Consumer medicine information

Rexulti

Brexpiprazole

BRAND INFORMATION

Brand name

Rexulti

Active ingredient

Brexpiprazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Rexulti.

What is in this leaflet

This leaflet answers some common questions about REXULTI.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking REXULTI against the benefits (s) he expects it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What REXULTI is used for

REXULTI is used to treat adults with schizophrenia.

Schizophrenia is a mental illness characterised by symptoms such as:

  • hallucinations; hearing, seeing or sensing things that are not there
  • suspiciousness, mistaken beliefs
  • incoherent speech and behaviour, emotional flatness.

People with this condition may also feel depressed, guilty, anxious, or tense.

The cause of schizophrenia is not understood but medicines like REXULTI and other similar medicines help to control the symptoms of the disorder by their actions in the brain.

REXULTI belongs to a group of medicines called antipsychotic agents.

Although REXULTI cannot cure schizophrenia, it can help to keep the symptoms under control and reduce the risk of relapse as you continue treatment.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

REXULTI is available only with a doctor's prescription.

There is no evidence that REXULTI is addictive.

REXULTI should not be given to children and adolescents under 18 years of age as safety and efficacy have not been established in this age group.

Before you take REXULTI

When you must not take it

Do not take REXULTI if you have an allergy to:

  • brexpiprazole, the active ingredient in REXULTI; or any of the other ingredients listed at the end of this leaflet under PRODUCT DESCRIPTION
  • any other similar medicines (such as medicines of the same class).

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking REXULTI, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant or plan to become pregnant. REXULTI is not recommended for use during pregnancy. If you need to take REXULTI during your pregnancy, your doctor will discuss the benefits and risks of taking it with you. The effect of REXULTI on your unborn baby is not known. Using REXULTI in the last three months of pregnancy may cause muscle movement problems, medicine withdrawal symptoms or both of these in a new-born.

Tell your doctor or pharmacist if you are breast-feeding or plan to breast-feed.

It is recommended that you do not breast-feed while taking REXULTI, as it is not known if REXULTI passes into breast milk and, therefore, there is a possibility that the breast-fed baby may be affected.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • dementia (loss of memory or other mental abilities) and you are elderly
  • neuroleptic malignant syndrome - a reaction to some medicines with a sudden increase in body temperature, sweating, fast heartbeat, muscle stiffness and fluctuating blood pressure, which may lead to coma
  • tardive dyskinesia - a reaction to some medicines with abnormal movements of the tongue, or other uncontrolled movements of the mouth, tongue, cheeks or jaw which may progress to the arms and legs
  • high or low blood pressure
  • rapid heartbeat and a drop in blood pressure when getting up
  • problems with your heart or blood vessels, including stroke, "mini" stroke, or family history of heart or blood vessel problems
  • epilepsy, seizures or fits
  • suicidal thoughts or behaviour
  • problems with your oesophagus (food pipe/gullet) such as difficulty in swallowing
  • high blood sugar or diabetes mellitus or a family history of diabetes or high blood sugar
  • high cholesterol, triglycerides, LDL - cholesterol or low levels of HDL-cholesterol
  • blood clots, or you have any of the following risk factors for developing blood clots:
    - family history of blood clots
    - 65 years of age or older,
    - smoking
    - obese
    - recent major surgery such as hip or knee replacement
    - immobility due to air travel or other reason
    - you take oral contraceptives
  • past experience with excessive gambling or other compulsive behaviours
  • have or had low white blood cell count
  • sleep apnoea (a sleep disorder where your breathing is interrupted during sleep).

Tell your doctor if you drink alcohol. You should avoid alcohol as it could magnify the side effects of this medicine.

If you have not told your doctor about any of the above, tell him/her before you start taking REXULTI.

Ask your doctor or pharmacist for advice before taking any medicine.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and REXULTI may interfere with each other. These include:

  • medicines and herbal remedies used to treat depression and anxiety (e.g. Saint John's Wort, fluoxetine and paroxetine)
  • anticonvulsants used to treat epilepsy or seizures
  • medicines used to treat high blood pressure
  • medicines used to treat heart rhythm disturbances
  • medicines used to treat blood disorders (e.g. ticlopidine)
  • medicines used to treat bacterial, fungal or viral infections (e.g. terbinafine and itraconazole).

These medicines may be affected by REXULTI or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

If you have not told your doctor or pharmacist about any of these things, tell them before you take REXULTI.

How to take REXULTI

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

How much to take

Your doctor or pharmacist will tell you how much you will need to take each day. This will depend on your condition and whether you are taking any other medicines.

Follow the instructions they give you. The label put on the carton by the pharmacist will tell you how much you should take. If you take the wrong dose, REXULTI may not work as well as expected and your disease may not improve.

How to take it

REXULTI tablets should be swallowed whole and washed down with a glass of water.

REXULTI can be taken with or without food.

When to take it

Unless your doctor gives you other directions, you should take REXULTI only once a day.

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking REXULTI even if you feel well.

If you forget to take it

Take your dose as soon as you remember, and continue to take it as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone Australia 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much REXULTI. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking REXULTI

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking REXULTI.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking REXULTI.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking REXULTI.

If you become pregnant while taking REXULTI, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

Do not take REXULTI to treat any other complaints unless your doctor tells you to.

Do not give REXULTI to anyone else, even if they have the same condition as you.

Do not stop taking REXULTI or lower the dosage without checking with your doctor. If you stop taking REXULTI suddenly, your condition may worsen. Your doctor may want you to gradually reduce the amount you are taking before stopping completely.

Things to be careful of

Be careful driving or operating machinery until you know how REXULTI affects you. This medicine may cause dizziness, light-headedness or tiredness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Avoid drinking alcohol while you are taking REXULTI.

You should avoid alcohol while taking REXULTI as it could magnify the side effects.

Make sure you keep cool in hot weather and keep warm in cool weather.

