Menopause: The Journal of The North American Menopause Society Vol. 22, No. 10, pp. 1134-1137 DOI: 10.1097/GME.0000000000000441 ß 2015 by The North American Menopause Society
BRIEF REPORT Safety of 3-year raloxifene treatment in Japanese postmenopausal women aged 75 years or older with osteoporosis: a postmarketing surveillance study Yasuhiro Takeuchi, MD, PhD,1 Etsuro Hamaya, RPh,2 Masanori Taketsuna, MSc,3 and Hideaki Sowa, MD, PhD 2 Abstract Objective: Long-term safety of medication is a concern for older persons because they may have several comorbidities that can influence drug metabolism, efficacy, and safety. In Japan, raloxifene is an effective and welltolerated medication for the treatment of osteoporosis in postmenopausal women, but there is little available evidence on whether raloxifene has an acceptable safety profile in older women. The objective of this post hoc analysis was to investigate the safety of raloxifene as a long-term treatment of osteoporosis in Japanese postmenopausal women aged 75 years or older. Methods: We report a post hoc analysis of a safety dataset (6,960 participants) from a published postmarketing surveillance study (postmenopausal women treated with raloxifene 60 mg/d for 3 y). The safety dataset was divided into two groups: (1) women younger than 75 years at baseline (4,522 participants) and (2) women aged 75 years or older at baseline (2,438 participants). Incidence of adverse drug reactions and reactions of note in each age group were compared using Fisher’s exact test. Results: Approximately 10% of women in each group reported at least one adverse drug reaction. This analysis did not identify any clinically important differences in the incidence or type of adverse drug reactions reported or in reactions of note between women aged 75 years or older and younger women. Conclusions: There were no obvious additional safety concerns for women aged 75 years or older who were treated with raloxifene. The findings in this post hoc evaluation suggest no differences in adverse events in the age groups evaluated. Key Words: Aged – Japan – Postmenopausal osteoporosis – Raloxifene – Safety.
aloxifene (RLX), a selective estrogen receptor modulator, is a medication for the long-term treatment of osteoporosis in postmenopausal women. In large-scale global clinical trials, RLX effectively reduced the risk of vertebral fracture at 3 years1 and at 4 years.2 In addition, RLX reduced the incidence of nonvertebral fractures in postmenopausal women with severe prevalent vertebral fractures at 3 years3 and increased
R
bone mineral density (BMD) for all women for at least 7 years.4 From a safety perspective, RLX is well tolerated in the long term. The Multiple Outcomes of Raloxifene Evaluation study (mean follow-up, 3.3 y) found that the only increased safety risk for women treated with RLX, compared with those receiving placebo, was for the clinically important adverse event venous thromboembolism (relative risk, 2.1).5
Received October 27, 2014; revised and accepted December 30, 2014. From the 1Toranomon Hospital Endocrine Center, Tokyo, Japan; 2 Medical Science, Medicines Development Unit Japan, Eli Lilly Japan KK, Kobe, Hyogo, Japan; and 3Asia Pacific Statistical Sciences, Medicines Development Unit Japan, Eli Lilly Japan KK, Kobe, Hyogo, Japan. ProScribe’s services complied with international guidelines for Good Publication Practice (GPP2). Eli Lilly Japan was involved in the study design, data collection, data analysis, and preparation of the manuscript. All authors participated in the interpretation of study results, and in the drafting, critical revision, and approval of the final version of the manuscript. E.H. was involved in the study design and data analyses. Statistical analysis was planned by M.T. and performed by EPS Corp (Tokyo, Japan). Funding/support: This study was sponsored by Eli Lilly and Company (manufacturer of raloxifene). Medical writing assistance was provided by
