Safety and tolerability findings
Extent of exposure
The mean treatment duration was similar for placebo-treated and cariprazine-treated patients (32 and 33 days, respectively); the mean treatment duration in the cariprazine 1.5–3, 4.5–6, and 9–12 mg/day dose groups was 31, 33, and 36 days, respectively. The overall cariprazine exposure was 117.9 patient-years.
TEAEs were reported in slightly more cariprazine-treated than placebo-treated patients, and showed a dose–response relationship, with the highest rates of TEAEs observed in the 9–12 mg/day group (Table 3). Discontinuation because of AEs was higher in the placebo group (12.2%) than in the cariprazine-dose groups (1.5–3 mg/day=10.8%; 4.5–6 mg/day=9.2%; 9–12 mg/day=3.4%); the only AE leading to discontinuation in 2% of patients or greater in any treatment group was exacerbated schizophrenia. There was no observed cariprazine dose response for discontinuations because of AEs.
Individual TEAEs occurring at an incidence of 5% or greater in any group are presented in Table 3; many of the TEAEs showed a dose–response relationship. AEs that occurred in the overall cariprazine group at an incidence of at least 5% and twice the rate of placebo were EPS (grouped terms) and akathisia; the risk of these TEAEs was lower at doses less than or equal to 6 mg/day. A dose response was observed for the grouped term for somnolence, with similar rates observed for cariprazine 1.5–3 mg/day (5.2%) and placebo (5.5%) and higher rates for cariprazine 4.5–6 mg/day (8.0%) and 9–12 mg/day (10.3%). The majority of TEAEs were considered mild or moderate in severity; some severe TEAEs were reported in all treatment groups (placebo=8.7%; cariprazine: 1.5–3 mg/day=6.1%, 4.5–6 mg/day=5.4%, 9–12 mg/day=3.9%; risperidone=8.6%; aripiprazole=3.9%). Most TEAEs were considered to be related to treatment in all groups. A complete listing of patients in the pooled population with a TEAE is presented in Supplementary Table 3 (Supplemental digital content 3, http://links.lww.com/ICP/A30); the occurrence of a TEAE may or may not be related to the study drug.
Serious adverse events (SAEs) occurred in 4.9% of cariprazine-treated and 7.2% of placebo-treated patients, with no dose response observed for the incidence of SAEs. Schizophrenia exacerbation and worsening of psychotic disorder were the most commonly reported SAEs (placebo=2.9 and 1.5%; cariprazine=1.4 and 0.8%, respectively).
Metabolic, laboratory, ECG, and additional safety parameters
A summary of safety parameters is presented in Table 4.
Overall, cariprazine-treated patients showed a decrease in mean total cholesterol, fasting low-density lipoprotein cholesterol, and triglyceride levels, whereas placebo-treated patients showed increases from baseline in these parameters. The decrease in high-density lipoprotein cholesterol was similar for cariprazine and placebo, as was the increase in the mean fasting blood glucose. Clinically relevant shifts in lipid and glucose parameters were similar for cariprazine and placebo. The percentage of patients with a fasting glucose increase 10 mg/dl or more was higher in the cariprazine group than in the placebo group; no clear dose response was observed.
Greater mean increases in weight occurred in the cariprazine-treatment groups versus the placebo group. The overall cariprazine weight increase was 1.1 kg for cariprazine-treated patients compared with 0.3 kg for placebo-treated patients; weight increase of 7% or more occurred in 9.2% of cariprazine-treated patients and 4.7% of placebo-treated patients. Both mean weight change and shifts in weight of 7% or more were larger in the 9–12 mg/day dose group. Within the recommended cariprazine-dose range (1.5–6 mg/day), weight gain was 0.8–1.0 kg for cariprazine; the proportion of patients with weight increase of 7% or more was 7.6 and 7.7% for the 1.5–3 and 4.5–6 mg/day groups, respectively.
Clinical laboratory values
Small increases occurred in alanine aminotransferase and aspartate aminotransferase levels with cariprazine relative to placebo; there were no mean increases in bilirubin levels with cariprazine or placebo, and alkaline phosphatase levels decreased slightly in both groups. No cariprazine patient fulfilled Hy’s Law criteria [alanine aminotransferase or aspartate aminotransferase≥3×upper limit of normal (ULN) with concurrent total bilirubin≥2×ULN and alkaline phosphatase<2×ULN]. The mean prolactin levels decreased in all treatment groups, except for risperidone; decreases were greater for cariprazine-treated women (−26.0) than for cariprazine-treated men (−8.1).