REXULTI may affect the way your body reacts to temperature changes. It may prevent sweating, even during heatwaves. You may feel dizzy or faint if you are too hot. To stay cool in hot weather, try to do the following:

  • drink plenty of water
  • wear light clothing
  • spend time in air-conditioned environments (or keep windows open and use electric fans)
  • take cool baths or showers and avoid hot baths and saunas
  • try to restrict exercise or heavy work to cool parts of the day

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking REXULTI.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

If you are over 65 years of age you may have an increased chance of getting side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • drowsiness
  • diarrhoea
  • indigestion
  • weight increase
  • shaking
  • inability to stand or sit still; restless movement of the arms and legs such as tapping, marching in places, rocking, crossing and uncrossing legs
  • feeling dizzy or fainting, especially when getting up from a lying or sitting position
  • impulsive behaviours or urges (including gambling)
  • sleep walking and related behaviours (including sleep related eating disorder).

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital, if you notice any of the side effects listed below. These side effects may occur rarely.

  • serious allergic reaction (symptoms of an allergic reaction may include swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing, or rash, itching or hives)
  • tardive dyskinesia - abnormal movements of the tongue, or other uncontrolled movements of the tongue, mouth, cheeks, or jaw which may progress to the arms and legs
  • neuroleptic malignant syndrome - sudden increase in body temperature, sweating, fast heartbeat, muscle stiffness, high blood pressure and convulsions
  • suicidal thoughts and actions or talk about death, suicide, self-harm or harm to others - pay close attention to any changes, especially sudden changes, in mood, behaviours, irritability, agitation, thoughts or feelings
  • swelling, pain or redness in the leg, chest pain or difficulty in breathing

Elderly patients with dementia may suffer serious side effects such as stroke, pneumonia, or heart problems. These serious side effects can be life threatening.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using REXULTI

Storage

Keep REXULTI in the original container.

If you take it out of its original container it may not keep well.

Keep REXULTI in a cool dry place where the temperature stays below 30°C.

Do not store REXULTI or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

REXULTI comes in six tablet strengths:

0.25 mg - Light brown, round, shallow convex, bevel-edged tablet, debossed with BRX and 0.25 on one side

0.5 mg - Light orange, round, shallow convex, bevel-edged tablet, debossed with BRX and 0.5 on one side

1 mg - Light yellow, round, shallow convex, bevel-edged tablet, debossed with BRX and 1 on one side

2 mg - Light green, round, shallow convex, bevel-edged tablet, debossed with BRX and 2 on one side

3 mg - Light purple, round, shallow convex, bevel-edged tablet, debossed with BRX and 3 on one side

4 mg - White, round, shallow convex, bevel-edged tablet, debossed with BRX and 4 on one side

REXULTI is available in blister packs of 30 tablets.

Ingredients

The active ingredient in REXULTI is brexpiprazole.

Inactive ingredients:

REXULTI tablets contain the following ingredients:

  • lactose monohydrate
  • maize starch
  • microcrystalline cellulose
  • hyprolose
  • hyprolose - low-substituted
  • magnesium stearate
  • OPADRY complete film coating system 03A465005 BROWN
  • OPADRY complete film coating system 03A430000 ORANGE
  • OPADRY complete film coating system 03A420002 YELLOW
  • OPADRY complete film coating system 03A410000 GREEN
  • OPADRY complete film coating system 03A400000 PURPLE
  • OPADRY complete film coating system 03A480004 WHITE

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Lundbeck Australia Pty Ltd
Ground Floor,
1 Innovation Road
North Ryde NSW 2113
Ph: 02 8669 1000

REXULTI is co-marketed by Lundbeck Australia and Otsuka Australia Pharmaceutical:

Otsuka Australia Pharmaceutical Pty. Limited
Suite 2.03, Level 2, 9 Help Street,
Chatswood NSW 2067
Ph: 02 8021 9825

This leaflet was prepared on 24 January 2020.

Australian Registration Numbers:

Blister packs:

0.25 mg - AUST R 273225*

0.5 mg - AUST R 273222*

1 mg - AUST R 273220

2 mg - AUST R 273223

3 mg - AUST R 273221

4 mg - AUST R 273224

* Not currently marketed

REXULTI is a registered Trademark of H. Lundbeck A/S.

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Rexulti

Active ingredient

Brexpiprazole

Schedule

S4

 

1 Name of Medicine

Brexpiprazole.

6.7 Physicochemical Properties

Brexpiprazole is 7-{4-[4-(1-benzothiophen-4-yl) piperazin-1-yl]butyloxy}quinolin-2(1H)-one.
Molecular formula: C25H27N3O2S.
Molecular weight: 433.57.
Brexpiprazole is nonhygroscopic, with white to off-white crystals or crystalline powders, and a melting point of 183°C (decomposition). It is practically insoluble in water, and the solubility of the drug substance is 0.56 mg/mL at pH 2.

Chemical structure.


CAS number.

913611-97-9.

2 Qualitative and Quantitative Composition

Rexulti contains brexpiprazole, a novel atypical antipsychotic agent. Rexulti is available as 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg tablets for oral use.
Rexulti tablets also contain the following inactive ingredients: lactose monohydrate, maize starch, microcrystalline cellulose, hyprolose, low-substituted hyprolose and magnesium stearate. The following Opadry complete coating systems are also contained in the tablets: 0.25 mg tablets - Opadry complete film coating system 03A465005 brown (Arping no. 110573); 0.5 mg tablets - Opadry complete film coating system 03A430000 orange (Arping no. 110574); 1 mg tablets - Opadry complete film coating system 03A420002 yellow (Arping no. 110572); 2 mg tablets - Opadry complete film coating system 03A410000 green (Arping no. 110570); 3 mg tablets - Opadry complete film coating system 03A400000 purple (Arping no. 110575) and 4 mg tablets - Opadry complete film coating system 03A480004 white (Arping no. 110571).