Janelle Keys, PhD, and Rebecca Lew, PhD, CMPP, of ProScribe (part of the Envision Pharma Group) and was funded by Eli Lilly Japan KK. Financial disclosure/conflicts of interest: Y.T. has received honoraria for speaking from Eli Lilly Japan KK, Chugai Pharma, Daiichi-Sankyo, Taisho Toyama Pharma, Teijin Pharma, Ono Pharmaß, Merck Sharp and Dohme, and Asahi Kasei Pharma. M.T. and H.S. are employees of Eli Lilly Japan KK. E.H. is a former employee of Eli Lilly Japan KK and current employee of R&D Japan at Amgen Astellas Biopharm KK (Tokyo, Japan). E.H. and H.S. are stockholders of Eli Lilly andCompany. Address correspondence to: Hideaki Sowa, MD, PhD, Medical Science, Medicines Development Unit Japan, Eli Lilly Japan KK, 7-1-5 Isogamidori, Chuo-ku, Kobe 651-0086, Japan. E-mail: sowa_hideaki@ lilly.com
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Menopause, Vol. 22, No. 10, 2015
Copyright @ 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
RALOXIFENE IN JAPANESE POSTMENOPAUSAL WOMEN
In Japan, treatment with RLX is recommended for postmenopausal women with osteoporosis.6 Daily use of RLX in Japan has been studied in a 3-year prospective postmarketing surveillance study of 7,557 Japanese postmenopausal women with osteoporosis.7 The study demonstrated that the long-term effectiveness outcomes of RLX treatment were reflective of clinical practice; lumbar spine BMD increased significantly across time, and the incidence of new clinical fractures was low (1.18%). In addition, treatment with RLX for up to 3 years was well tolerated by Japanese postmenopausal women with osteoporosis; 11% of participants reported an adverse drug reaction (ADR), and only 1% of ADRs were serious. Given that the number of women with osteoporosis in Japan increases substantially with age,8 long-term treatment with RLX is expected to be commonplace in women aged 75 years or older. For this reason, we believe that the long-term safety of RLX in Japanese postmenopausal women aged 75 years or older with osteoporosis is an issue worthy of consideration. In addition, long-term safety is an important concern for older persons because they may have several comorbidities that can influence drug metabolism, efficacy, and safety. However, there is little available evidence on whether RLX displays the same safety profile in postmenopausal women aged 75 years or older and younger women. Therefore, the aim of this post hoc analysis of a postmarketing surveillance study7 was to investigate the safety of RLX as a long-term treatment of osteoporosis in Japanese postmenopausal women aged 75 years or older. METHODS Postmarketing surveillance study The safety and effectiveness of RLX for long-term use in Japanese postmenopausal women with osteoporosis were assessed in a large-scale postmarketing surveillance study.7 In brief, the participants included in the surveillance study were postmenopausal women with primary osteoporosis,9 which physicians intended to treat with RLX 60 mg/day (Evista; Eli Lilly and Company, Indianapolis, IN). Participants were included if they were ambulatory, had not been previously prescribed RLX, and were available for follow-up. Participants were excluded as per the RLX package insert, and any participants judged by the investigator to be inappropriate were also excluded. A total of 7,557 participants met the inclusion criteria and gave a written informed consent form to participate. Safety population Safety population was defined as participants who received at least one dose of RLX. The follow-up period from the start of RLX treatment (baseline) was 3 years (as requested by the Japanese Ministry of Health, Labor, and Welfare), although not all participants completed the 3-year visit; the mean (SD) dosing period for the safety population was 614 (458) days. A total of 953 institutions participated in the surveillance study; the observation period for safety was from October 1, 2004 to May 31, 2009. Safety was assessed by report of ADRs, with particular note of ADRs related to stroke, coronary heart disease, venous thromboembolism, and breast/gynecological
