Real-World Safety and Effectiveness of Tadalafil in Patients with Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: A Japanese Post-Marketing Surveillance Study

Figures & data

Figure 1 Patient population for the safety and effectiveness analysis.

Abbreviations: CRF, case report form; n, number of patients.

Table 1 Baseline Demographics and Patient Characteristics

Category	Variable	Safety Population
		(n = 1393)
Age (years)	Mean ± SD	69.3 ± 8.8
	<75	976	(70.1)
	≥75	417	(29.9)
BPH/LUTS duration (years)	<1	439	(31.5)
	≥1–<5	518	(37.2)
	≥5	299	(21.5)
	Unknown	137	(9.8)
eGFR stage	G1 (≥90)	52	(3.7)
	G2 (≥60–<90)	410	(29.4)
	G3a (≥45–<60)	138	(9.9)
	G3b (≥30–<45)	34	(2.4)
	G4 (≥15–<30)	3	(0.2)
	Not tested	756	(54.3)
Prostate volume (cm^3)	<20	160	(11.5)
	≥20–<30	382	(27.4)
	≥30–<40	324	(23.3)
	≥40–<50	155	(11.1)
	≥50–<60	84	(6.0)
	≥60	113	(8.1)
	Not tested	175	(12.6)
Prostate specific antigen (ng/mL)	<4	691	(49.6)
	≥4–<10	169	(12.1)
	≥10	28	(2.0)
	Not tested	505	(36.3)
BPH/LUTS severity (total IPSS)	Mild (≤7)	131	(9.4)
	Moderate (8–19)	674	(48.4)
	Severe (20–35)	351	(25.2)
	Not tested	237	(17.0)

Note: Values are presented as mean ± standard deviation or number (%).

Abbreviations: BPH/LUTS, lower urinary tract symptoms secondary to benign prostatic hyperplasia; eGFR, estimated glomerular filtration rate; IPSS, International Prostate Symptom Score; SD, standard deviation.

Table 2 Patient’s Medical Background

Category	Variable	Safety Population
		(n = 1393)
Complication	No	760	(54.6)
	Yes* (top 5)	631	(45.3)
	Hypertension	352	(55.8)
	Diabetes	114	(18.1)
	Hypertonic bladder	75	(11.9)
	Hyperuricemia	59	(9.4)
	Hyperlipidemia	58	(9.2)
	Unknown	2	(0.1)
Previous medication	No	798	(57.3)
(BPH/LUTS specific)	Yes*	593	(42.6)
	Alpha-blockers	511	(86.2)
	5-alpha reductase inhibitors	107	(18.0)
	Antiandrogen drugs	2	(0.3)
	Other BPH/LUTS drugs	77	(13.0)
	Unknown	2	(0.1)
Previous surgical treatment	No	1354	(97.2)
(BPH/LUTS specific)	Yes	38	(2.7)
	Unknown	1	(0.1)
Concurrent medication	No	603	(43.3)
	Yes*	788	(56.6)
	Alpha-blockers	482	(61.2)
	5-alpha reductase inhibitors	142	(18.0)
	Antiandrogen drugs	6	(0.8)
	Strong CYP3A4 inhibitors	1	(0.1)
	Other BPH/LUTS drugs	85	(10.8)
	None of the above ^†	396	(50.3)
	Unknown	2	(0.1)

Notes: *Patients may appear in more than one category. ^†All other concurrent medications except BPH/LUTS drugs. Values are presented as number (%).

Abbreviations: BPH/LUTS, lower urinary tract symptoms secondary to benign prostatic hyperplasia; CYP3A4, cytochrome P450 3A4.

Figure 2 Persistence with treatment during the 18-month observation study (Kaplan–Meier curve). *At 12 months, 4 patients were censored because they had final exposure information and were not considered to have discontinued tadalafil treatment. At 18 months, patients with continuous tadalafil treatment were considered as right-censored.

Abbreviation: CI, confidence interval.