3 Pharmaceutical Form

Rexulti (brexpiprazole) tablets are available as: (see Table 1).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Brexpiprazole has high affinity (Ki < 5 nanoM) for multiple monoaminergic receptors, including serotonin 5-HT1A, 5-HT2A, 5-HT2B and 5-HT7, dopamine D2 and D3, and noradrenergic α1A, α1B, α1D, and α2C receptors. Brexpiprazole acts as a partial agonist at 5-HT1A, D2, and D3 receptors and as an antagonist at 5-HT2A, 5-HT2B, 5-HT7, α1A, α1B, α1D, and α2C receptors. Brexpiprazole exhibits moderate affinity for histamine H1 receptors (19 nanoM) and very weak affinity for muscarinic M1 receptors (67% inhibition at 10 microM). Dose-response occupancy and brain/plasma exposure relationship were determined in vivo or ex vivo for D2/D3, 5-HT2A, 5-HT1A, 5-HT6, and 5-HT7 receptors as well as for the 5-HT transporter in preclinical studies. These results are consistent with the relative in vitro binding affinities and indicate that brexpiprazole has potent activity at several targets in the central nervous system (CNS) at relevant plasma exposures.
Despite low intrinsic activity at D2 receptors and potent antipsychotic effect, brexpiprazole showed low liability for catalepsy (animal model for extrapyramidal side effects) and for inducing tardive dyskinesia (indicative of increased sensitivity of the post-synaptic D2 receptors). The potencies of these effects were similar to or lower than those of other antipsychotic agents. Brexpiprazole showed a relatively low binding affinity for H1 receptors compared with that for D2 receptors, implying a low potential for H1 receptor-related sedative effects.
In a thorough QTc study in patients with schizophrenia or schizoaffective disorder, Rexulti did not prolong QTcI or QTcF after 12 days dosing at the clinical (4 mg/day) or at a supra-therapeutic (12 mg/day) dose, and no correlation was observed between brexpiprazole concentrations and QTcI or QTcF prolongation. Based on in vitro data the risk of hERG channel-mediated effects at the clinical dose appears to be low. There are no data on the potential for QTc prolongation via effects on the IKs (KCNQ1-KCNE1 complex) and Nay (SCN5A) ion currents.

Mechanism of action.

Rexulti is a novel atypical antipsychotic agent, which has pharmacological activity as a serotonin-dopamine activity modulator. While the precise mechanism of action of brexpiprazole in treating schizophrenia is not fully understood, the pharmacology of brexpiprazole is believed to be mediated by a combination of high binding affinity and functional activities at multiple monoaminergic receptors. It has modulatory activity at the serotonin and dopamine systems that combines partial agonist activity at serotonergic 5-HT1A and at dopaminergic D2 receptors with antagonist activity at serotonergic 5-HT2A receptors, with similar high affinities at all of these receptors (Ki: 0.1-0.5 nanoM). Brexpiprazole also shows antagonist activity at noradrenergic α1B/2C receptors with affinity in the same sub-nanomolar Ki range (Ki: 0.2-0.6 nanoM). The 5-HT1A/D2 receptor partial agonist activity in combination with the 5-HT2A and α1B/2C receptor antagonism of brexpiprazole may contribute to its antipsychotic effect.

Clinical trials.

