原著
Incidence of dizziness and somnolence in Japanese patients with renal impairment treated with mirogabalin: a post-marketing surveillance
2024 年 31 巻 2 号 p. 42-50
詳細
2024 年 31 巻 2 号 p. 42-50
This multicenter, post-marketing surveillance study (August 2019–November 2021) investigated the risk of dizziness-/somnolence-related events in patients receiving mirogabalin for peripheral neuropathic pain for ≤14 weeks. By renal impairment group, 57.3％–86.2％ and 37.2％–58.5％ of patients received the initial (2.5–10 mg) and effective (7.5–30 mg) mirogabalin doses recommended in the package insert, respectively. Dizziness-/somnolence-related event incidences were 6.29％/6.55％, and 7.46％/7.33％ in patients with normal renal function/mild impairment (n＝1,160) and moderate/severe impairment (n＝764). Median risk ratios of moderate/severe impairment vs normal/mild impairment for dizziness- (1.188; posterior probability ≥1.2 and ≥2.0, 47.67％ and 0.09％, respectively) and somnolence-related events (1.121; posterior probability ≥1.2 and ≥2.0, 34.20％ and 0.03％, respectively) did not reach the predefined increased risk criteria (posterior probabilities of risk ratios ≥1.2 [probability ≥90％] and ≥2.0 [probability ≥10％]). Similar results were obtained after adjusting for confounding factors. In clinical practice, dizziness-/somnolence-related event risk did not increase with renal impairment severity except for patients with end-stage renal failure/requiring hemodialysis.
Neuropathic pain is difficult to treat effectively1), and many patients have a reduced quality of life2–4). Elderly patients are more likely to experience neuropathic pain5,6) and often have impaired renal function. Therefore, there is a need for a treatment that can effectively and safely treat neuropathic pain in patients with renal function impairment.
Mirogabalin besylate (mirogabalin) is an analgesic that selectively binds to the α2δ subunit of voltage-gated calcium channels7). In Japan, mirogabalin has been approved for treating neuropathic pain. Mirogabalin has an acceptable safety profile, similar to other comparable analgesics, and may be used for the treatment of neuropathic pain in patients with renal dysfunction8–11). As mirogabalin is excreted in the urine, patients with impaired renal function have higher plasma concentrations of mirogabalin12). The major side effects of mirogabalin, dizziness and somnolence, are known to be dose-dependent; the incidence of these side effects can be reduced by initiating mirogabalin at a lower starting dose and gradually increasing to an effective dose8,13–18). Thus, the mirogabalin package insert states that the dosage should be reduced according to the severity of renal impairment.
A previous phase 3 clinical study showed that there were no major safety concerns in patients with severe renal impairment (n＝5) or those with moderate renal impairment (n＝30)18). However, this study had a small sample size and did not include patients with end-stage renal failure or those requiring hemodialysis. Therefore, this post-marketing surveillance examined the risk of dizziness- and somnolence-related events following mirogabalin treatment of patients with normal renal function or mild renal impairment (for whom dose adjustments are not required) and patients with moderate or severe renal impairment (for whom dose adjustments are required) in clinical practice.
This multicenter, observational, post-marketing surveillance study was performed at 349 Japanese institutions between August 2019 and November 2021. The observation period was 14 weeks from the start of mirogabalin treatment, or until 1 week after the date of discontinuation. An electronic data capture system (PostMaNet, Fujitsu Japan Ltd.) was used for case registration and data collection.
The protocol was approved by the Japan Ministry of Health, Labour and Welfare, and the study was conducted in accordance with the Japanese Good Post-Marketing Study Practice regulations. These regulations do not require the collection of ethical approval from participating institutions. Written informed consent was obtained, and this study was registered under the identifier jRCT1080224834.
