Cariprazine for acute and maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy

Figures & data

Figure 1 Plasma concentration at trough (mean ± SE)–time profile during and following 12-weeks of treatment with cariprazine 6 mg/day.

Notes: Reproduced from the product label.¹⁰ DDCAR is the predominant circulating moiety, representing about 70% of the total exposure. When treatment is discontinued, DDCAR concentrations persist longer than for cariprazine or DCAR.
Abbreviations: CAR, cariprazine; DDCAR, didesmethyl-cariprazine; total CAR, summed concentration of cariprazine, DCAR, and DDCAR.

Table 1 Completed, randomized, placebo-controlled, phase II/III double-blind clinical trials of cariprazine for acute schizophrenia

Study	Randomized to receive treatment	Cariprazine dose (and dose of active control if applicable)	Completion rate (%)	LS mean change at week 6 in PANSS total score (MMRM analysis)	Responder ratesa	Comments on dose titration and tolerability
Durgam et al,^Citation14 NCT00404573, RGH-MD-03, phase II	392	Flexible dose ranges 1.5–4.5 and 6–12 mg/day Overall mean daily doses 3.8 and 8.7 mg/day for 1.5–4.5 and 6–12 mg/day, respectively	54	Placebo: −13.00 1.5-4.5 mg/day: −17.99 6-12 mg/day: −16.83 P-values for difference from placebo: 0.063 and 0.151, respectively	Placebo: 31% 1.5–4.5 mg/day: 43% 6–12 mg/day: 35% NNT vs placebo as calculated: 9 and 25, respectively	Cariprazine dosing was initiated at 1.5 mg/day for all patients. Dose adjustments were based on investigator judgment of response and tolerability. In the low-dose group, cariprazine could be up titrated to 3 mg starting on day 3 and to a maximum dose of 4.5 mg starting on day 5. In the high-dose group, cariprazine dosage could be increased to 3 mg starting on day 3, 6 mg starting on day 5, 9 mg starting on day 7, and to a maximum dose of 12 mg by day 9. In patients with tolerability issues, reduction to a previous dose or a drug holiday of 1–2 days was allowed. Patients were required to be hospitalized for at least 3 weeks after randomization. AEs reported in ≥5% of the patients in either cariprazine group and at least twice the rate seen with placebo were akathisia (both groups), restlessness (1.5–4.5 mg/day), tremor (1.5–4.5 mg/day), back pain (1.5–4.5 mg/day), and EPS (6–12 mg/day). This was a failed study. Because there was no active comparator, it is not possible to state definitively that the study failed because of a high placebo response; however, the authors of the study noted that this study was conducted only at study centers in the US, whereas subsequent trials were conducted at both US and non-US study centers, and that increasing placebo response and decreasing treatment effect over time have been observed in schizophrenia trials conducted in the US.
