Last updated May 18, 2023, by Marisa Wexler, MS
Fact-checked by Joana Carvalho, PhD
What is Rexulti for Alzheimer’s disease?
Rexulti (brexpiprazole) is a once-daily oral therapy that is approved to help manage agitation — abnormal or inappropriate displays of emotion, such as shouting or shoving — associated with dementia due to Alzheimer’s disease. It was co-developed by Otsuka Pharmaceutical and Lundbeck.
The medication is the first and only treatment ever approved for this specific indication in the U.S.
How does Rexulti work?
Rexulti is an antipsychotic agent known to have mood-modulating properties, but it’s not known exactly how the therapy exerts its effects on the brain. It’s thought that Rexulti may alter the activity of certain brain signaling molecules, namely dopamine and serotonin, which may play a role in its effects.
Who can take Rexulti?
Rexulti was approved by the U.S. Food and Drug Administration (FDA) in May 2023 to treat agitation associated with dementia due to Alzheimer’s disease.
The therapy had previously been approved in the U.S. to treat schizophrenia in patients ages 13 and older, and as an add-on treatment to help manage major depressive disorder in adults.
Who should not take Rexulti?
Rexulti should not be used by people with a known allergy to the medication or any of its components. It also should not be used as an on-demand treatment, on an “as needed” basis to control agitation associated with Alzheimer’s dementia.
The prescribing label for Rexulti has a boxed warning noting the medication may increase the risk of death in elderly people with dementia-related psychosis, as well as increase the risk of suicidal thoughts and actions in patients ages 24 and younger.
The therapy should not be given to treat people with dementia-related psychosis who do not have agitation associated with Alzheimer’s dementia.
How is Rexulti administered?
Rexulti is taken by mouth, once daily, with or without food.
For patients with agitation due to Alzheimer’s dementia, the recommended daily dosage is:
- 0.5 mg for the first week
- 1 mg for the second week
- 2 mg thereafter.
While 2 mg per day is the recommended dose, the dosage may be increased up to a maximum of 3 mg per day after two weeks on therapy, based on tolerability and a patient’s response to treatment. However, for patients with kidney impairments, a maximum dose of 2 mg per day should not be exceeded.
Rexulti in clinical trials
Rexulti’s approval to treat agitation associated with dementia due to Alzheimer’s was supported by data from two Phase 3 clinical trials: Study 331-12-283 (NCT01862640) and Study 331-14-213 (NCT03548584).
These studies collectively enrolled 778 people with agitation associated with Alzheimer’s dementia. In both studies, just less than half of the participants were male, and more than 90% were white individuals. Patients in the two studies had a mean age of 74.
In both trials, participants were randomly assigned to take Rexulti at doses ranging from 1 to 3 mg per day after an initial period of increase, or a placebo, for 12 weeks (about three months). The studies’ main goal was to assess the impact of treatment on the frequency of agitation symptoms, as measured with a standardized clinician-rated scale called the Cohen-Mansfield Agitation Inventory total (CMAI).
Results from the trials showed that, after 12 weeks, total CMAI scores had improved significantly more in patients treated with Rexulti than in those given a placebo. CMAI scores improved by a mean of 3.8 points for patients given Rexulti at a dose of 2 mg/day in Study 331-12-283, and by a mean of 5.3 points for patients given the therapy at a dose of 2 or 3 mg/day in Study 331-14-213.
Analyses of CMAI subscales suggested that Rexulti broadly reduced many different types of agitation behaviors, including aggressive and non-aggressive physical behaviors, as well as verbal behaviors.
Common side effects of Rexulti
In clinical trials of agitation associated with Alzheimer’s dementia, the most commonly reported side effects of Rexulti included:
- dizziness
- the common cold.
Increased risk of death in elderly patients with dementia-related psychosis
The medication carries a boxed warning stating that, similar to other antipsychotic therapies, its use in elderly people with dementia-related psychosis may increase the risk of death. The therapy’s label also includes a warning stating that Rexulti may increase the risk of stroke and other cerebrovascular adverse events in elderly patients with with dementia-related psychosis.