Study population and treatmentEligible patients had peripheral neuropathic pain, were treated with mirogabalin for the first time, had creatinine clearance by calculated Cockcroft–Gault equation19) measurements taken within 12 months prior to the start of mirogabalin treatment, and were judged by a physician to have normal renal function, or mild, moderate, or severe renal impairment.
As this study investigated the use and safety of mirogabalin in clinical practice, mirogabalin treatment decisions were made at the discretion of each patient's physician. The recommended initial dose of mirogabalin is 10 mg/day for patients with normal renal function or mild impairment, 5 mg/day for patients with moderate impairment, and 2.5 mg/day for patients with severe impairment. Doses are recommended to be titrated at intervals of at least 1 week, and the final effective dose (recommended dose) is 20–30 mg/day for patients with normal renal function or mild renal impairment, 10–15 mg/day for patients with moderate renal impairment, and 5–7.5 mg/day for patients with severe impairment.
Study outcomesThe primary outcomes were the physician-determined onset of two types of adverse drug reactions (ADRs): dizziness- and somnolence-related events.
Statistical analysesThe target number of patients was 1,800 (normal renal function or mild renal impairment [normal/mild group]: 1,200 patients; moderate or severe renal impairment [moderate/severe group]: 600 patients). The incidences of floating dizziness and somnolence were assumed to be 3％ in the normal/mild group20). With a risk ratio of 1.2 and 2.0 for moderate/severe to normal/mild, a total of 1,650 patients was required to obtain 10％ and 90％ probability of achieving the following criteria for an increase in risk: risk ratio ≥1.2 with ≥90％ posterior probability and ≥2.0 with ≥10％. The analysis was performed using the safety analysis set, which comprised all enrolled patients (excluding those who did not meet the inclusion criteria). The risk ratio for the normal/mild and the moderate/severe group was evaluated using a Bayesian approach. The posterior distribution of the risk ratio was generated by assuming beta distribution (1,1) for the prior distribution of ADR incidence rates in each group. Mean, median, 95％ credible interval (CrI), and posterior probability of the risk ratio being ≥1.2 and ≥2.0 were described.
To adjust for confounding factors, the odds ratio (OR) was estimated using a Bayesian multivariate logistic model, in which sex (female, male), age (<65 years, ≥65 years), body mass index (<25 kg/m2, ≥25 kg/m2, unknown), use of concomitant medications (pregabalin) at the start of treatment for pain (yes, no), and presence of complications (liver disease, diabetes mellitus, or hypertension) (yes, no) were used as covariates, with a non-informative prior distribution assumed for each coefficient. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc.; Cary, NC, USA).
Among 2,021 patients enrolled, case report forms were collected from 2,002 patients, and 1,924 patients were evaluated for safety. The reasons for exclusion (n＝78) were serious violation of the protocol (n＝49; including a lack of creatinine clearance values prior to mirogabalin administration [n＝24] and pain identified as not peripheral neuropathic pain after registration, [n＝15]), lack of safety evaluation (n＝27), and consent withdrawal (n＝2). Of the patients evaluated for safety, 1,160 were in the normal/mild group, and 764 were in the moderate/severe group.
The patients' baseline characteristics are shown in Table 1. Patients in the moderate/severe group were typically older than those in the normal/mild group (78.1 years vs 67.3 years, respectively). The mean (standard deviation) body weight in the moderate/severe group was 53.82 (11.160) kg, and 61.41 (12.016) kg in the normal/mild group. In the moderate/severe group, 18.5％ of patients had severe renal impairment. Patients with severe renal impairment were further divided into patients without end-stage renal failure (n＝76) and patients with end-stage renal failure/requiring hemodialysis (n＝65).