Durgam et al,^Citation15 NCT00694707, RGH-MD-16, phase II	732	Fixed-dose 1.5, 3, 4.5 mg/day (risperidone dose 4 mg/day)	64	Placebo: −13.3 1.5 mg/day: −21.3 3 mg/day: −21.5 4.5 mg/day: −23.8 Risperidone: −29.3 P-values for difference from placebo: ≤0.01, ≤0.01, ≤0.001, and ≤0.001, respectively	Placebo: 18.9% 1.5 mg/day: 31.4% 3 mg/day: 35.7% 4.5 mg/day: 35.9% risperidone: 43.5% NNT vs placebo as calculated: 8, 6, 6, and 5, respectively	Cariprazine was initiated at 1.5 mg/day and increased by 1.5 mg until the target dose was reached (day 2 or 3), and risperidone was initiated at 2 mg/day and increased to 4 mg/day on day 3. Patients were required to be hospitalized for at least 4 weeks after randomization. AEs reported in ≥5% of the patients in any cariprazine group and at least twice the rate seen with placebo were insomnia, EPS, akathisia, sedation, nausea, dizziness, and constipation. A 48-week open-label treatment extension was available to responders (NCT00839852; RGH-MD-17).^Citation21
Durgam et al,^Citation17 NCT01104766, RGH-MD-04, phase III	617	Fixed-dose 3, 6 mg/day (aripiprazole dose 10 mg/day)	67	Placebo: −14.3 3 mg/day: −20.2 6 mg/day: −23.0 Aripiprazole: −21.2 P-values for difference from placebo: ≤0.01, ≤0.001, and ≤0.001, respectively	Placebo: 19.5% 3 mg/day: 24.5% 6 mg/day: 31.8% Aripiprazole: 30.0% NNT vs placebo as calculated: 20, 9, and 10, respectively	Cariprazine was initiated at 1.5 mg/day, and dosage was increased by 1.5 mg/day until the target dose was achieved (day 2 and day 4 for cariprazine 3 and 6 mg/day, respectively). Patients were required to be hospitalized for at least 4 weeks after randomization. AE reported in ≥5% of the patients in either cariprazine group and at least twice the rate seen with placebo was akathisia in the 6 mg/day group. A 48-week open- label treatment extension was available to completers (NCT01104792; RGH-MD-11).^Citation22
Kane et al,^Citation16 NCT01104779, RGH-MD-05, phase III	446	Flexible-dose ranges 3–6 and 6–9 mg/day Final mean daily doses were 5.2 and 7.7 mg/day for 3–6 and 6–9 mg/day, respectively	60.5	Placebo: -16.0 3-6 mg/day: -22.8 6-9 mg/day: -25.9 P-values for difference from placebo: 0.003 and ≤0.001, respectively	Placebo: 24.8% 3–6 mg/day: 28.6% 6–9 mg/day: 34.7% NNT vs placebo as calculated: 27 and 11, respectively	Cariprazine was initiated at 1.5 mg on day 1 and 3 mg on days 2 and 3. The 3–6 mg/day group remained at 3 mg until the end of week 2 of double-blind treatment. Starting on day 4, the 6–9 mg/day group received 6 mg until the end of week 2 of double-blind treatment. In cases of inadequate response (<20% improvement from baseline on PANSS total score and Clinical Global Impressions – severity score ≥4), cariprazine dose was increased at the end of week 2. In the 3–6 mg/day group, patients received 4.5 mg/day for days 14–15 and 6 mg/day thereafter. In the 6–9 mg/day group, patients received 7.5 mg/day for days 14–15 and 9 mg/day thereafter. Patients who did not qualify as inadequate responders or had significant tolerability issues did not receive a dose increase. Dosage was fixed from the end of week 3 to week 6. Patients were required to be hospitalized for at least 4 weeks after randomization. AEs reported in ≥5% of patients in either cariprazine group and at least twice the rate seen with placebo were akathisia (both groups), restlessness (6–9 mg/day), EPS (both groups), dyspepsia (6–9 mg/day), constipation (3–6 mg/day), tremor (both groups), vomiting (6–9 mg/day), weight increase (6–9 mg/day), and diarrhea (3–6 mg/day). A 48-week open-label treatment extension was available to completers (NCT01104792; RGH-MD-11).^Citation22

