electrocardiogram repolarization abnormality, electrocardiogram U-wave abnormality, loss of consciousness, sudden cardiac death, sudden death, syncope, ventricular arrhythmia, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia.

Narrow: includes 1 or more of 6 adverse event terms: electrocardiogram QT interval abnormal, electrocardiogram QT prolonged, long QT syndrome, long QT syndrome congenital, torsade de pointes, and ventricular tachycardia.

²Count = total cases with an adverse event–drug pair.

³EB05 = Lower limit of the 90% empiric Bayes geometric mean confidence interval; a value ≥2 (highlighted in boldface) indicates a disproportionate number of adverse event reports.

Table 2. Cardiac arrhythmia disproportionality results, VigiBase database, 1978–June 2014 (9,350,995 total cases).

	Buprenorphine								Methadone
	All formulations N = 16,266		Transdermal N = 5095		BTDS-N 5–20 mcg/h N = 2118		BTDS-T 35–70 mcg/h N = 1638		All formulations N = 20,167
Case Characteristics	N	%	N	%	N	%	N	%	N	%
Arrhythmia (broad search)^1	386	2	77	2	20	1	26	2	2913	14
Age (years)
0–17	16	4	1	1	0	0	0	0	112	4
18–64	225	58	25	32	7	35	11	42	2460	84
65–109	78	20	29	38	13	65	13	50	56	2
Unspecified	67	17	22	29	0	0	2	8	285	10
Gender
Female	194	50	47	61	10	50	18	69	960	33
Male	181	47	30	39	10	50	8	31	1308	45
Unknown	11	3	0	0	0	0	0	0	645	22
Drug category
Primary suspect	304	79	64	83	12	60	11	42	2412	83
Disproportionality results	Count^2	IC025^3	Count	IC025	Count	IC025	Count	IC025	Count	IC025
Arrhythmia (broad search)^1	386	−0.04	77	−0.88	20	−1.90	26	−1.07	2913	2.66
-Gender
Males only	181	−0.04	30	−1.12	10	−1.73	8	−1.92	1308	2.35
Females only	194	−0.15	47	−0.95	10	−2.51	18	−1.01	960	2.46
-Age
≥65 years	78	−0.73	29	−1.04	13	−1.79	13	−1.74	56	0.69
-Arrhythmia (narrow search)^1	20	−1.63	5	−2.72	1	−5.68	1	−5.34	538	3.36
ECG QT interval abnormal	1	−2.93	0	−10.25	0	−10.10	0	−10.08	8	2.07
ECG QT prolonged	10	−1.90	5	−1.73	0	−12.54	1	−4.46	379	3.86
Long QT syndrome	2	−1.57	0	−10.54	0	−10.24	0	−10.19	14	2.51
Long QT synd.congenital	0	−10.03	0	−10.00	0	−9.99	0	−9.99	0	−10.04
Torsade de pointes	7	−1.29	1	−4.66	1	−3.73	0	−11.27	260	4.62
Ventricular tachycardia	5	−3.17	0	−13.51	1	−4.63	0	−12.11	100	1.95

BTDS-N: NORSPAN® (buprenorphine transdermal delivery system 5–20 mcg/h); BTDS-T: TRANSTEC® (buprenorphine transdermal delivery system 35–70 mcg/h).

¹Broad: includes 1 or more of 20 adverse event terms: electrocardiogram QT interval abnormal, electrocardiogram QT prolonged, long QT syndrome, long QT syndrome congenital, torsade de pointes, and ventricular tachycardia cardiac arrest, cardiac death, cardiac fibrillation, cardio-respiratory arrest, electrocardiogram repolarization abnormality, electrocardiogram U-wave abnormality, loss of consciousness, sudden cardiac death, sudden death, syncope, ventricular arrhythmia, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia.

Narrow: includes 1 or more of 6 adverse event terms: electrocardiogram QT interval abnormal, electrocardiogram QT prolonged, long QT syndrome, long QT syndrome congenital, torsade de pointes, and ventricular tachycardia.

²Count = total cases with an adverse event–drug pair.

³IC025 = Lower limit of the 95% informational component credibility interval; a value ≥0 (highlighted in boldface) indicates a disproportionate number of adverse event reports.