| Normal renal function or mild renal impairment （n＝1,160） |
Moderate or severe renal impairment （n＝764） |
Total （n＝1,924） |
|
|---|---|---|---|
| Sex | |||
| Female | 632 （54.5） | 466 （61.0） | 1,098 （57.1） |
| Male | 528 （45.5） | 298 （39.0） | 826 （42.9） |
| Age （years） | 67.3±12.74 | 78.1±9.69 | 71.6±12.78 |
| 18‐64 | 420 （36.2） | 71 （9.3） | 491 （25.5） |
| 65‐74 | 359 （30.9） | 157 （20.5） | 516 （26.8） |
| ≥75 | 381 （32.8） | 536 （70.2） | 917 （47.7） |
| Body mass index （kg/m2） | 24.13±4.095 | 22.5±3.623 | 23.4±3.973 |
| Body weight （kg） | 61.41±12.016 | 53.82±11.160 | 58.16±12.243 |
| Admission statusa | |||
| Inpatient | 77 （6.6） | 69 （9.0） | 146 （7.6） |
| Outpatient | 1,083 （93.4） | 695 （91.0） | 1,778 （92.4） |
| Duration of pain | |||
| <3 months | 377 （32.5） | 188 （24.6） | 565 （29.4） |
| ≥3‐<12 months | 202 （17.4） | 119 （15.6） | 321 （16.7） |
| ≥1‐<5 years | 260 （22.4） | 192 （25.1） | 452 （23.5） |
| ≥5 years | 180 （15.5） | 137 （17.9） | 317 （16.5） |
| Unknown | 141 （12.2） | 128 （16.8） | 269 （14.0） |
| Complications | |||
| Yesb | 470 （40.5） | 540 （70.7） | 1,010 （52.5） |
| Renal disease | 29 （2.5） | 245 （32.1） | 274 （14.2） |
| Liver disease | 39 （3.4） | 41 （5.4） | 80 （4.2） |
| Diabetes mellitus | 213 （18.4） | 207 （27.1） | 420 （21.8） |
| Hypertension | 361 （31.1） | 418 （54.7） | 779 （40.5） |
| Severity of renal impairment at enrollment | |||
| Normal | 644 （55.5） | 0 （0.0） | 644 （33.5） |
| Mild | 516 （44.5） | 0 （0.0） | 516 （26.8） |
| Moderate | 0 （0.0） | 623 （81.5） | 623 （32.4） |
| Severe | 0 （0.0） | 141 （18.5） | 141 （7.3） |
| Severe renal impairmentc | 0 （0.0） | 76 （9.9） | 76 （4.0） |
| Severe renal impairmentd | 0 （0.0） | 65 （8.5） | 65 （3.4） |
| Creatinine clearance （ml/min） | 80.87±23.454 | 41.36±15.953 | 65.18±28.401 |
| <15 | 0 （0.0） | 65 （8.5） | 65 （3.4） |
| ≥15‐<30 | 2 （0.2） | 85 （11.1） | 87 （4.5） |
| ≥30‐<60 | 129 （11.1） | 569 （74.5） | 698 （36.3） |
| ≥60‐<90 | 710 （61.2） | 43 （5.6） | 753 （39.1） |
| ≥90 | 319 （27.5） | 2 （0.3） | 321 （16.7） |
| Dialysis | 0 （0.0） | 61 （8.0） | 61 （3.2） |
| Prior treatment for pain | 479 （41.3） | 367 （48.0） | 846 （44.0） |
| Switched from prior treatment for pain | 179 （15.4） | 155 （20.3） | 334 （17.4） |
| Reasons for discontinuing prior treatment | |||
| ADR | 4 （2.2） | 6 （3.9） | 10 （3.0） |
| Insufficient pain relief | 141 （78.8） | 133 （85.8） | 274 （82.0） |
| ADR and insufficient pain relief | 10 （5.6） | 1 （0.6） | 11 （3.3） |
| Other | 26 （14.5） | 18 （11.6） | 44 （13.2） |
| Concomitant analgesic use | 519 （44.7） | 347 （45.4） | 866 （45.0） |
Data are shown as n （％） or mean±SD.
aPatients were either hospitalized or were treated as outpatients at the initiation of mirogabalin treatment.
bPresence of any of the following complications （excluding any considered responsible for the peripheral neuropathic pain）: renal disease, liver disease, diabetes mellitus, or hypertension.
cExcluding patients with end-stage renal failure.
dPatients with end-stage renal failure or patients on hemodialysis.