cancer (as requested by the Japanese Ministry of Health, Labor and Welfare). ADRs were coded using MedDRA (Medical Dictionary for Regulatory Activities) version 12.0. Of the 7,557 participants enrolled, 590 were excluded from the safety population (378 did not return after the first visit, 195 had uncollectable case cards, 16 had unconfirmed drug administration, and 1 had off-label use). Baseline characteristics of the safety population are presented by Iikuni et al.7 Statistical analysis Here, we report a post hoc analysis of a safety dataset from a postmarketing surveillance study.7 For this post hoc analysis, the safety dataset was divided into two groups: (1) women younger than 75 years at baseline and (2) women aged 75 years or older at baseline (seven participants were excluded from the post hoc analysis because their age was not specified). Incidence of ADRs and ADRs of note in each age group were compared using Fisher’s exact test (P < 0.05 was considered statistically significant). All statistical analyses were conducted using SAS version 9.1 (SAS Institute, Cary, NC). RESULTS A total of 6,960 participants from the safety dataset of the postmarketing surveillance study7 were included in this post hoc analysis. A total of 4,522 (65.0%) participants were younger than 75 years, whereas 2,438 (35.0%) participants were aged 75 years or older. ADRs were reported by approximately 10% of women in each group (Table 1); approximately 1% of ADRs were serious (Table 1). The most frequent serious ADR for women younger than 75 years was cerebral infarction (n ¼ 5). The most frequent serious ADRs for women aged 75 years or older were cerebral infarction (n ¼ 3), cardiac failure (n ¼ 3), and femoral neck fracture (n ¼ 3). Very few deaths were reported (Table 1). Women in both age groups reported a low incidence of cardiovascular ADRs of note, including ADRs related to stroke, coronary heart disease, and venous thromboembolism; there were no differences between age groups (Table 1). ADRs related to gynecological cancer were only reported by women younger than 75 years (Table 1). There were no clinically important between-group differences in the most frequent ADRs reported (Table 2). Although there were statistically significant between-group differences in gastritis (higher incidence in women younger than 75 y), abnormal hepatic function (higher incidence in women younger than 75 y), and diarrhea (higher incidence in women aged 75 y or older), these differences were not considered clinically important. DISCUSSION This post hoc analysis did not identify any clinically important age-related differences in the incidence or type of ADRs reported by Japanese postmenopausal women with osteoporosis who were treated with RLX for up to 3 years. Of note, there was no evidence of obvious safety concerns for women aged 75 years or older who were treated with RLX. These findings reassure clinicians that RLX is a long-term treatment option for postmenopausal women with osteoporosis, regardless of age. Menopause, Vol. 22, No. 10, 2015
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Copyright @ 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
TAKEUCHI ET AL TABLE 1. Overall ADRs and incidence of ADRs of note, by age group, in a postmarketing surveillance study of Japanese postmenopausal women with osteoporosis who were treated with raloxifene 60 mg/day for up to 3 years ADR
Women younger than 75 y (N ¼ 4,522)
Women aged 75 y or older (N ¼ 2,438)
Pa
541 (11.96) 673 40 (0.88) 45 2
235 (9.64) 289 36 (1.48) 42 1
0.003 – 0.029 – –
Overall ADRs Participants reporting ADRs ADRs reported Participants reporting a serious ADR Serious ADRs reported Deaths ADRs of note ADRs related to stroke Cerebral infarction Cerebral hemorrhage Thrombotic stroke ADRs related to coronary heart disease Angina pectoris Myocardial ischemia Prinzmetal angina Myocardial infarction ADRs related to venous thromboembolism Deep vein thrombosis Thrombophlebitis Venous thrombosis ADRs related to breast/gynecological cancer Breast cancer Ovarian cancer recurrent Ovarian adenoma
7 7 (0.15)b 0 0 5 3 (0.07)d 1 (0.02) 1 (0.02) 0 6 4 (0.09)f 1 (0.02) 1 (0.02) 8h 4 (0.09) 3 (0.07) 1 (0.02)
5 3 (0.12)c 1 (0.04) 1 (0.04) 1 0 0 0 1 (0.04)e 5 3 (0.12)g 2 (0.08) 0 0 0 0 0
0.663 0.350 0.350 0.556 1.000 1.000 0.350 0.702 0.282 1.000 0.305 0.556 1.000
ADRs were coded using on MedDRA version 12.0. Data are presented as n (%). ADR, adverse drug reaction. a Difference between age groups by Fisher’s exact test. b Five cases were serious. c Three cases were serious. d One case was serious. e This case was serious. f Two cases were serious. g One case was serious. h All cases were serious.