The efficacy of Rexulti in the treatment of adults with schizophrenia was demonstrated in two 6-week, randomised, double-blind, placebo-controlled, fixed-dose clinical trials (trials 1 and 2) and one long-term maintenance trial (trial 3) in subjects who met DSM-IV-TR criteria for schizophrenia.
In the two fixed-dose trials, subjects were randomised to Rexulti 2 mg once daily, 4 mg once daily or placebo. Subjects in the Rexulti groups initiated treatment at 1 mg once daily on day 1. The Rexulti dosage was increased to 2 mg once daily on day 5. On day 8, the dosage was either maintained at 2 mg once daily or increased to 4 mg once daily, depending on treatment assignment, for the 5 remaining weeks. Trials 1 and 2 also included a low dose group, 0.25 mg/day and 1 mg/day Rexulti, respectively, but these dose groups were not included in the primary analysis.
The primary efficacy endpoint for both trials was the change from baseline to week 6 in the Positive and Negative Syndrome Scale (PANSS) total score. The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); the total PANSS scores range from 30 (best) to 210 (worst). The key secondary endpoint of both trials was the change from baseline to week 6 in Clinical Global Impression - Severity of Illness scale (CGI-S) score, a validated clinician-rated scale that measures the subject's current illness state and overall clinical state on a 1- (normal, not at all ill) to 7-point (extremely ill) scale. Other secondary endpoints included the Personal and Social Performance scale (PSP), a validated clinician-rated scale that measures personal and social functioning.
In trials 1 and 2, Rexulti 2 mg/day and 4 mg/day demonstrated efficacy with clinically meaningful changes in several efficacy endpoint measures.
At endpoint, Rexulti 4 mg was consistently superior to placebo in both fixed dose trials, reducing disease symptoms and severity as assessed using the primary endpoint, the PANSS total score. The onset of action with Rexulti occurred as early as week 1. In trial 1, a significant improvement was achieved in PANSS total score by week 1 for 2 mg/day (p = 0.0139) and week 2 for 4 mg/day (p = 0.0009). In trial 2, a significant improvement was achieved in PANSS total score by week 1 and then from week 3 onwards with 4 mg/day (p < 0.05).
Results for the primary efficacy endpoint for trials 1 and 2 are shown in Table 6.
Figure 1 shows the time course of response based on the primary efficacy measure (PANSS) in trial 1.
Examination of population subgroups based on age, sex and race did not show any statistical evidence of differential responsiveness.
In addition, Rexulti 2 mg/day and 4 mg/day demonstrated superiority to placebo in the key secondary endpoint, CGI-S score. Significant improvements in CGI-S score were seen as early as week 2 in trial 1 and week 3 in trial 2.
In trial 1, Rexulti also demonstrated superiority to placebo across several pre-specified secondary endpoints, including: the change from baseline to week 6 in PSP score (2 mg/day), PANSS positive subscale score (2 mg/day and 4 mg/day) and PANSS negative subscale score (2 mg/day and 4 mg/day); Clinical Global Impression - Improvement scale (CGI-I) score (2 mg/day and 4 mg/day); response rate at week 6 (2 mg/day and 4 mg/day); and discontinuation for lack of efficacy (4 mg/day).
In trial 2, Rexulti 4 mg/day demonstrated superiority to placebo in the change from baseline to week 6 in PSP score, PANSS positive subscale score and PANSS negative subscale score; CGI-I score; response rate at week 6.
Thus, the secondary endpoint results for CGI-S, PSP, CGI-I, PANSS positive subscale, PANSS negative subscale and response rate support the superiority and clinically meaningful effect of Rexulti compared to placebo.
Additionally, both trials had high overall completion rates, which were higher in the Rexulti groups than in the placebo group.
Results for the secondary efficacy endpoints for trials 1 and 2 are shown in Table 7.
The long-term trial (trial 3) was a randomised, double-blind, placebo-controlled trial to assess the efficacy, safety, and tolerability of Rexulti 1-4 mg/day as maintenance treatment in adults with schizophrenia. The primary endpoint was the time to impending relapse. The key secondary endpoint was the percentage of subjects with impending relapse, and other secondary endpoints included the mean change in PANSS total score and CGI-S score.
A pre-specified interim analysis demonstrated a statistically significantly longer time to impending relapse in subjects randomised to the Rexulti group (1-4 mg/day) compared to subjects randomised to the placebo group (p = 0.0008, log-rank test) and the trial was subsequently terminated early because maintenance of efficacy was demonstrated. The final analysis also demonstrated a statistically significantly longer time to impending relapse in subjects randomised to the Rexulti group compared to subjects randomised to the placebo group (p < 0.0001, log-rank test). The Kaplan-Meier curves of the cumulative proportion of subjects who relapsed during the double-blind treatment phase for the Rexulti and placebo groups in the final analysis set are shown in Figure 2. For the final analysis, the hazard ratio from the Cox proportional hazard model for the placebo to Rexulti comparison was 3.42 (95% CI: 1.82, 6.41); thus, subjects in the placebo group had a 3.42-fold greater risk of experiencing impending relapse than the subjects in the Rexulti group.
The key secondary endpoint, the proportion of subjects who met the criteria for impending relapse, was statistically significantly lower with the Rexulti group compared with the placebo group in both the interim and final analyses (15.38% vs. 37.08%, p = 0.0016 and 13.54% vs. 38.46%, p < 0.0001, respectively).
In the double-blind maintenance phase, the PANSS Total score and CGI-S score both showed supportive patterns of stability of symptoms, which were maintained over time with Rexulti treatment, whereas they worsened with placebo treatment (p = 0.0011, p = 0.0006, for the comparison of Rexulti vs. placebo for PANSS total score and CGI-S, respectively).

5.2 Pharmacokinetic Properties

Absorption.

Brexpiprazole is well absorbed after administration of Rexulti tablets, with peak plasma concentrations occurring within 4.0 hours after single-dose administration; the absolute oral bioavailability of the tablet formulation is 95.1%. Brexpiprazole steady-state concentrations are attained within 10-12 days of dosing. Rexulti can be administered with or without food. Administration of a Rexulti 4 mg tablet with a standard high-fat meal did not significantly affect the Cmax or AUC of brexpiprazole. After single and multiple once-daily dose administration, brexpiprazole exposure (Cmax and AUC) increased in proportion to the dose administered. In vitro studies did not indicate that brexpiprazole is a substrate of efflux transporters such as MDRI (P-gp) and BCRP.

Distribution.

The volume of distribution of brexpiprazole following intravenous administration is high (1.56 ± 0.418 L/kg), indicating extravascular distribution. Brexpiprazole is highly protein bound in plasma (greater than 99%) to serum albumin and α1-acid glycoprotein, and its protein binding is not affected by renal or hepatic impairment. Based on results of in vitro studies, brexpiprazole protein binding is not affected by warfarin, diazepam, or digoxin.

Metabolism and excretion.

Based on in vitro metabolism studies of brexpiprazole using recombinant human cytochrome P450 (CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4), the metabolism of brexpiprazole was shown to be mainly mediated by CYP3A4 and CYP2D6. Based on the results of in vitro data, brexpiprazole showed little to no inhibition of CYP450 isozymes. The in vitro inhibitory potential of brexpiprazole on MDR1 (P-gp), OAT1, OAT3, OCT2, multidrug and toxin extruders (MATE1), MATE2-K, OATP1B1, OATP1B3, and OCT1 has also been evaluated; brexpiprazole was only identified as a potential inhibitor of the BCRP efflux transporter, but was not considered to be an inhibitor of the other tested transporters.
In vivo, brexpiprazole is metabolised primarily by CYP3A4 and CYP2D6 enzymes. After single- and multiple-dose administrations, brexpiprazole and a major metabolite, DM-3411, are the predominant drug moieties in the systemic circulation. At steady-state, DM-3411 represents 23.1-47.7% of brexpiprazole exposure (AUC) in plasma. It should be noted that in vivo preclinical studies have shown that at clinically relevant plasma exposures of brexpiprazole, DM-3411 brain exposures were below the detection limit. Thus, DM-3411 is considered not to contribute to the therapeutic effects of brexpiprazole.
Following a single oral dose of [14C]-labelled brexpiprazole, approximately 24.6% and 46% of the administered radioactivity was recovered in the urine and faeces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine and approximately 14% of the oral dose was recovered unchanged in the faeces. The apparent oral clearance of brexpiprazole after once-daily tablet administration is 19.8 (± 11.4) mL/h/kg. After multiple once-daily administrations of Rexulti, the terminal elimination half-life of brexpiprazole and its major metabolite, DM-3411, is 91.4 hours and 85.7 hours, respectively.