ADR: adverse drug reaction, SD: standard deviation.
In the normal/mild group, 57.3％ received the recommended initial mirogabalin dose of 10 mg/day (Table 2). In addition, 70.1％ (813/1,160) did not reach the recommended effective daily dose (20–30 mg). Most patients (61.3％) with moderate renal impairment received an initial mirogabalin dose of 5 mg/day as recommended; 27.8％ (173/623) of these patients received higher than the recommended initial dose. Among patients with severe renal impairment, 71.1％ of those without end-stage renal failure and 86.2％ of patients with end-stage renal failure/requiring hemodialysis received an initial mirogabalin dose of below 2.5 mg/day as recommended.
| Normal renal function or mild renal impairment （n＝1,160） |
Moderate renal impairment （n＝623） |
Severe renal impairmenta （n＝76） |
Severe renal impairmentb （n＝65） |
Total （n＝1,924） |
|
|---|---|---|---|---|---|
| Initial dose | |||||
| ≤2.5 mg/day | 37 （3.2） | 68 （10.9） | 54 （71.1） | 56 （86.2） | 215 （11.2） |
| 5 mg/day （>2.5‐5 mg/day） | 444 （38.3） | 382 （61.3） | 18 （23.7） | 9 （13.8） | 853 （44.3） |
| 7.5 mg/day （>5‐7.5 mg/day） | 4 （0.3） | 0 （0.0） | 0 （0.0） | 0 （0.0） | 4 （0.2） |
| 10 mg/day （>7.5‐10 mg/day） | 665 （57.3） | 170 （27.3） | 4 （5.3） | 0 （0.0） | 839 （43.6） |
| 15 mg/day （>10‐15 mg/day） | 3 （0.3） | 2 （0.3） | 0 （0.0） | 0 （0.0） | 5 （0.3） |
| 20 mg/day （>15‐20 mg/day） | 6 （0.5） | 1 （0.2） | 0 （0.0） | 0 （0.0） | 7 （0.4） |
| 30 mg/day （>20‐30 mg/day） | 1 （0.1） | 0 （0.0） | 0 （0.0） | 0 （0.0） | 1 （0.1） |
| >30 mg/day | 0 （0.0） | 0 （0.0） | 0 （0.0） | 0 （0.0） | 0 （0.0） |
| Maximum dose | |||||
| ≤2.5 mg/day | 18 （1.6） | 45 （7.2） | 28 （36.8） | 38 （58.5） | 129 （6.7） |
| 5 mg/day （>2.5‐5 mg/day） | 270 （23.3） | 232 （37.2） | 36 （47.4） | 18 （27.7） | 556 （28.9） |
| 7.5 mg/day （>5‐7.5 mg/day） | 10 （0.9） | 4 （0.6） | 5 （6.6） | 6 （9.2） | 25 （1.3） |
| 10 mg/day （>7.5‐10 mg/day） | 470 （40.5） | 204 （32.7） | 4 （5.3） | 2 （3.1） | 680 （35.3） |
| 15 mg/day （>10‐15 mg/day） | 45 （3.9） | 46 （7.4） | 2 （2.6） | 0 （0.0） | 93 （4.8） |
| 20 mg/day （>15‐20 mg/day） | 189 （16.3） | 63 （10.1） | 1 （1.3） | 1 （1.5） | 254 （13.2） |
| 30 mg/day （>20‐30 mg/day） | 155 （13.4） | 29 （4.7） | 0 （0.0） | 0 （0.0） | 184 （9.6） |
| >30 mg/day | 3 （0.3） | 0 （0.0） | 0 （0.0） | 0 （0.0） | 3 （0.2） |
| Dose changesc | |||||
| Yes | 553 （47.7） | 282 （45.3） | 31 （40.8） | 28 （43.1） | 894 （46.5） |
| No | 607 （52.3） | 341 （54.7） | 45 （59.2） | 37 （56.9） | 1,030 （53.5） |
| Mirogabalin administration status （at 14 weeks of treatment） | |||||
| Ongoing | 712 （61.4） | 410 （65.8） | 47 （61.8） | 45 （69.2） | 1,214 （63.1） |