There was a modest dose-related increase in the mean creatine phosphokinase (CPK) level with cariprazine. However, large fluctuations in CPK levels occurred over time as evidenced by large SDs and a relatively high percentage of patients entered the studies with elevated CPK levels. Treatment-emergent CPK levels more than 1000 U/l were similar for placebo (3.5%), overall cariprazine (4.7%), and risperidone (4.5%) and lower for aripiprazole (2.0%); ∼60% of events resolved during the study for patients in all treatment groups. Elevations greater than 1.5×ULN occurred in patients in all treatment groups (placebo=14.2%, cariprazine=22.7%, risperidone=23.0%, aripiprazole=18.9%). Most elevations greater than 1.5×ULN did not resolve during treatment, but data should be interpreted with caution as laboratory tests were not scheduled after the end of treatment. CPK elevations were not associated with altered renal function or renal failure.
Overall, no clinically significant changes in pulse or blood pressure were observed in cariprazine-treated patients, with the exception of patients in the 9–12 mg/day dose group, where the mean increase in diastolic blood pressure was 3.4 mmHg and five (6.8%) patients shifted from baseline normotensive values to stage I hypertension. No mean increases were observed in the overall cariprazine group versus the placebo group on ECG parameters; no cariprazine patient had a QTc interval greater than 500 ms (Bazett or Fridericia formula).
The incidence of orthostatic hypotension (reduction of ≥20 mmHg in systolic blood pressure or ≥10 mmHg in diastolic blood pressure while changing from a supine position to standing) was similar for placebo (12.3%) and cariprazine (13.4%). No syncopal episodes were reported in the controlled schizophrenia studies.
A dose–response relationship was observed for the incidence of akathisia and EPS AEs (excluding akathisia and restlessness). Most events of akathisia and EPS were considered mild or moderate in severity; AEs of akathisia that were considered severe occurred in one (4.8%) of 21 placebo-treated patients and four (2.7%) of 149 cariprazine-treated patients (1.5–3 and 9–12 mg/day=one patient each; 4.5–6 mg=two patients). Severe EPS-related AEs (excluding akathisia and restlessness) were reported in one (2.2%) of 45 placebo-treated patients and three (1.3%) of 229 cariprazine-treated patients (4.5–6 mg/day=two patients; 9–12 mg/day=one patient). Rates of discontinuation for EPS TEAEs, including akathisia and restlessness, were less than or equal to 2% among cariprazine-treated patients and no akathisia, restlessness, or EPS SAEs were reported. EPS was assessed by rating scales and TEAEs (Table 5); a greater percentage of cariprazine-treated than placebo-treated patients had treatment-emergent parkinsonism (SAS total score ≤3 at baseline and >3 postbaseline) and akathisia (BARS total score ≤2 at baseline and >2 postbaseline).
During double-blind treatment, the mean duration of akathisia was 24 days for cariprazine-treated and 29 days for placebo-treated patients; the peak onset of akathisia generally occurred within 2–3 weeks of initiation of cariprazine treatment. A greater percentage of cariprazine-treated patients (21.9%) than placebo-treated patients (8.7%) received EPS medication. In accordance with the constituent study protocols, investigators used beta-blocking agents (e.g. propranolol) and antiparkinson medications (e.g. benztropine and trihexyphenidyl) to manage symptoms of akathisia and EPS. Among active-treatment groups, the use of any EPS medication was the highest for risperidone (39/140, 27.9%) and the lowest for aripiprazole (18/152, 11.8%); EPS medications were used by 21.9% (288/1317) of cariprazine-treated patients. A lower rate of medication use for EPS-related AEs (excluding akathisia and restlessness) was observed in patients with mild AEs (96/158; 60.8%) than in patients with moderate (58/68; 85.3%) or severe (3/3; 100%) AEs. Antiparkinson drugs were used to control EPS in 25.0% (35/140) of risperidone-treated patients, 17.3% (228/1317) of cariprazine-treated patients, and 7.9% (12/152) of aripiprazole-treated patients.
Per C-SSRS assessment, suicidal ideation was reported in 4.7% of placebo-treated and 3.6% of cariprazine-treated patients, with the majority of instances in the least severe category. No suicidal behavior was recorded by the C-SSRS in the placebo-treatment or the cariprazine-treatment groups, including patients who had akathisia or restlessness. The incidence of suicidality TEAEs for cariprazine (0.4%) was low and similar to placebo (0.2%); suicidal ideation was reported as a TEAE in one placebo-treated patient and four cariprazine-treated patients. There were two suicidality SAEs in the cariprazine group, including one completed suicide that was not considered to be treatment related.