Special populations.

Age/ sex.

After single-dose administration of Rexulti (2 mg), healthy elderly subjects (older than 65 years old) exhibited similar brexpiprazole systemic exposure (Cmax and AUC) in comparison with adult subjects (18-45 years old) and female subjects exhibited approximately 40-50% higher brexpiprazole systemic exposure (Cmax and AUC) in comparison with male subjects. Population pharmacokinetic evaluation identified age and female sex as statistically significant covariates affecting brexpiprazole pharmacokinetics and not considered clinically relevant.

Race.

Although no specific pharmacokinetic study was conducted to investigate the effects of race on the disposition of brexpiprazole, population pharmacokinetic evaluation revealed no evidence of clinically significant race-related differences in the pharmacokinetics of brexpiprazole.

CYP2D6 poor metabolisers.

Approximately 8% of Caucasians and 3-8% of Blacks/African Americans lack the capacity to metabolise CYP2D6 substrates and are classified as PM, whereas the rest are EM. Population pharmacokinetic evaluation shows that CYP2D6 PMs have 47% higher exposure to brexpiprazole compared to EMs. (See Section 4.2 Dose and Method of Administration).

Smoking.

Based on studies utilising human liver enzymes in vitro, brexpiprazole is not a substrate for CYP1A2. Smoking should, therefore, not have an effect on the pharmacokinetics of brexpiprazole.

Hepatic impairment.

Patients with moderate to severe hepatic impairment (Child-Pugh score ≥ 7) generally had higher exposure to brexpiprazole than patients with normal hepatic function; therefore, the recommended maximum dose should be reduced. In subjects with varying degrees of hepatic impairment (Child-Pugh classes A, B, and C), the AUC of oral brexpiprazole (2 mg single dose), compared to matched healthy subjects, increased 24% in mild hepatic impairment, increased 60% in moderate hepatic impairment, and did not change in severe hepatic impairment.

Renal impairment.

Patients with impaired renal function (CLcr < 60 mL/minute) had higher exposure to brexpiprazole than patients with normal renal function; therefore, the recommended maximum dose should be reduced. In subjects with severe renal impairment (CLcr < 30 mL/min), the AUC of oral brexpiprazole (2 mg single dose) compared to matched healthy subjects, increased 68% while its Cmax did not change.

5.3 Preclinical Safety Data

Genotoxicity.

The mutagenic potential of brexpiprazole was tested in the in vitro bacterial reverse mutation assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster ovary (CHO) cells, the in vivo micronucleus assay in rats, and the unscheduled DNA synthesis assay in rats. Brexpiprazole was mutagenic and induced chromosomal aberrations in mammalian cells in vitro but only at cytotoxic concentrations. No mutagenicity or genotoxicity was observed in the higher tier in vivo studies. Brexpiprazole is unlikely to affect the mitotic spindle or kinetochores. Based on the weight of evidence, brexpiprazole is not considered to present a genotoxic risk to humans.

Carcinogenicity.

The lifetime carcinogenic potential of brexpiprazole was evaluated in two year oral (gavage) studies in ICR mice and Sprague-Dawley rats. Brexpiprazole was administered to mice at doses of 0.75, 2 and 5 mg/kg/day, with plasma AUC exposures of 0.4-4-fold (males) and 0.2-1-fold (females) clinical exposure at the 4 mg/day MRHD. There was no increase in the incidence of tumours in males at any dose group. In female mice, there was an increased incidence of mammary gland adenocarcinoma and adenosquamous carcinoma, and pars distalis adenoma of the pituitary gland, at all doses. Brexpiprazole was administered to rats at doses of 1, 3 and 10 mg/kg/day (males) or 3, 10 and 30 mg/kg/day (females), with plasma AUC exposure up to 1-fold (males) and 6-fold (females) clinical exposure at the 4 mg/day MRHD. Long-term administration of brexpiprazole to rats did not induce neoplastic lesions.
Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be secondary to D2-antagonist-induced hyperprolactinaemia. The potential for increasing serum prolactin level of brexpiprazole was shown in both mice and rats. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown.

4 Clinical Particulars

4.1 Therapeutic Indications

Rexulti is indicated in adult patients for the treatment of schizophrenia.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Increased mortality in elderly patients with dementia-related psychosis.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared to placebo.
Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in placebo-treated patients. Rexulti is not approved for the treatment of dementia-related psychosis.

Cerebrovascular adverse reactions.

In placebo-controlled trials with some antipsychotic drugs in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo.

Suicidal risk.

The possibility of a suicide attempt is inherent in psychotic illnesses. Close supervision and appropriate clinical management of high-risk patients should accompany drug therapy.

Venous thromboembolism.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Rexulti and preventive measures undertaken.

Neuroleptic malignant syndrome (NMS).

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs including Rexulti. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic drugs including Rexulti must be discontinued. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.

Tardive dyskinesia.

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.
If signs and symptoms of tardive dyskinesia appear in a patient on Rexulti, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.

Metabolic parameters.

Hyperglycaemia and diabetes mellitus.

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics.
Patients treated with any antipsychotic agents should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) should be monitored regularly for worsening of glucose control. In patients with significant treatment-emergent hyperglycaemia, discontinuation of Rexulti should be considered.
In clinical trials with Rexulti in patients with schizophrenia (trials 1 and 2) changes in fasting glucose were comparable between Rexulti- and placebo-treated subjects.
In the long-term maintenance trial (trial 3), the mean changes from baseline to last visit in serum glucose were also small for the Rexulti (2.11 mg/dL) and placebo (-1.62 mg/dL) groups, and not considered clinically relevant.
In the long-term, open-label studies, the mean change from baseline to last visit in fasting serum glucose was 2.31 mg/dL (N = 1120).