| Discontinued | 448 （38.6） | 213 （34.2） | 29 （38.2） | 20 （30.8） | 710 （36.9） |
| Duration of administration in discontinued cases （days）, mean±SD | 39.8±25.70 | 38.7±24.88 | 41.0±29.64 | 21.8±17.54 | 39.0±25.56 |
| Dose was not increased to the effective dosed | 467 （65.6） | 169 （41.2） | 17 （36.2） | 28 （62.2） | 681 （56.1） |
| Reason for not increasing the dosee | |||||
| Adequate efficacy reached per physician’s judgment | 216 （46.3） | 56 （33.1） | 4 （23.5） | 11 （39.3） | 287 （42.1） |
| Patient’s request （sufficient efficacy） | 104 （22.3） | 48 （28.4） | 5 （29.4） | 7 （25.0） | 164 （24.1） |
| Prevention of an ADR at physician’s discretion | 51 （10.9） | 42 （24.9） | 6 （35.3） | 7 （25.0） | 106 （15.6） |
| Patient’s request （fear of increasing the dose） | 58 （12.4） | 19 （11.2） | 2 （11.8） | 1 （3.6） | 80 （11.7） |
| Adverse event | 19 （4.1） | 2 （1.2） | 0 （0.0） | 2 （7.1） | 23 （3.4） |
| Other | 9 （1.9） | 1 （0.6） | 0 （0.0） | 0 （0.0） | 10 （1.5） |
| Not stated | 9 （1.9） | 1 （0.6） | 0 （0.0） | 0 （0.0） | 10 （1.5） |
| Unknown | 1 （0.2） | 0 （0.0） | 0 （0.0） | 0 （0.0） | 1 （0.1） |
| Reason for treatment discontinuationf | |||||
| Symptom improvement | 159 （35.5） | 69 （32.4） | 7 （24.1） | 3 （15.0） | 238 （33.5） |
| Adverse event | 112 （25.0） | 67 （31.5） | 10 （34.5） | 11 （55.0） | 200 （28.2） |
| No visit/transfer | 105 （23.4） | 37 （17.4） | 9 （31.0） | 2 （10.0） | 153 （21.5） |
| Inadequate efficacy | 65 （14.5） | 29 （13.6） | 4 （13.8） | 3 （15.0） | 101 （14.2） |
| Other | 14 （3.1） | 15 （7.0） | 1 （3.4） | 1 （5.0） | 31 （4.4） |
Data are shown as n （％） unless otherwise stated.
aExcluding patients with end-stage renal failure.
bPatients with end-stage renal failure or patients on hemodialysis.
cIncluding both dose increases and decreases.
dAmong patients who continued mirogabalin treatment.
eAmong patients who did not receive a dose increase to the effective dose.
fAmong patients who discontinued mirogabalin treatment. More than one reason was permitted.
ADR: adverse drug reaction, SD: standard deviation.
Approximately 60％ of patients continued mirogabalin treatment at 14 weeks post-treatment; of those who discontinued treatment, 28.2％ did so because of adverse events (Table 2). Of the patients who continued treatment, 56.1％ did not reach the effective dose. Reasons for not increasing the recommended effective daily dose included: the physician judged that adequate efficacy had been reached (42.1％); safety concerns (approximately 20％); the prevention of ADRs (15.6％); and the occurrence of adverse events (3.4％).