Change from baseline in ophthalmologic parameters is presented in Supplementary Table 4 (Supplemental digital content 4, http://links.lww.com/ICP/A31). The most commonly reported ocular TEAE was blurred vision (placebo=0.3%; cariprazine=1.5%; risperidone=2.1%, aripiprazole=1.3%); all other ocular AEs were reported in less than 1% of patients in any group. No AEs of cataract or lens opacity were reported.
In this pooled analysis of safety data from 4 short-term randomized, controlled studies in adult patients with acute exacerbation of schizophrenia, cariprazine at doses up to 12 mg/day was generally safe and well tolerated; patients receiving doses above 6 mg/day showed higher likelihood for AEs, EPS, akathisia, and blood pressure changes. The most frequent TEAEs in cariprazine overall (reported in ≥5% of cariprazine-treated patients and at least twice the rate of placebo) were EPS reported by grouped terms and akathisia. A dose–response relationship was observed for akathisia and EPS in cariprazine-treated patients. No cariprazine dose response was observed for SAEs and discontinuations because of AEs. The most commonly reported SAEs and discontinuations because of AEs were associated with worsening of schizophrenia or psychotic symptoms.
Of the distinct TEAEs associated with atypical antipsychotics, those that increase the risk for cardiometabolic disease are among the most important (Hennekens, 2007). Cardiovascular disease is the second leading cause of premature death for patients with schizophrenia, surpassed only by suicide (Goff et al., 2005). Compared with the general population, the prevalence of several modifiable risk factors associated with cardiovascular disease, including obesity, smoking, diabetes, and hypertension, is high in patients with schizophrenia (Newcomer, 2007). The propensity for medication-induced metabolic and weight TEAEs in this at-risk population varies among atypical antipsychotics (Newcomer, 2007; Riordan et al., 2011). For example, the incidence of clinically significant weight gain (≥7%) associated with atypical antipsychotics has been reported to range from 8.1% for aripiprazole (Abilify, 2014) to 22.2% for olanzapine (Zyprexa, 2011).
As such, the cardiometabolic profile of cariprazine is important to patients with schizophrenia. In our analyses, the mean changes and clinically relevant shifts in lipid parameters and fasting glucose were generally similar for placebo and cariprazine, suggesting that short-term cariprazine exposure had minimal effects on these parameters; glucose increase of more than 10 dl was greater in cariprazine than in the other treatment groups. No QTc values greater than 500 ms were observed; overall, there were no clinically significant changes in pulse or blood pressure in cariprazine-treated patients, however dose-related increases in blood pressure were observed. The mean body weight increase was greater in all active-treatment groups than in the placebo group. For cariprazine, the mean increase in body weight was lower in the lower-dose groups than in the 9–12 mg group. Weight increase for cariprazine in the approved dose range was similar to aripiprazole, and in the 9–12 mg/day group, it was similar to risperidone. In the approved dose range, weight gain of 7% or more occurred in ∼8% of cariprazine patients, which was less than that in the cariprazine 9–12 mg (17.2%) and risperidone (16.7%) groups, and similar to the aripiprazole (6.0%) group. Collectively, these values suggest that cariprazine in the approved dose range is on the lower end of the atypical antipsychotic weight gain hierarchy.
Despite improved safety profiles for atypical antipsychotics versus first-generation agents, EPS and akathisia are consistently noted in the literature (Caroff et al., 2002; Kane et al., 2009; Kumar and Sachdev, 2009; Kane et al., 2010; Poyurovsky, 2010). Analyses from the CATIE study found no significant differences in the incidence of EPS for some second-generation antipsychotics (olanzapine, quetiapine, risperidone, ziprasidone) relative to each other or to perphenazine, a mid-potency first-generation agent (Miller et al., 2008). In the current analyses, akathisia was among the most frequent TEAEs for cariprazine and both active-comparator groups. A dose–response relationship was observed for cariprazine, with a lower risk for akathisia and EPS (grouped terms) in the approved dose range. The incidence of akathisia TEAEs in the lowest cariprazine-dose group (9.1%) was slightly higher than aripiprazole (7.2%) and risperidone (8.6%), and EPS across the cariprazine-dose groups (14.8–20.2%) was lower than risperidone (27.1%). At doses up to 6 mg/day, the rates of akathisia with cariprazine were similar to some antipsychotic agents marketed in the USA (e.g. lurasidone=6–22%, asenapine=4–11%) (Latuda, 2013; Saphris, 2014) and EPS was lower than others (risperidone and olanzapine=20–30%) (Zyprexa, 2011; Risperdal, 2014).