TABLE 2. Incidence of frequent ADRs (reported by 10 participants), by age group, in a postmarketing surveillance study of Japanese postmenopausal women with osteoporosis who were treated with raloxifene 60 mg/day for up to 3 years Safety dataset (N ¼ 6,967)a
ADR Edema peripheral Abdominal discomfort Abdominal pain upper Hot flash Nausea Constipation Dizziness Gastritis Pruritus Muscle spasms Rash Hypertension Hyperhidrosis Diarrhea Hypoesthesia Stomatitis Abdominal distension Insomnia Reflux esophagitis Hepatic function abnormal Cerebral infarction Headache Gastrointestinal disorder
45 39 33 32 31 29 27 25 23 20 19 18 17 16 15 14 13 12 11 11 10 10 10
(0.65) (0.56) (0.47) (0.46) (0.44) (0.42) (0.39) (0.36) (0.33) (0.29) (0.27) (0.26) (0.24) (0.23) (0.22) (0.20) (0.19) (0.17) (0.16) (0.16) (0.14) (0.14) (0.14)
Women younger than 75 y (N ¼ 4,522) 28 21 19 25 25 20 16 24 16 15 13 10 13 6 11 12 10 10 8 11 7 7 8
(0.62) (0.46) (0.42) (0.55) (0.55) (0.44) (0.35) (0.53) (0.35) (0.33) (0.29) (0.22) (0.29) (0.13) (0.24) (0.27) (0.22) (0.22) (0.18) (0.24) (0.15) (0.15) (0.18)
Women aged 75 y or older (N ¼ 2,438)
Pb
17 (0.70) 18 (0.74) 14 (0.57) 7 (0.29) 6 (0.25) 9 (0.37) 11 (0.45) 1 (0.04) 7 (0.29) 5 (0.21) 6 (0.25) 8 (0.33) 4 (0.16) 10 (0.41) 4 (0.16) 2 (0.08) 3 (0.12) 2 (0.08) 3 (0.12) 0 3 (0.12) 3 (0.12) 2 (0.08)
0.754 0.177 0.367 0.139 0.088 0.702 0.548
BRIEF REPORT Safety of 3-year raloxifene treatment in Japanese postmenopausal women aged 75 years or older with osteoporosis: a postmarketing surveillance study Yasuhiro Takeuchi, MD, PhD,1 Etsuro Hamaya, RPh,2 Masanori Taketsuna, MSc,3 and Hideaki Sowa, MD, PhD 2 Abstract Objective: Long-term safety of medication is a concern for older persons because they may have several comorbidities that can influence drug metabolism, efficacy, and safety. In Japan, raloxifene is an effective and welltolerated medication for the treatment of osteoporosis in postmenopausal women, but there is little available evidence on whether raloxifene has an acceptable safety profile in older women. The objective of this post hoc analysis was to investigate the safety of raloxifene as a long-term treatment of osteoporosis in Japanese postmenopausal women aged 75 years or older. Methods: We report a post hoc analysis of a safety dataset (6,960 participants) from a published postmarketing surveillance study (postmenopausal women treated with raloxifene 60 mg/d for 3 y). The safety dataset was divided into two groups: (1) women younger than 75 years at baseline (4,522 participants) and (2) women aged 75 years or older at baseline (2,438 participants). Incidence of adverse drug reactions and reactions of note in each age group were compared using Fisher’s exact test. Results: Approximately 10% of women in each group reported at least one adverse drug reaction. This analysis did not identify any clinically important differences in the incidence or type of adverse drug reactions reported or in reactions of note between women aged 75 years or older and younger women. Conclusions: There were no obvious additional safety concerns for women aged 75 years or older who were treated with raloxifene. The findings in this post hoc evaluation suggest no differences in adverse events in the age groups evaluated. Key Words: Aged – Japan – Postmenopausal osteoporosis – Raloxifene – Safety.
aloxifene (RLX), a selective estrogen receptor modulator, is a medication for the long-term treatment of osteoporosis in postmenopausal women. In large-scale global clinical trials, RLX effectively reduced the risk of vertebral fracture at 3 years1 and at 4 years.2 In addition, RLX reduced the incidence of nonvertebral fractures in postmenopausal women with severe prevalent vertebral fractures at 3 years3 and increased
R
bone mineral density (BMD) for all women for at least 7 years.4 From a safety perspective, RLX is well tolerated in the long term. The Multiple Outcomes of Raloxifene Evaluation study (mean follow-up, 3.3 y) found that the only increased safety risk for women treated with RLX, compared with those receiving placebo, was for the clinically important adverse event venous thromboembolism (relative risk, 2.1).5
Received October 27, 2014; revised and accepted December 30, 2014. From the 1Toranomon Hospital Endocrine Center, Tokyo, Japan; 2 Medical Science, Medicines Development Unit Japan, Eli Lilly Japan KK, Kobe, Hyogo, Japan; and 3Asia Pacific Statistical Sciences, Medicines Development Unit Japan, Eli Lilly Japan KK, Kobe, Hyogo, Japan. ProScribe’s services complied with international guidelines for Good Publication Practice (GPP2). Eli Lilly Japan was involved in the study design, data collection, data analysis, and preparation of the manuscript. All authors participated in the interpretation of study results, and in the drafting, critical revision, and approval of the final version of the manuscript. E.H. was involved in the study design and data analyses. Statistical analysis was planned by M.T. and performed by EPS Corp (Tokyo, Japan). Funding/support: This study was sponsored by Eli Lilly and Company (manufacturer of raloxifene). Medical writing assistance was provided by
Janelle Keys, PhD, and Rebecca Lew, PhD, CMPP, of ProScribe (part of the Envision Pharma Group) and was funded by Eli Lilly Japan KK. Financial disclosure/conflicts of interest: Y.T. has received honoraria for speaking from Eli Lilly Japan KK, Chugai Pharma, Daiichi-Sankyo, Taisho Toyama Pharma, Teijin Pharma, Ono Pharmaß, Merck Sharp and Dohme, and Asahi Kasei Pharma. M.T. and H.S. are employees of Eli Lilly Japan KK. E.H. is a former employee of Eli Lilly Japan KK and current employee of R&D Japan at Amgen Astellas Biopharm KK (Tokyo, Japan). E.H. and H.S. are stockholders of Eli Lilly andCompany. Address correspondence to: Hideaki Sowa, MD, PhD, Medical Science, Medicines Development Unit Japan, Eli Lilly Japan KK, 7-1-5 Isogamidori, Chuo-ku, Kobe 651-0086, Japan. E-mail: sowa_hideaki@ lilly.com
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Menopause, Vol. 22, No. 10, 2015
Copyright @ 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
RALOXIFENE IN JAPANESE POSTMENOPAUSAL WOMEN
In Japan, treatment with RLX is recommended for postmenopausal women with osteoporosis.6 Daily use of RLX in Japan has been studied in a 3-year prospective postmarketing surveillance study of 7,557 Japanese postmenopausal women with osteoporosis.7 The study demonstrated that the long-term effectiveness outcomes of RLX treatment were reflective of clinical practice; lumbar spine BMD increased significantly across time, and the incidence of new clinical fractures was low (1.18%). In addition, treatment with RLX for up to 3 years was well tolerated by Japanese postmenopausal women with osteoporosis; 11% of participants reported an adverse drug reaction (ADR), and only 1% of ADRs were serious. Given that the number of women with osteoporosis in Japan increases substantially with age,8 long-term treatment with RLX is expected to be commonplace in women aged 75 years or older. For this reason, we believe that the long-term safety of RLX in Japanese postmenopausal women aged 75 years or older with osteoporosis is an issue worthy of consideration. In addition, long-term safety is an important concern for older persons because they may have several comorbidities that can influence drug metabolism, efficacy, and safety. However, there is little available evidence on whether RLX displays the same safety profile in postmenopausal women aged 75 years or older and younger women. Therefore, the aim of this post hoc analysis of a postmarketing surveillance study7 was to investigate the safety of RLX as a long-term treatment of osteoporosis in Japanese postmenopausal women aged 75 years or older. METHODS Postmarketing surveillance study The safety and effectiveness of RLX for long-term use in Japanese postmenopausal women with osteoporosis were assessed in a large-scale postmarketing surveillance study.7 In brief, the participants included in the surveillance study were postmenopausal women with primary osteoporosis,9 which physicians intended to treat with RLX 60 mg/day (Evista; Eli Lilly and Company, Indianapolis, IN). Participants were included if they were ambulatory, had not been previously prescribed RLX, and were available for follow-up. Participants were excluded as per the RLX package insert, and any participants judged by the investigator to be inappropriate were also excluded. A total of 7,557 participants met the inclusion criteria and gave a written informed consent form to participate. Safety population Safety population was defined as participants who received at least one dose of RLX. The follow-up period from the start of RLX treatment (baseline) was 3 years (as requested by the Japanese Ministry of Health, Labor, and Welfare), although not all participants completed the 3-year visit; the mean (SD) dosing period for the safety population was 614 (458) days. A total of 953 institutions participated in the surveillance study; the observation period for safety was from October 1, 2004 to May 31, 2009. Safety was assessed by report of ADRs, with particular note of ADRs related to stroke, coronary heart disease, venous thromboembolism, and breast/gynecological
cancer (as requested by the Japanese Ministry of Health, Labor and Welfare). ADRs were coded using MedDRA (Medical Dictionary for Regulatory Activities) version 12.0. Of the 7,557 participants enrolled, 590 were excluded from the safety population (378 did not return after the first visit, 195 had uncollectable case cards, 16 had unconfirmed drug administration, and 1 had off-label use). Baseline characteristics of the safety population are presented by Iikuni et al.7 Statistical analysis Here, we report a post hoc analysis of a safety dataset from a postmarketing surveillance study.7 For this post hoc analysis, the safety dataset was divided into two groups: (1) women younger than 75 years at baseline and (2) women aged 75 years or older at baseline (seven participants were excluded from the post hoc analysis because their age was not specified). Incidence of ADRs and ADRs of note in each age group were compared using Fisher’s exact test (P < 0.05 was considered statistically significant). All statistical analyses were conducted using SAS version 9.1 (SAS Institute, Cary, NC). RESULTS A total of 6,960 participants from the safety dataset of the postmarketing surveillance study7 were included in this post hoc analysis. A total of 4,522 (65.0%) participants were younger than 75 years, whereas 2,438 (35.0%) participants were aged 75 years or older. ADRs were reported by approximately 10% of women in each group (Table 1); approximately 1% of ADRs were serious (Table 1). The most frequent serious ADR for women younger than 75 years was cerebral infarction (n ¼ 5). The most frequent serious ADRs for women aged 75 years or older were cerebral infarction (n ¼ 3), cardiac failure (n ¼ 3), and femoral neck fracture (n ¼ 3). Very few deaths were reported (Table 1). Women in both age groups reported a low incidence of cardiovascular ADRs of note, including ADRs related to stroke, coronary heart disease, and venous thromboembolism; there were no differences between age groups (Table 1). ADRs related to gynecological