Safety analysisThe incidence of dizziness-related events was 6.29％, 6.58％, 5.26％, and 18.46％ in patients with normal renal function or mild impairment, patients with moderate renal impairment, patients with severe renal impairment (excluding end-stage renal failure), and patients with end-stage renal failure/requiring hemodialysis, respectively (Table 3). The respective incidences of somnolence-related events were 6.55％, 6.74％, 7.89％, and 12.31％.
| Normal renal function or mild renal impairment （n＝1,160） |
Moderate or severe renal impairment | Total （n＝1,924） |
||||
|---|---|---|---|---|---|---|
| Moderate renal impairment （n＝623） |
Severe renal impairmenta （n＝76） |
Severe renal impairmentb （n＝65） |
Total （n＝764） |
|||
| Patients with dizziness-related events | 73 （6.29） | 41 （6.58） | 4 （5.26） | 12 （18.46） | 57 （7.46） | 130 （6.76） |
| Nervous system disorders | 72 （6.21） | 39 （6.26） | 4 （5.26） | 12 （18.46） | 55 （7.20） | 127 （6.60） |
| Dizziness | 67 （5.78） | 38 （6.10） | 4 （5.26） | 9 （13.85） | 51 （6.68） | 118 （6.13） |
| Dizziness on exertion | 1 （0.09） | 1 （0.16） | 0 （0.00） | 1 （1.54） | 2 （0.26） | 3 （0.16） |
| Dizziness postural | 4 （0.34） | 0 （0.00） | 0 （0.00） | 2 （3.08） | 2 （0.26） | 6 （0.31） |
| Ear and labyrinth disorder | 1 （0.09） | 0 （0.00） | 0 （0.00） | 0 （0.00） | 0 （0.00） | 1 （0.05） |
| Head discomfort | 1 （0.09） | 0 （0.00） | 0 （0.00） | 0 （0.00） | 0 （0.00） | 1 （0.05） |
| Vertigo | 1 （0.09） | 0 （0.00） | 0 （0.00） | 0 （0.00） | 0 （0.00） | 1 （0.05） |
| General disorders and administration site conditions | 0 （0.00） | 3 （0.48） | 0 （0.00） | 0 （0.00） | 3 （0.39） | 3 （0.16） |
| Feeling abnormal | 0 （0.00） | 2 （0.32） | 0 （0.00） | 0 （0.00） | 2 （0.26） | 2 （0.10） |
| Gait disturbance | 0 （0.00） | 1 （0.16） | 0 （0.00） | 0 （0.00） | 1 （0.13） | 1 （0.05） |
| Patients with somnolence-related events | 76 （6.55） | 42 （6.74） | 6 （7.89） | 8 （12.31） | 56 （7.33） | 132 （6.86） |
| Nervous system disorders | 68 （5.86） | 40 （6.42） | 5 （6.58） | 8 （12.31） | 53 （6.94） | 121 （6.29） |
| Hypersomnia | 1 （0.09） | 1 （0.16） | 0 （0.00） | 2 （3.08） | 3 （0.39） | 4 （0.21） |
| Somnolence | 67 （5.78） | 39 （6.26） | 5 （6.58） | 6 （9.23） | 50 （6.54） | 117 （6.08） |
| General disorders and administration site conditions | 8 （0.69） | 2 （0.32） | 1 （1.32） | 0 （0.00） | 3 （0.39） | 11 （0.57） |
| Decreased activity | 1 （0.09） | 0 （0.00） | 0 （0.00） | 0 （0.00） | 0 （0.00） | 1 （0.05） |
| Feeling abnormal | 7 （0.60） | 2 （0.32） | 1 （1.32） | 0 （0.00） | 3 （0.39） | 10 （0.52） |
Data are shown as n （％）.
aExcluding patients with end-stage renal failure.
bPatients with end-stage renal failure or patients on hemodialysis.
The risk ratio for the moderate/severe group compared with the normal/mild group for dizziness-related events (median＝1.188, posterior probability ≥1.2 and ≥2.0 of 47.67％ and 0.09％) and somnolence-related events (median＝1.121, probability ≥1.2 and ≥2.0 of 34.20％ and 0.03％) did not meet the predefined risk criteria (Table 4). The respective median-adjusted OR of dizziness-related and somnolence-related events were 1.060 (95％ CrI: 0.710–1.577) and 1.254 (95％ CrI: 0.849–1.892). When patients in the moderate/severe group were further divided by renal severity, there was an increased incidence of dizziness- (median risk ratio＝3.090, posterior probability ≥1.2 and ≥2.0 of 99.79％ and 91.79％) and somnolence-related events (median risk ratio＝2.050, posterior probability ≥1.2 and ≥2.0 of 91.62％ and 48.66％) in patients with end-stage renal failure/requiring hemodialysis.
| Incidence rate （Posterior mean and 95％ CrI） | Risk ratioa （mean） | Risk ratioa （median） | Probability （％） that the risk ratio is ≥1.2 | Probability （％） that the risk ratio is ≥2.0 | Increased risk criteria metb | |
|---|---|---|---|---|---|---|
| Dizziness-related events | ||||||
| Normal or mild renal impairment （n＝1,160） | 6.37 ［5.04, 7.84］ | |||||
| Moderate or severe renal impairment （n＝764） | 7.57 ［5.81, 9.55］ | 1.204 | 1.188 | 47.67 | 0.09 | No |
| Moderate renal impairment （n＝623） | 6.72 ［4.89, 8.81］ | 1.068 | 1.052 | 23.94 | 0.01 | No |
| Severe renal impairmentc （n＝76） | 6.41 ［2.14, 12.77］ | 1.020 | 0.952 | 30.11 | 3.36 | No |
| Severe renal impairmentd （n＝65） | 19.40 ［10.93, 29.61］ | 3.090 | 3.011 | 99.79 | 91.79 | Yes |
| Somnolence-related events | ||||||
| Normal or mild renal impairment （n＝1,160） | 6.63 ［5.27, 8.13］ | |||||
| Moderate or severe renal impairment （n＝764） | 7.44 ［5.69, 9.40］ | 1.136 | 1.121 | 34.20 | 0.03 | No |
| Moderate renal impairment （n＝623） | 6.88 ［5.03, 8.99］ | 1.051 | 1.035 | 20.72 | 0.01 | No |
| Severe renal impairmentc（n＝76） | 8.97 ［3.73, 16.19］ | 1.369 | 1.306 | 58.57 | 11.60 | No |
| Severe renal impairmentd（n＝76） | 13.43 ［6.43, 22.49］ | 2.050 | 1.979 | 91.62 | 48.66 | Yes |
aRisk ratio of patients with moderate or severe renal impairment to patients with normal renal function or mild renal impairment.
bIncrease in risk defined as risk ratio ≥1.2 with ≥90％ posterior probability and ≥2.0 with ≥10％.
cExcluding patients with end-stage renal failure （creatinine clearance ≥15‐<30 ml/min）.
dPatients with end-stage renal failure or patients on hemodialysis （creatinine clearance <15 ml/min）.
CrI: credible interval.
This is the first prospective, observational study to report the prescribing patterns and safety of mirogabalin in patients with renal impairment in clinical practice. Patients in the moderate/severe group were treated with the recommended initial dose of mirogabalin in 61.3％–86.2％ of cases. There was no difference in the risk of dizziness- or somnolence-related events between the normal/mild group and the moderate/severe group. However, the incidence of dizziness- and somnolence-related events was higher in patients with end-stage renal failure/requiring hemodialysis. Our findings show that most patients with renal impairment received initial treatment with mirogabalin according to the package insert, and that there were no major safety concerns.
A previous study reported that oral analgesics, including pregabalin, are often prescribed at lower doses than the approved dose3). Another study found that 53.6％ of patients received the initial dose as recommended, and fewer than 20％ of patients reached the recommended effective dose20). However, these previous studies did not investigate prescribing patterns according to renal function. In our prospective study, we found that 57.3％ of patients with normal renal function or mild impairment received the recommended initial dose, and 29.7％ (344/1,160) reached the recommended effective dose, similar to the rates reported previously20). The rate of patients receiving the recommended dose was also high in patients for whom dose adjustments are recommended: 61.3％–86.2％ of the moderate/severe group received the recommended initial dose. Importantly, most patients with severe renal impairment received the recommended initial dose (71.1％ of patients with severe renal impairment, excluding end-stage renal failure, and 86.2％ of patients with end-stage renal failure/requiring hemodialysis). These findings show that in clinical practice, mirogabalin is often administered at the recommended initial daily dose to patients with impaired renal function.
The previous database study did not investigate the reasons for not increasing the dose to the recommended effective dose20). In this analysis, the main reasons for not increasing the dose were that the dose of mirogabalin was deemed sufficient by the physician (42.1％), whereas adverse events, prevention of ADRs, and the patient's fear of adverse events accounted for 3.4％, 15.6％, and 11.7％, respectively. This indicates that the dose of mirogabalin may not be increased in some cases because of concerns about side effects.
The package insert recommends that the dose of mirogabalin be adjusted according to the degree of renal impairment12). In this study, we focused on dizziness and somnolence as these are known to be dose-dependent, major side effects of mirogabalin13–16). The risk ratio of these events in the moderate/severe group to the normal/mild group did not reach the predefined criteria for an increase in risk; therefore, we confirmed that patients with moderate or severe renal impairment did not have an increased risk of dizziness or somnolence with mirogabalin treatment in clinical practice.
A previous phase 3 study in small number of patients with renal impairment, excluding those with end-stage renal failure/requiring hemodialysis, reported that the incidence of dizziness- and somnolence-related events was similar among patients with normal renal function or mild renal impairment, moderate renal impairment, and severe renal impairment (excluding end-stage renal failure)18). Although the incidence of dizziness- and somnolence-related events was higher in patients with end-stage renal failure/requiring hemodialysis—a finding first made in this study—these events improved or recovered without treatment or with discontinuation of mirogabalin. Therefore, patients with end-stage renal failure/requiring hemodialysis can be treated with mirogabalin with careful monitoring.
This study has several limitations. As this study had a non-interventional design, there may have been a bias between groups by renal function. Efficacy was not examined in patients with renal impairment, meaning that the risk–benefit balance could not be assessed. Additionally, the long-term real-world safety of mirogabalin in patients was not assessed.
We confirmed that most patients with renal impairment are treated in clinical practice with the recommended initial dose of mirogabalin. In addition, the mirogabalin dose was not increased to the recommended effective dose in some patients. No major safety concerns were found; however, our findings suggest that patients with end-stage renal failure/requiring hemodialysis should be carefully monitored and the dose of mirogabalin adjusted accordingly.
The authors thank the study investigators and the patients who participated in this study. Medical writing support was provided by Hannah Read, PhD, of Edanz (www.edanz.com). Support for this assistance was funded by Daiichi Sankyo Co., Ltd., in accordance with Good Publication Practice 2022 guidelines (https://www.ismpp.org/gpp-2022).
All authors were involved in the study design and conduct, the data analysis, and the interpretation of the data. All authors contributed to writing and reviewing the manuscript and provided final approval of the manuscript for submission. Yayoi Amma and Kazuhiro Uchino were mainly involved in planning the study and compiling the results. Shuhei Yamamoto was mainly involved in developing the analysis plan. As a medical advisor, Jitsu Kato contributed to the planning of the study, the analysis plan, and compilation of the results, as required by the implementation plan.