Weight gain and dyslipidaemia.

Antipsychotic drugs have been associated with metabolic changes, including weight gain and dyslipidaemia. Clinical monitoring of body weight is recommended. (See Section 4.8 Adverse Effects (Undesirable Effects), Weight gain; Section 4.8 Adverse Effects (Undesirable Effects), Dyslipidaemia).

Orthostatic hypotension and syncope.

In the short-term, placebo-controlled clinical studies of Rexulti in subjects with schizophrenia, the incidence of orthostatic hypotension-related adverse reactions in Rexulti-treated subjects compared to placebo-treated subjects included: dizziness (2.3% versus 1.4%), orthostatic hypotension (0.4% versus 0.2%), and syncope (0.1% versus 0%).
Adverse reactions related to orthostatic hypotension can include dizziness, light-headedness and tachycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g. heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose and slower titration, and monitor orthostatic vital signs.

QT interval.

In a thorough QTc study in patients with schizophrenia or schizoaffective disorder, Rexulti did not prolong QT interval (see Section 5.1 Pharmacodynamic Properties). However, in patients with a family history of QT prolongation antipsychotics should be used with caution.

Seizures.

As with other antipsychotic drugs, Rexulti should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold.

Body temperature regulation.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing Rexulti for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g. exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

Dysphagia.

Oesophageal dysmotility and aspiration have been associated with antipsychotic drug use. Rexulti and other antipsychotic drugs should be used cautiously in patients at risk of aspiration pneumonia.

Leukopenia, neutropenia and agranulocytosis.

Leukopenia/neutropenia has been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in the class.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and Rexulti should be discontinued at the first sign of decline in WBC, in the absence of other causative factors.
Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm3) should discontinue Rexulti and have their WBC followed until recovery.

Impulse control disorders.

Post-marketing reports of impulse-control disorders including gambling have been reported very rarely with antipsychotics, including brexpiprazole. Patients with a prior history of impulse-control disorders may be at increased risk and should be monitored carefully. It should be noted that impulse-control symptoms can be associated with the underlying disorder.

Sleep apnoea.

Sleep apnoea and related disorders have been reported in patients treated with antipsychotic medications, with or without prior history of sleep apnoea, and with or without concomitant weight-gain. In patients who have a history of or are at risk for sleep apnoea, or who are concomitantly using central nervous system depressants, Rexulti should be used with caution.

Lactose.

Rexulti tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Use in hepatic impairment.

In patients with hepatic impairment, dosage adjustment is required.
(See Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Use in renal impairment.

In patients with renal impairment, dosage adjustment is required.
(See Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Use in the elderly.

Clinical studies of Rexulti included limited numbers of subjects aged 65 and older to allow for determining whether they respond differently than younger subjects. Elderly subjects (older than 65 years old) exhibited similar brexpiprazole systemic exposure in comparison with adult subjects (18-45 years old) (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration). Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared to placebo (see Section 4.4 Special Warnings and Precautions for Use, Increased mortality in elderly patients with dementia-related psychosis).

Paediatric use.

Safety and effectiveness in patients under the age of 18 years has not yet been evaluated.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Rexulti is predominantly metabolised by CYP3A4 and CYP2D6. Based on results of drug interaction trials, dose adjustment to half the maintenance dose is recommended for subjects administered strong CYP2D6 or CYP3A4 inhibitors. Based on estimations from the population pharmacokinetic analysis, CYP2D6 extensive metabolisers (EM) receiving both CYP3A4 and CYP2D6 inhibitors or CYP2D6 poor metabolisers (PM) receiving strong CYP3A4 inhibitors are expected to have an approximately 4-5-fold increase in brexpiprazole concentrations; therefore, the Rexulti dose should be reduced to ¼ of the recommended dosage in these situations (see Section 4.2 Dose and Method of Administration).
If Rexulti is used concomitantly with a strong CYP3A4 inducer (i.e. rifampicin), it is necessary to increase the dose by two fold and further adjust it based on clinical response (see Section 4.2 Dose and Method of Administration).

Quinidine and other strong CYP2D6 inhibitors.

Co-administration of a 2 mg single oral dose of Rexulti with quinidine (324 mg/day for 7 days), a potent inhibitor of CYP2D6, increased the AUC of brexpiprazole by 94%.

Ketoconazole and other strong CYP3A4 inhibitors.

Co-administration of ketoconazole (200 mg twice daily for 7 days), a potent inhibitor of CYP3A4, with a 2 mg single oral dose of Rexulti increased the AUC of brexpiprazole by 97%.

Ticlopidine and other CYP2B6 inhibitors.

Co-administration of a 2 mg single oral dose of Rexulti with ticlopidine (250 mg twice daily for 7 days), a potent inhibitor of CYP2B6, had no effect on the pharmacokinetics of brexpiprazole.

Rifampicin and other CYP3A4 inducers.

Co-administration of rifampin (600 mg twice daily for 12 days), a potent CYP3A4 inducer, with a single 4 mg oral dose of Rexulti resulted in an approximate 31% and 73% decrease in brexpiprazole Cmax and AUC.

Gastric acid pH modifiers.

Co-administration of omeprazole (40 mg once daily, 5 days), a widely used proton pump inhibitor (PPI), with a single oral dose of Rexulti (4 mg) resulted in no effect on absorption of brexpiprazole. Other gastric acid pH modifiers (PPIs, H2 receptor antagonists, etc.) are also not expected to affect the absorption of brexpiprazole.

Potential for Rexulti to affect other drugs.