Rexulti is not approved to treat people with dementia-related psychosis who do not have agitation associated with Alzheimer’s dementia, and therefore should not be used in such cases.
Sleepiness and cognitive abnormalities
Like other antipsychotics, Rexulti may impair a person’s judgment and motor skills, and it may cause drowsiness. Patients who are starting on the therapy should avoid doing potentially dangerous tasks, such as driving, until they know how the therapy affects them.
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a potentially life-threatening condition characterized by symptoms like a high fever, excessive sweating, irregularities in heartbeat and blood pressure, and altered mental status. This condition has been reported in patients given antipsychotics, including Rexulti.
If patients on Rexulti show signs of neuroleptic malignant syndrome, the therapy should be immediately discontinued.
Uncontrolled movements
Tardive dyskinesia, a syndrome characterized by jerky, uncontrolled movements that may be irreversible, can develop in people treated with antipsychotic agents like Rexulti. The risk of this side effect appears to be particularly higher in elderly women. Rexulti may be discontinued if this side effect causes problems that outweigh its potential benefits.
Metabolic changes
Antipsychotic medications like Rexulti can cause metabolic changes, such as elevations in blood sugar levels, diabetes, and weight gain. Metabolic markers like blood sugar and certain fatty molecules should be monitored while patients are on Rexulti.
Uncontrolled urges and gambling
Some people given Rexulti report feeling intense, uncontrollable urges that can give rise to compulsive behaviors. This most commonly manifests with excessive gambling, but some patients report urges related to other behaviors, including shopping, sexual activity, or eating. If these urges develop, the dosage of medication may be reduced or it may be discontinued altogether.
Low immune cell counts
Antipsychotics in the same class as Rexulti may lower the levels of certain immune cells in the blood. Treatment should be discontinued if immune cell counts dip below certain cutoffs, and patients with low immune cell levels should be monitored for potential signs of infection.
The risk of this side effect is higher in patients who have low immune cell counts prior to starting treatment, or in those who have experienced reduced immune cell counts as a side effect of other medicines. In these patients, immune cell counts should be regularly checked in the first months of treatment. In such patients, the medication should be stopped at the first sign of a significant decline in immune cell counts.
Orthostatic hypotension
Rexulti may cause orthostatic hypotension, which happens when blood pressure drops suddenly when a person stands from a lying or seated position. This can reduce blood flow to the brain, which may result in a brief loss of consciousness (syncope).
Blood pressure should be monitored in patients with a history of heart disease, or those at risk of low blood pressure, such as patients who are elderly, dehydrated, or treated with medications that lower blood pressure.
Falls and seizures
Due to side effects like dizziness and drowsiness, Rexulti may increase the risk of falls and fall-related problems like bone fractures. Fall risk should be assessed regularly for patients on the therapy.
Antipsychotic medications like Rexulti can cause seizures. The risk of seizures is increased in patients with a history of seizures or in those who have conditions that increase their predisposition to have seizures.
Body temperature regulation
Rexulti may disrupt the body’s ability to cool off, leading to potentially dangerous increases in core body temperature. The therapy should be used with caution in patients who are at high risk of increased body temperature, such as those who are regularly exposed to high temperatures or who do a lot of strenuous exercise.
Swallowing problems
Rexulti can cause problems with the esophagus — the muscular tube that carries food to the stomach — and increase the risk of aspiration (choking) in some patients. Therefore, Rexulti should be used with caution in people who have a high risk of choking.
Use in pregnancy and breastfeeding
There have not been well-controlled studies on the use of Rexulti during pregnancy. However, available data suggest that babies exposed to antipsychotics like Rexulti during the third trimester of pregnancy may be at risk of withdrawal symptoms and movement abnormalities when they are born. Sometimes these symptoms are mild and resolve over time without treatment, but in other cases babies may require prolonged hospitalization.
The National Pregnancy Registry for Psychiatric Medications is collecting data on the outcomes of people who take Rexulti or related medications during pregnancy.
Studies assessing the presence of Rexulti in human breast milk, its effects on the breastfed infant, or on milk production have not been conducted. The potential benefits of Rexulti should be weighed against its potential risks when it comes to deciding whether the therapy should be used during breastfeeding.
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