In clinical practice, akathisia is a routinely managed treatment-induced symptom (Lehman et al., 2004). For cariprazine, most EPS-related TEAEs were considered mild or moderate and resulted in relatively few discontinuations. Medication use to manage EPS generally correlated with symptom severity. In short-term aripiprazole schizophrenia trials, the rates of akathisia that were considered severe (<10%) or led to study discontinuation (0.3%) (Kane et al., 2010) were consistent with this cariprazine analysis. Collectively, these results suggest that akathisia and EPS were manageable for most cariprazine-treated patients.
Another noteworthy safety consideration for cariprazine-treated patients was the absence of increase in the prolactin level, which is important since hyperprolactinemia increases the risk of sexual function side effects (Henderson and Doraiswamy, 2008). In addition, although some atypical antipsychotics produce undesirable sedation and somnolence (Kane and Sharif, 2008), these effects for overall cariprazine were similar to placebo, less than risperidone, and slightly greater than (sedation) or equal to (somnolence) aripiprazole. The rates of sedation were lower in the cariprazine approved dose range than in the 9–12 mg/day group. A modest dose-related increase in the mean CPK level, which did not result in altered renal function, was observed in cariprazine-treated patients; large SDs suggest considerable fluctuations in CPK level over time, although cariprazine may cause transient increases that normalize with continued treatment. Cariprazine was not associated with an increased risk of suicidality, an essential finding considering that individuals with schizophrenia compared with the general population have a 12-fold higher risk of dying from suicide (Saha et al., 2007). Ophthalmologic testing indicated no evidence of retinal toxicity or clinically significant lenticular changes.
These analyses were subject to the limitations inherent in post-hoc analyses. Safety parameters were analyzed by descriptive statistics; no inferential statistical analyses were carried out. A tolerability bias in favor of patients in the higher modal daily dose groups may exist as patients with tolerability issues at lower doses may have been more likely to discontinue the study and less likely to increase their dosage. Short treatment duration and the inclusion of active comparators in only two studies are additional limitations.
In this pooled analysis of four short-term clinical trials, cariprazine at doses of 1.5–12 mg/day was generally safe and well tolerated. Patients in the modal dose group above 6 mg/day showed a higher likelihood for AEs, EPS, akathisia, weight increases, and blood pressure changes, as well as higher rates of CPK and transaminase elevations. This observation, together with the beneficial effects observed on efficacy, resulted in the FDA approving a recommended dose range for schizophrenia of 1.5–6 mg/day. Within the FDA-approved dose range, cariprazine was a generally safe and well-tolerated treatment option for patients with schizophrenia.
Writing assistance and editorial support for the preparation of this manuscript were provided by Carol Brown, MS, of Prescott Medical Communications Group, a contractor of Allergan.
This study was funded by Forest Research Institute Inc., an Allergan affiliate (Jersey City, New Jersey), and Gedeon Richter Plc. (Budapest, Hungary). Forest Research Institute Inc., an Allergan affiliate, and Gedeon Richter Plc. were involved in the study design, collection (through contracted clinical investigator sites), analysis, and interpretation of data, and the decision to present these results.
Conflicts of interest
Willie Earley, Suresh Durgam, and Kaifeng Lu are employees of Allergan. István Laszlovszky is an employee of Gedeon Richter Plc. Marc Debelle is a former employee of Gedeon Richter Plc. John M. Kane serves or has served as a consultant for Alkermes Plc.; Bristol-Myers Squibb Company; Eli Lilly and Company; Forest Laboratories Inc.; FORUM Pharmaceuticals; Genentech Inc., a Member of the Roche Group; H. Lundbeck A/S; Hoffmann-La Roche Inc.; Intra-Cellular Therapies Inc.; Janssen Pharmaceuticals Inc.; Johnson & Johnson Services Inc.; Otsuka Pharmaceutical Co. Ltd; Pierre Fabre; Reviva Pharmaceuticals Inc.; and Teva. He also serves or has served on speaker bureaus for Bristol-Myers Squibb Company; Genentech Inc., a member of the Roche Group; Janssen Pharmaceuticals Inc.; and Otsuka Pharmaceutical Co. Ltd. He owns or has owned shares in LB Pharmaceuticals; MedAvante Inc.; and Vanguard Research Group.
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antipsychotic; cariprazine; post-hoc analysis; safety and tolerability; schizophrenia
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