Based on results of in vitro studies, brexpiprazole is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolised by cytochrome P450 enzymes. Clinical studies show that oral Rexulti (2 mg/day, 11 days) had no effect on the metabolism of dextromethorphan (a CYP2D6 substrate), lovastatin (a CYP3A4 substrate) or bupropion (a CYP2B6 substrate). Rexulti does not affect absorption of drugs that are substrates of the BCRP transporter (rosuvastatin) or the P-gp transporter (fexofenadine).
As with other antipsychotics, caution should be used if brexpiprazole is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Drugs with D2-antagonist properties are potential causes of hypothalamic-pituitary-gonadal axis disruption. Brexpiprazole was given once daily by oral gavage to female rats at doses of 0, 0.3, 3 or 30 mg/kg/day prior to mating with untreated males and continuing through conception and implantation. Prolonged diestrus and decreased fertility were observed at 3 and 30 mg/kg/day, with exposure (plasma AUC) ≥ 0.2-fold the clinical exposure at the 4 mg MRHD. At 30 mg/kg/day (AUC exposure 4-fold clinical exposure) a doubling of the mating phase and significantly increased preimplantation losses were seen. The no observed adverse effect level for brexpiprazole was 0.3 mg/kg/day (AUC exposure < 0.2-fold clinical exposure).
Brexpiprazole was given once daily by oral gavage to male rats at doses of 0, 3, 10 or 100 mg/kg/day, with exposure (plasma AUC) up to 18-fold the clinical exposure at the 4 mg MRHD. Following 63 days of dosing (one spermatic cycle), treated males were cohabited with untreated females for a maximum of 14 days. No noticeable differences were noted in the duration of mating or fertility indices in any brexpiprazole treated group. Testicular lesions including atrophy of the seminiferous tubule were observed at doses of 30 mg/kg/day and higher (AUC exposure ≥ 6-fold clinical exposure) in repeat-dose toxicity studies, and a decrease in sperm in the epididymis was observed at 300 mg/kg/day (AUC exposure 37-fold clinical exposure) with minimal incidence (2 of 15 rats).
(Category C)
Safe use of Rexulti during pregnancy or lactation has not been established. Therefore, use of Rexulti in pregnancy, in nursing mothers, or in women of childbearing potential requires that the benefits of treatment be weighed against the possible risks to mother and child.
Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk of extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalisation.
The effect of Rexulti on labour and delivery in humans is unknown. Parturition in rats was not affected by brexpiprazole.

Animal data.

Brexpiprazole was not teratogenic and did not cause adverse developmental effects in embryofetal developmental toxicity studies in which pregnant rats and rabbits were given brexpiprazole during the period of organogenesis at oral doses up to 30 mg/kg/day (with respective exposures (plasma AUC) 4-fold and 7-fold the clinical exposure at the 4 mg/day MRHD).
In the rabbit study an oral dose that induced severe maternal toxicity (150 mg/kg/day, AUC exposure 21-fold clinical exposure) was associated with decreased body weight, retarded ossification, and increased incidences of visceral and skeletal variations in fetuses.
When pregnant rats were administered brexpiprazole orally during the period of organogenesis through lactation, the number of perinatal deaths of pups was increased at 30 mg/kg/day (plasma AUC exposure 4-fold exposure at the 4 mg/day MRHD); the no-effect dose was 10 mg/kg/day (exposure similar to clinical exposure).
Brexpiprazole and/or its metabolites was excreted in milk of rats during lactation, with milk levels about 1-2-fold maternal blood levels. It is not known whether brexpiprazole or its metabolites are excreted in human milk. Because of the potential for serious, potentially long-lived, adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug considering the risk of drug discontinuation to the mother.

4.8 Adverse Effects (Undesirable Effects)

The following findings are based on the two 6-week, placebo-controlled, fixed-dose clinical trials (trials 1 and 2) in schizophrenia in which Rexulti was administered at daily doses of 1 mg, 2 mg and 4 mg (n = 852), and the long-term maintenance trial (trial 3) with Rexulti 1-4 mg/day (n = 97).

Common adverse reactions.

There are no common adverse reactions that meet the criteria "incidence ≥ 5% and at least twice the rate of placebo" in trials 1 and 2, the 6-week, placebo-controlled, fixed-dose trials, or trial 3, the long-term maintenance trial.
Adverse reactions associated with Rexulti (incidence of 2% or greater and Rexulti incidence greater than placebo incidence) that occurred during acute therapy (up to 6 weeks in subjects with schizophrenia) and long-term therapy (up to 52 weeks) are shown in Tables 3 and 4, respectively.
Discontinuations due to TEAEs occurred at less than half the rate in the Rexulti group (5.2%) compared with the placebo group (11.5%) in the double blind maintenance phase of trial 3. No subjects discontinued due to weight gain or akathisia.

Selected adverse events.

Extrapyramidal symptoms.

In trials 1 and 2, the incidence of EPS-related events, excluding akathisia events, was 5.1% for Rexulti-treated subjects versus 3.5% for placebo-treated subjects. The incidence of akathisia events (akathisia, psychomotor hyperactivity) for Rexulti-treated subjects was 5.4% versus 4.9% for placebo treated subjects. Akathisia was reported in all treatment arms and were more often during Weeks 1 through 3 and was mild to moderate in severity.
In trials 1 and 2, data were objectively collected on the Simpson Angus Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Rating Scale (BARS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia. The mean changes from baseline at last visit for Rexulti-treated subjects for the SAS, BARS and AIMS were comparable to those for placebo-treated subjects (-0.10, 0.02 and -0.08 compared to 0.00, 0.01 and -0.07 respectively).
Similarly, in trial 3, the mean changes from baseline at last visit for Rexulti-treated subjects for the SAS, BARS and AIMS were comparable to those for the placebo-treated subjects.

Dyslipidaemia.

Undesirable alterations in lipids have been observed in subjects treated with atypical antipsychotics.
In trials 1 and 2, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in Rexulti- and placebo-treated subjects. Table 5 shows the proportions of subjects with changes in fasting triglycerides.
In trial 3, no clinically meaningful differences between treatment groups were observed for the incidences of metabolic parameters meeting potentially clinically relevant criteria.
In the long-term open-label studies, the mean change from baseline to last visit in fasting triglycerides was -2.14 mg/dL (N = 1123).