Notes: All trials 6 weeks’ duration.

a Response reported using definition of ≥20% improvement from baseline in PANSS total score at week 6 in Durgam et al¹⁴ and using definition of ≥30% improvement from baseline in PANSS total score at week 6 for the other three studies.^15–17

Abbreviations: AEs, adverse events; EPS, extrapyramidal symptoms; LS, least squares; MMRM, mixed-effect model for repeated measures; NNT, number needed to treat; PANSS, Positive and Negative Syndrome Scale.

Table 2 Potentially relevant adverse events associated with the use of cariprazine

Adverse event	Placebo (n=584)	Cariprazine modal dose group
		1.5–3 mg/d (n=539)		4.5–6 mg/d (n=575)		9–12 mg/d (n=203)		Overall (n=1,317)
	n (%)	n (%)	NNH (95% CI)	n (%)	NNH (95% CI)	n (%)	NNH (95% CI)	n (%)	NNH (95% CI)
Extrapyramidal symptoms	45 (7.7)	80 (14.8)	14 (10–30)	108 (18.8)	9 (7–14)	41 (20.2)	8 (6–16)	229 (17.4)	11 (8–15)
Headache	74 (12.7)	46 (8.5)	NA	65 (11.3)	NA	37 (18.2)	18 (NS)	148 (11.2)	NA
Insomnia	64 (11.0)	65 (12.1)	91 (NS)	74 (12.9)	53 (NS)	23 (11.3)	270 (NS)	162 (12.3)	75 (NS)
Somnolence	32 (5.5)	28 (5.2)	NA	46 (8.0)	40 (NS)	21 (10.3)	21 (11–348)	95 (7.2)	58 (NS)
Akathisia	21 (3.6)	49 (9.1)	19 (12–38)	72 (12.5)	12 (9–18)	28 (13.8)	10 (7–20)	149 (11.3)	13 (10–19)
Constipation	29 (5.0)	31 (5.8)	128 (NS)	39 (6.8)	55 (NS)	20 (9.9)	21 (11–236)	90 (6.8)	54 (NS)
Abdominal pain	28 (4.8)	17 (3.2)	NA	25 (4.3)	NA	15 (7.4)	39 (NS)	57 (4.3)	NA
Nausea	29 (5.0)	29 (5.4)	242 (NS)	38 (6.6)	61 (NS)	16 (7.9)	35 (NS)	83 (6.3)	75 (NS)
Restlessness	18 (3.1)	21 (3.9)	123 (NS)	33 (5.7)	38 (20–340)	11 (5.4)	43 (NS)	65 (4.9)	54 (28–3,643)
Anxiety	24 (4.1)	31 (5.8)	61 (NS)	27 (4.7)	171 (NS)	6 (3.0)	NA	64 (4.9)	134 (NS)
Hypertension	6 (1.0)	13 (2.4)	73 (NS)	15 (2.6)	64 (33–2,325)	13 (6.4)	19 (12–53)	41 (3.1)	48 (30–119)
Vomiting	20 (3.4)	22 (4.1)	153 (NS)	29 (5.0)	62 (NS)	11 (5.4)	51 (NS)	62 (4.7)	78 (NS)
Dizziness	12 (2.1)	17 (3.2)	91 (NS)	28 (4.9)	36 (21–141)	11 (5.4)	30 (15–2,279)	56 (4.3)	46 (27–164)
Toothache	21 (3.6)	14 (2.6)	NA	20 (3.5)	NA	12 (5.9)	44 (NS)	46 (3.5)	NA
Weight increase	8 (1.4)	17 (3.2)	56 (29–3,014)	14 (2.4)	94 (NS)	6 (3.0)	64 (NS)	37 (2.8)	70 (37–708)

Notes: Incidence ≥5% in any cariprazine group and greater than placebo observed in acute trials for schizophrenia. Data from Earley et al;²⁴ NNH values calculated by the author.

Abbreviations: CI, confidence interval; NA, not applicable (adverse-event rate higher for placebo); NNH, number needed to harm; NS, not significant at the p<0.05 threshold and thus the 95% CI is not shown.

Table 3 Potentially relevant adverse events associated with the use of cariprazine 1.5 mg/day as observed in Durgam et al¹⁵,a

Adverse event	Cariprazine 1.5 mg/day (n=l 45)	Placebo group^Citation15 (n= 151)		Pooled placebo group^Citation24 (n=584)
	n (%)	n (%)	NNH (95% CI)	n (%)	NNH (95% CI)
Extrapyramidal symptoms	13 (9.0)	7 (4.6)	24 (NS)	45 (7.7)	80 (NS)
Headache	16(11.0)	16 (10.6)	229 (NS)	74(12.7)	NA
Insomnia	15 (10.3)	1 1 (7.3)	33 (NS)	64(11.0)	NA
Somnolence or sedation	7 (4.8)	5 (3.3)	66 (NS)	32 (5.5)	NA
Akathisia	13 (9.0)	7 (4.6)	24 (NS)	21 (3.6)	19 (10–209)
Constipation	14(9.7)	5 (3.3)	16(9-133)	29 (5.0)	22 (NS)
Nausea	7 (4.8)	5 (3.3)	66 (NS)	29 (5.0)	NA
Anxiety	6(4.1)	5 (3.3)	121 (NS)	24 (4.1)	3,529 (NS)
Vomiting	4 (2.8)	5 (3.3)	NA	20 (3.4)	NA
Dizziness	5 (3.4)	3 (2.0)	69 (NS)	12(2.1)	72 (NS)
Weight increased	3(2.1)	1 (0.7)	72 (NS)	8(1.4)	143 (NS)

Note:

a Data for pooled placebo group was taken from Earley et al²⁴ and NNH values were calculated by the author.

Abbreviations: CI, confidence interval; NA, not applicable (adverse-event rate higher for placebo); NNH, number needed to harm; NS, not significant at the p<0.05 threshold and thus the 95% CI is not shown.

Figure 2 Kaplan–Meier curves of cumulative rate of relapse during the double-blind treatment period.

Notes: Reproduced from the product label.¹⁰ Although the study permitted dosing of cariprazine at 3–9 mg/day, the maximum recommended daily dose is 6 mg. Between-group separation of the curves did not occur until around day 50, possibly because of the long half-life of cariprazine (and specifically DDCAR) lending some extended protection against the risk of relapse.
Abbreviations: DB, double-blind; DDCAR, didesmethyl-cariprazine.

Table 4 Completed, longer term, randomized, controlled, phase III double-blind clinical trials of cariprazine for schizophrenia

Study	Randomized, n	Cariprazine dose (and dose of active control if applicable)	Comments, including regarding dose titration and tolerability
Durgam et al,^Citation19 NCT01412060, RGH-MD-06	200	Flexible-dose range 3–9 mg/day About 50% of all cariprazine patients were receiving 9 mg/day at randomization, 37% 6 mg/day, and 14% 3 mg/day	The aim of this study was to assess longer term maintenance treatment with cariprazine. The study included 20 weeks of open-label treatment with cariprazine for all patients, followed by a variable- length randomized phase where stable patients received either cariprazine or placebo. Cariprazine was started at 1.5 mg/day and increased to 3 mg/day on day 2. For patients with inadequate response and no significant tolerability issues, dosage increases were allowed on day 6 (6 mg/day [interim increase to 4.5 mg/day on day 4]) and day 10 (9 mg/day) if needed. Dose decreases to 3 or 6 mg/day were allowed for significant tolerability issues. During double-blind treatment, cariprazine was administered at the same fixed dose as in the stabilization phase. Patients were required to be hospitalized during screening and for the first 2 weeks in the run-in phase. The most commonly observed AEs during the open-label phase were akathisia (19%), insomnia (14%), and headache (12%). During open-label treatment, akathisia and other EPS AEs (excluding akathisia or restlessness) each led to discontinuation in ~1% of patients. No EPS-related AEs led to discontinuation during double-blind treatment.
Németh et al,^Citation27 EudraCT 2012-005485-36, RGH-188–005	461	Fixed dose 4.5 mg/day (risperidone dose 4 mg/day)	The aim of this study was to assess the efficacy of cariprazine on negative symptoms. From random- ization (day 0) to day 6, patients received cariprazine 1.5 mg/day or risperidone 2 mg/day. On days 7–13, patients received 3 mg/day of their respective study drug, and on day 14, patients received the target dose of cariprazine 4.5 mg/day or risperidone 4 mg/day. Antipsychotic treatment taken during the lead-in period was downtitrated during this period and discontinued on day 14. The dose of the double-blind study medication could be decreased to 3 mg/day in case of poor tolerability. In casesof impending psychotic deterioration, the dose could be increased to 6 mg/day. The mean dose for cariprazine was 4.2 mg/day and that for risperidone 3.8 mg/day. AEs (eg, insomnia, akathisia, worsening of schizophrenia, headache, anxiety) were reported in 54% of patients treated with cariprazine and 57% of patients treated with risperidone. The most common AE for cariprazine was akathisia (8%), which was also observed for 5% of persons randomized to risperidone.

Abbreviations: AEs, adverse events; EPS, extrapyramidal symptoms.

Table 5 NNH vs placebo for approved first-line oral second-generation antipsychotics in adults, as observed in acute short-term studies for schizophreniaa

Antipsychotic	NNH for weight gain ≥7%	Rank order	NNH for somnolence adverse events	Rank	NNH for akathisia adverse events	Rank	Average of ranking values
Cariprazine (to 6 mg/day)	34	3	100b	1	15	8	4.0
Brexpiprazole	17	7	50b	2	112	3	4.0
Aripiprazole	21	5	20c	4	25	7	5.3
Risperidone (to 8 mg/day)	18c	6	13	8	15	8	4.7
Olanzapine	6c	10	7c	11	25	7	9.3
Quetiapine immediate release	6	10	10c	10	NA	1	7.0
Quetiapine extended release	22	4	7	11	188	2	5.7
Ziprasidone	16	8	15	7	100	4	6.3
Paliperidone	35	2	42	3	39	5	3.3
Iloperidone	10	9	16	6	NA	1	5.3
Asenapine	35	2	17	5	34	6	4.3
Lurasidone	67	1	11	9	10	9	6.3

Notes:

a Table adapted (NNH values extracted),¹¹ with permission;

b somnolence, sedation, hypersomnia;

c reported in product labeling for schizophrenia and bipolar mania pooled together.

Abbreviations: NA, not applicable (no difference or rate with medication lower than rate with placebo); NNH, number needed to harm.

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