Table 3 Number and Frequency of Adverse Drug Reactions During Tadalafil Treatment

Variable	n (%)
	Total		<75 Years		≥75 Years
Number of patients analyzed	1393		976		417
Number of patients experienced ADR	115		75		40
Incidence* (%) (b/a × 100)	8.3		7.7		9.6
MedDRA PT^†, n (%)
Headache	21	(1.5)	16	(1.6)	5	(1.2)
Dyspepsia	7	(0.5)	6	(0.6)	1	(0.2)
Spontaneous penile erection	7	(0.5)	6	(0.6)	1	(0.2)
Palpitations	5	(0.4)	2	(0.2)	3	(0.7)
Diarrhea	5	(0.4)	3	(0.3)	2	(0.5)
Pollakiuria	5	(0.4)	3	(0.3)	2	(0.5)
Blood pressure decreased	5	(0.4)	2	(0.2)	3	(0.7)
Dizziness	4	(0.3)	2	(0.2)	2	(0.5)
Vision blurred	3	(0.2)	3	(0.3)	0	(0.0)
Dysuria	3	(0.2)	2	(0.2)	1	(0.2)
Malaise	3	(0.2)	2	(0.2)	1	(0.2)

Notes: *Fisher exact test or chi-square test was performed between the two age groups. ^†Frequently reported ADRs (≥3 incidence) in total population were selected.

Abbreviations: ADRs, adverse drug reactions; MedDRA, Medical Dictionary for Regulatory Activities version 20.0; PT, preferred term.

Table 4 Long-Term Safety During Tadalafil Treatment

Variable	n (%)
	Entire Period		≤3M		4–6M		7–12M		≥12M
Number of patients analyzed	1393		1393		1086		970		817
Number of patients experienced ADR	115		90		12		4		3
Incidence (%) (b/a × 100)	8.3		6.5		1.1		0.4		0.4
MedDRA PT*, n (%)
Headache	21	(1.5)	19	(1.4)	1	(0.1)	0	(0.0)	0	(0.0)
Dyspepsia	7	(0.5)	5	(0.4)	1	(0.1)	0	(0.0)	0	(0.0)
Spontaneous penile erection	7	(0.5)	5	(0.4)	1	(0.1)	0	(0.0)	0	(0.0)
Palpitations	5	(0.4)	5	(0.4)	0	(0.0)	0	(0.0)	0	(0.0)
Diarrhea	5	(0.4)	4	(0.3)	0	(0.0)	0	(0.0)	0	(0.0)
Pollakiuria	5	(0.4)	4	(0.3)	1	(0.1)	0	(0.0)	0	(0.0)
Blood pressure decreased	5	(0.4)	5	(0.4)	0	(0.0)	0	(0.0)	0	(0.0)
Dizziness	4	(0.3)	2	(0.1)	1	(0.1)	1	(0.1)	0	(0.0)
Vision blurred	3	(0.2)	1	(0.1)	1	(0.1)	1	(0.1)	0	(0.0)
Dysuria	3	(0.2)	2	(0.1)	1	(0.1)	0	(0.0)	0	(0.0)
Malaise	3	(0.2)	3	(0.2)	0	(0.0)	0	(0.0)	0	(0.0)
Abdominal discomfort	2	(0.1)	1	(0.1)	0	(0.0)	0	(0.0)	1	(0.1)
Constipation	2	(0.1)	1	(0.1)	0	(0.0)	0	(0.0)	1	(0.1)
Myocardial infarction	1	(0.1)	0	(0.0)	0	(0.0)	0	(0.0)	1	(0.1)

Note: *Frequently reported ADRs (≥3 incidence) over an entire period and ADRs reported after 12 months were selected.

Abbreviations: ADRs, adverse drug reactions; M, months; MedDRA, Medical Dictionary for Regulatory Activities version 20.0; PT, preferred term.