Weight gain.

The percentage of subjects in short-term trials 1 and 2 who had a potentially clinically relevant increase in body weight (≥ 7%) was 10.5% and 10.2% in the Rexulti 2 and 4 mg/day groups, respectively, compared with 4.1% in the placebo group. The mean body weight increase in the short-term trials at last visit was 1.2 kg for both the Rexulti 2 and 4 mg/day groups compared with 0.2 kg in the placebo group.
During trial 3 the proportion of subjects with a ≥ 7% increase in body weight at last visit was 3.1% in the Rexulti group compared to 1.0% in the placebo group.
In the long-term, open-label schizophrenia studies, the mean change in body weight from baseline to last visit was 1.1 kg at last observation.

Less common clinical trial adverse drug reactions (< 2%).

Other adverse reactions (< 2% frequency and greater than for placebo) in the short-term, fixed-dose placebo-controlled trials and the long-term maintenance trial in subjects with schizophrenia are shown below. The following listing does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labelling; 2) for which a drug cause was remote; 3) which were so general as to be uninformative; or 4) which were not considered to have clinically significant implications.

Cardiovascular disorders.

Sinus bradycardia, atrioventricular block first degree, palpitations.

Endocrine disorders.

Hyperprolactinaemia.

Eye disorders.

Vision blurred, blepharospasm.

Gastrointestinal disorders.

Dry mouth, abdominal pain, flatulence, dental caries, abdominal distension, gastrooesophageal reflux disease.

General disorders and administration site conditions.

Fatigue, asthenia.

Infections and infestations.

Upper respiratory tract infection.

Investigations.

Hepatic enzyme increased.

Musculoskeletal and connective tissue disorders.

Myalgia, musculoskeletal pain, musculoskeletal stiffness.

Nervous system disorders.

Dizziness, dyskinesia, Parkinsonism, psychomotor activity.

Psychiatric disorders.

Abnormal dreams, bruxism.

Skin and subcutaneous tissue disorders.

Rash.

Vascular disorders.

Hypertension, flushing, hypotension.

Abnormal hematologic and clinical chemistry findings.

No clinically relevant mean changes from baseline in serum chemistry, haematology, urinalysis, or other laboratory test (insulin, fasting insulin and prolactin) results were observed during the clinical trials with Rexulti.

Post-marketing adverse drug reactions.

Post-marketing reports of impulse-control disorders (including gambling), and also sleep walking and related behaviours (including sleep related eating disorder) have been reported very rarely with antipsychotics, including Rexulti. While causality has not been established, Lundbeck Australia Pty Ltd will continue to monitor the situation closely.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

The recommended starting dose for Rexulti in the treatment of patients with schizophrenia is 1 mg once daily on days 1 to 4.
The recommended target dose range is 2 mg to 4 mg once daily. Titrate to 2 mg once daily on day 5, then to 4 mg on day 8 based on the patient's clinical response and tolerability. The maximum recommended daily dosage is 4 mg.

Maintenance treatment.

The recommended maintenance dose range is 2 mg/day to 4 mg/day. Periodically reassess to determine the continued need for maintenance treatment and appropriate dosage.
Rexulti can be given with or without food.

Use in elderly.

Similar exposure to brexpiprazole was seen when Rexulti was administered in healthy elderly subjects (older than 65 years) and in adult subjects (18-45 years old). (See Section 5.2 Pharmacokinetic Properties). In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, concomitant diseases, and other drug therapy.

Dosing adjustment for hepatic impairment.

For patients with moderate to severe hepatic impairment (Child-Pugh score ≥ 7), the maximum recommended dosage is 3 mg once daily for patients with schizophrenia.

Dosing adjustment for renal impairment.

For patients with moderate, severe or end-stage renal impairment (creatinine clearance CLcr < 60 mL/minute), the maximum recommended dosage is 3 mg once daily for patients with schizophrenia.

Other special populations.

No dosage adjustment for Rexulti is required on the basis of a patient's sex, race, or smoking status. (See Section 5.2 Pharmacokinetic Properties).

Dosing modifications for CYP2D6 poor metabolisers and for concomitant use with CYP inhibitors/ inducers.

See Table 2.

Abuse potential.

Brexpiprazole showed neither a potential to produce physical dependence in rats nor a reinforcing effect in rhesus monkeys. In a drug abuse liability study in rats, no withdrawal signs suggestive of physical dependence were evident. Brexpiprazole is not considered to have potential to produce physical dependence.

4.7 Effects on Ability to Drive and Use Machines

As with other antipsychotics that have the potential to impair judgment, thinking or motor skills, patients should be cautioned about operating hazardous machinery including motor vehicles until they are certain that Rexulti therapy does not affect them adversely.
In the short-term, placebo-controlled clinical trials in patients with schizophrenia, somnolence (including sedation and hypersomnia) was reported in 5% of Rexulti-treated patients compared to 4% of placebo-treated patients.

4.9 Overdose

No specific information is available on the treatment of overdose with Rexulti. Gastric lavage and treatment with an emetic may be useful immediately after overdose. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers.
For information on the management of overdose, contact the Poison Information Centre (Tel: 13 11 26 for Australia).
Oral activated charcoal and sorbitol (50 g/240 mL), administered one hour after ingesting oral Rexulti, decreased brexpiprazole Cmax and AUC by approximately 5% to 23% and 31% to 39% respectively; however, there is insufficient information available on the therapeutic potential of activated charcoal in treating an overdose with Rexulti. Although there is no information on the effect of haemodialysis in treating an overdose with Rexulti, haemodialysis is unlikely to be useful in overdose management since brexpiprazole is highly bound to plasma proteins.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Rexulti tablets are packaged in polyvinyl chloride (PVC)/aluminium foil blisters.
Pack sizes of 30 film-coated tablets (all strengths). Starter pack size of 10 film-coated tablets: 1 mg and 2 mg.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes