First published 15 August 2017

Approved indication: schizophrenia
Rexulti (Lundbeck)
0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg tablets
Australian Medicines Handbook section 18.2

Brexpiprazole is a new antipsychotic for schizophrenia. It is structurally similar to aripiprazole and has a similar mechanism of action. It acts at many receptors. For example, it is a partial agonist at serotonin 5-HT1A and dopamine D2 and D3 receptors and an antagonist at the serotonin 5-HT2A and noradrenergic receptors.

Two six-week randomised, placebo-controlled trials investigated the safety and efficacy of brexpiprazole in 1310 patients with acute schizophrenia (see Table).1,2 The primary outcome measure was improvement on the Positive and Negative Syndrome Scale (PANSS). This is a 30-item scale assessing positive (e.g. delusions, hallucinations), negative (e.g. emotional withdrawal) and general symptoms (e.g. anxiety, depression). In one trial, mean improvements in the PANSS scores after treatment were significantly higher with brexpiprazole 2 mg/day and 4 mg/day than with placebo.1 However, in the other trial, only the 4 mg/day dose was significantly better than placebo.2

Table - The efficacy of brexpiprazole for acute schizophrenia in six-week trials

 

Correll et al. 20151

Placebo

brexpiprazole/day

0.25 mg

2 mg

4 mg

Number of patients

184

90

182

180

Mean baseline PANSS score

95.9

93.4

95.9

94.9

Mean improvement in PANSS score

12.0

14.9

20.7*

19.7*

Response rate

30.3%

39.1%

47.8%

46.1%

Kane et al 20152

Placebo

brexpiprazole/day

1 mg

2 mg

4 mg

Number of patients

184

120

186

184

Mean baseline PANSS score

94.8

93.3

96.3

95.1

Mean improvement in PANSS score

13.5

16.9

16.6

20*

Response rate

31.7%

43.6%

38.6%

49.7%

Citrome et al 20163

brexpiprazole 1–4 mg/day

aripiprazole 10–20 mg/day

Number of patients

64

33

Mean baseline PANSS score

94.1

93.3

Mean improvement in PANSS score

22.9

19.4

Response rate

60.9%

48.5%

PANSS Positive and Negative Syndrome Scale
* statistical significance over placebo
proportion of patients with a ≥30% improvement in their PANSS score or Clinical Global Impression (CGI) score after 6 weeks treatment

Another efficacy measure was response rate. This was defined as the proportion of patients with a ≥30% improvement in their PANSS score or Clinical Global Impression (CGI) score. In the trials, 46.1–49.7% of patients had responded to the 4 mg/day dose compared with 30.3–31.7% in the placebo groups (see Table).1,2

In another trial, flexible doses of open-label brexpiprazole (1–4 mg/day) and aripiprazole (10–20 mg/day) were compared in 97 patients with acute schizophrenia. After six weeks of treatment, mean changes in PANSS scores with brexpiprazole were comparable to aripiprazole (see Table).3

A longer term trial assessed brexpiprazole as a maintenance treatment for schizophrenia in patients who had been stabilised on brexpiprazole.4 These patients were randomised to 52 weeks of brexpiprazole 1–4 mg/day (97 patients) or placebo (105 patients). The primary outcome was time between randomisation and exacerbation of psychotic symptoms or impending relapse. At the interim analysis, time to impending relapse was significantly delayed in the brexpiprazole group compared to the placebo group (hazard ratio 0.292, 95% confidence interval 0.156–0.548, p<0.0001) and the trial was terminated. As the trial was cut short, only 23 patients completed 52 weeks of treatment.4

Tolerance to brexpiprazole after short- and long-term exposure was assessed in a safety study.5 In short-term studies of patients taking up to 6 mg/day brexpiprazole (n=1256), akathisia (5.8%) and gain in weight of more than 7% (4.7%) were more frequently reported with brexpiprazole than with placebo.5 These effects appeared to be dose-related. Newly diagnosed metabolic syndrome was also more common with brexpiprazole than with placebo in the short-term trials (1.2% vs 0.8%), and was even higher in the longer term trials (3.1%). Of the patients who took the drug for a year or more, 5.6% gained at least 15 kg in weight.5 Brexpiprazole did not increase the QT interval in the trials.

Brexpiprazole has not been tested during pregnancy. However, exposure to other antipsychotics during the third trimester increases the risk of extrapyramidal or withdrawal symptoms in neonates. In animal studies, brexpiprazole did not have teratogenic effects.

Brexpiprazole can be taken with or without food. The starting dose is 1 mg. This should be titrated to the recommended target dose of 2–4 mg over eight days depending on clinical response and tolerability. In people with moderate–severe hepatic or renal impairment, the maximum recommended daily dose is 3 mg.

After oral administration, peak plasma concentrations are reached within four hours. The terminal half-lives of brexpiprazole and its major metabolite are 86–91 hours. Approximately 25% of the dose is excreted in urine and 46% in faeces.

Brexpiprazole is mainly metabolised by cytochrome P450 (CYP) 3A4 and CYP2D6. Strong CYP3A4 inhibitors, such as ketoconazole, increase serum concentrations of brexpiprazole, while inducers (e.g. rifampicin) reduce concentrations so adjustment of the brexpiprazole dose is required with concomitant dosing. Dose reduction is recommended in patients who are poor CYP2D6 metabolisers.

The 4 mg/day dose of brexpiprazole seems to be effective for acute schizophrenia in short-term trials. Up to half of the patients responded to this dose.1,2 In a longer term placebo-controlled trial, brexpiprazole reduced the risk of relapse in patients already established on brexpiprazole.4 As with other antipsychotics, akathisia and weight gain are common. Brexpiprazole has been approved as an adjunct treatment of major depression in the USA but not in Australia. 

Read about The Transparency Score  manufacturer provided additional useful information

The Transparency Score is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.

At the time the comment was prepared, information about this drug was available on the website of the Food and Drug Administration in the USA.

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