cancer were only reported by women younger than 75 years (Table 1). There were no clinically important between-group differences in the most frequent ADRs reported (Table 2). Although there were statistically significant between-group differences in gastritis (higher incidence in women younger than 75 y), abnormal hepatic function (higher incidence in women younger than 75 y), and diarrhea (higher incidence in women aged 75 y or older), these differences were not considered clinically important. DISCUSSION This post hoc analysis did not identify any clinically important age-related differences in the incidence or type of ADRs reported by Japanese postmenopausal women with osteoporosis who were treated with RLX for up to 3 years. Of note, there was no evidence of obvious safety concerns for women aged 75 years or older who were treated with RLX. These findings reassure clinicians that RLX is a long-term treatment option for postmenopausal women with osteoporosis, regardless of age. Menopause, Vol. 22, No. 10, 2015
1135
Copyright @ 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
TAKEUCHI ET AL TABLE 1. Overall ADRs and incidence of ADRs of note, by age group, in a postmarketing surveillance study of Japanese postmenopausal women with osteoporosis who were treated with raloxifene 60 mg/day for up to 3 years ADR
Women younger than 75 y (N ¼ 4,522)
Women aged 75 y or older (N ¼ 2,438)
Pa
541 (11.96) 673 40 (0.88) 45 2
235 (9.64) 289 36 (1.48) 42 1
0.003 – 0.029 – –
Overall ADRs Participants reporting ADRs ADRs reported Participants reporting a serious ADR Serious ADRs reported Deaths ADRs of note ADRs related to stroke Cerebral infarction Cerebral hemorrhage Thrombotic stroke ADRs related to coronary heart disease Angina pectoris Myocardial ischemia Prinzmetal angina Myocardial infarction ADRs related to venous thromboembolism Deep vein thrombosis Thrombophlebitis Venous thrombosis ADRs related to breast/gynecological cancer Breast cancer Ovarian cancer recurrent Ovarian adenoma
7 7 (0.15)b 0 0 5 3 (0.07)d 1 (0.02) 1 (0.02) 0 6 4 (0.09)f 1 (0.02) 1 (0.02) 8h 4 (0.09) 3 (0.07) 1 (0.02)
5 3 (0.12)c 1 (0.04) 1 (0.04) 1 0 0 0 1 (0.04)e 5 3 (0.12)g 2 (0.08) 0 0 0 0 0
0.663 0.350 0.350 0.556 1.000 1.000 0.350 0.702 0.282 1.000 0.305 0.556 1.000
ADRs were coded using on MedDRA version 12.0. Data are presented as n (%). ADR, adverse drug reaction. a Difference between age groups by Fisher’s exact test. b Five cases were serious. c Three cases were serious. d One case was serious. e This case was serious. f Two cases were serious. g One case was serious. h All cases were serious.
TABLE 2. Incidence of frequent ADRs (reported by 10 participants), by age group, in a postmarketing surveillance study of Japanese postmenopausal women with osteoporosis who were treated with raloxifene 60 mg/day for up to 3 years Safety dataset (N ¼ 6,967)a
ADR Edema peripheral Abdominal discomfort Abdominal pain upper Hot flash Nausea Constipation Dizziness Gastritis Pruritus Muscle spasms Rash Hypertension Hyperhidrosis Diarrhea Hypoesthesia Stomatitis Abdominal distension Insomnia Reflux esophagitis Hepatic function abnormal Cerebral infarction Headache Gastrointestinal disorder
45 39 33 32 31 29 27 25 23 20 19 18 17 16 15 14 13 12 11 11 10 10 10
(0.65) (0.56) (0.47) (0.46) (0.44) (0.42) (0.39) (0.36) (0.33) (0.29) (0.27) (0.26) (0.24) (0.23) (0.22) (0.20) (0.19) (0.17) (0.16) (0.16) (0.14) (0.14) (0.14)
Women younger than 75 y (N ¼ 4,522) 28 21 19 25 25 20 16 24 16 15 13 10 13 6 11 12 10 10 8 11 7 7 8
(0.62) (0.46) (0.42) (0.55) (0.55) (0.44) (0.35) (0.53) (0.35) (0.33) (0.29) (0.22) (0.29) (0.13) (0.24) (0.27) (0.22) (0.22) (0.18) (0.24) (0.15) (0.15) (0.18)
Women aged 75 y or older (N ¼ 2,438)
Pb
17 (0.70) 18 (0.74) 14 (0.57) 7 (0.29) 6 (0.25) 9 (0.37) 11 (0.45) 1 (0.04) 7 (0.29) 5 (0.21) 6 (0.25) 8 (0.33) 4 (0.16) 10 (0.41) 4 (0.16) 2 (0.08) 3 (0.12) 2 (0.08) 3 (0.12) 0 3 (0.12) 3 (0.12) 2 (0.08)
0.754 0.177 0.367 0.139 0.088 0.702 0.548