Table 5 Mean Change from Baseline in Vital Signs During Tadalafil Treatment

Observation Period	n	Mean	95% CI
Systolic Blood Pressure (mmHg)
1M	481	−3.2	−4.4 to –2.0
2M	325	−2.8	−4.3 to –1.3
3M	419	−2.0	−3.4 to –0.5
6M	396	−1.3	−2.8 to 0.2
9M	297	−4.2	−6.0 to –2.5
12M	337	−3.5	−5.2 to –1.8
18M	310	−1.9	−3.7 to 0.0
LOCF	587	−2.1	−3.4 to –0.8
Diastolic Blood Pressure (mmHg)
1M	481	−2.5	−3.3 to –1.6
2M	325	−2.9	−3.9 to –1.8
3M	419	−2.7	−3.7 to –1.7
6M	395	−2.5	−3.5 to –1.4
9M	297	−3.9	−5.1 to –2.8
12M	337	−3.4	−4.4 to –2.3
18M	310	−2.8	−4.0 to –1.6
LOCF	586	−2.8	−3.6 to –1.9

Abbreviations: CI, confidence interval; LOCF, last observation carried forward; M, month(s); n, number of patients analyzed.

Table 6 Effect of Tadalafil on Maximum Urinary Flow Rate and Post-Voiding Residual Urine Volume

	Observation Period	Measured Value			Mean Change From Baseline
		n	Mean	SD	n	Mean	95% CI
Qmax (mL/s)	Baseline	333	13.4	6.83	−	−	−
	3M	213	14.0	5.7	124	0.50	−0.62 to 1.61
	6M	217	13.7	6.29	118	0.36	−0.94 to 1.66
	12M	176	13.5	5.88	99	−0.43	−1.91 to 1.04
	18M	159	13.8	5.98	83	1.01	−0.19 to 2.21
	LOCF	578	11.7	6.52	236	−0.65	−1.53 to 0.24
PVR (mL)	Baseline	1006	45.9	65.7	−	−	−
	3M	545	37.8	54.1	484	−12.7	−17.9 to –7.6
	6M	550	42.7	70.7	486	−8.0	−13.3 to –2.6
	12M	473	37.4	55.5	409	−9.0	−14.4 to –3.7
	18M	427	33.9	48.8	371	−9.8	−15.2 to –4.5
	LOCF	848	41.8	72.8	699	−7.6	−12.5 to –2.7

Abbreviations: CI, confidence interval; LOCF, last observation carried forward; M, months; n, number of patients analyzed; PVR, post-voiding residual urine volume; Q_max, maximum urinary flow rate; SD, standard deviation.

Table 7 Effect of Tadalafil on Total IPSS and IPSS-QOL

	Observation Period	Measured Value			Mean Change From Baseline
		n	Mean	SD	n	Mean	95% CI
Total IPSS	Baseline	1150	15.8	6.9	−	−	−
	1M	861	12.5	6.5	818	−3.4	−3.8 to –3.1
	3M	717	11.3	6.1	685	−4.5	−5.0 to –4.1
	6M	701	11.2	6.3	663	−4.7	−5.1 to –4.2
	12M	577	11.1	6.5	553	−4.7	−5.2 to –4.2
	18M	485	11.0	6.2	467	−5.0	−5.6 to –4.4
	LOCF	1063	11.5	6.8	988	−4.3	−4.7 to –3.9
IPSS-QOL	Baseline	1149	4.2	1.1	−	−	−
	1M	856	3.4	1.4	815	−0.9	−1.0 to –0.8
	3M	718	3.0	1.3	686	−1.2	−1.3 to –1.1
	6M	702	2.8	1.4	664	−1.4	−1.5 to –1.3
	12M	580	2.8	1.3	554	−1.5	−1.6 to –1.3
	18M	484	2.7	1.3	465	−1.5	−1.6 to –1.4
	LOCF	1059	3.0	1.4	989	−1.3	−1.4 to –1.2

Abbreviations: CI, confidence interval; IPSS, International Prostate Symptom Score; LOCF, last observation carried forward; M, month(s); n, number of patients analyzed; QOL, quality of life; SD, standard deviation.