Consumer medicine information

Tevaripiprazole

Aripiprazole

BRAND INFORMATION

Brand name

Tevaripiprazole

Active ingredient

Aripiprazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tevaripiprazole.

What is in this leaflet

This leaflet answers some common questions about Tevaripiprazole. It does not contain all the available information. Some of the information contained in this leaflet may not apply to you.

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 Tevaripiprazole against the benefits it is expected to 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 Tevaripiprazole is used for

Tevaripiprazole is a trade name (manufacturer's name) for the medicine aripiprazole (Ari-pip-rah-zol).

Aripiprazole belongs to a group of medicines called antipsychotic agents which improve the symptoms of certain types of mental illness.

Tevaripiprazole is used to treat symptoms of schizophrenia.

Schizophrenia is a mental illness with disturbances in thinking, feelings and behaviour.

Your doctor may have prescribed aripiprazole for another reason. Ask your doctor if you have any questions about why aripiprazole has been prescribed for you.

There is no evidence that aripiprazole is addictive.

This medicine is available only with a doctor's prescription.

Aripiprazole is not recommended for use in children under the age of 18, as safety and efficacy have not been established in this age group.

Before you take Tevaripiprazole

When you must not take it

Do not take Tevaripiprazole if you have an allergy to:

  • aripiprazole
  • any of the ingredients listed at the end of this leaflet

Symptoms of an allergic reaction include:

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

Do not take Tevaripiprazole after the expiry or use by date printed on the pack. If you take this medicine after this date has passed, it may not work as well.

Do not take Tevaripiprazole if the packaging is torn or shows signs of tampering. If this is the case, return it to your pharmacist.

If you are not sure whether you should start taking Tevaripiprazole, talk to your doctor or pharmacist.

Before you start to take it

Tell your doctor or pharmacist if you have allergies to:

  • any other medicines
  • any other substances such as foods, preservatives or dyes

Tell your doctor if you are pregnant or intend to become pregnant. Tevaripiprazole is not recommended for use during pregnancy. If you need to take Tevaripiprazole during your pregnancy, your doctor will discuss with you the benefits and risks of taking it. Babies exposed to antipsychotics (including Tevaripiprazole) during the third trimester of pregnancy are at risk of experiencing shaking, muscle stiffness, difficulty in feeding and/or withdrawal symptoms. These symptoms may resolve spontaneously or require additional medical treatment.

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 Tevaripiprazole, as it may pass 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:

  • a reaction to some medicines with a sudden increase in body temperature, sweating, fast heart beat, muscle stiffness and fluctuating blood pressure, which may lead to coma. This reaction is called neuroleptic malignant syndrome.
  • 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. This reaction is called tardive dyskinesia.
  • low blood pressure
  • problems with your heart or blood vessels
  • epilepsy, seizures or fits
  • problems with your oesophagus (food pipe) such as difficulty in swallowing
  • high blood sugar or diabetes mellitus
  • Alzheimer's disease or dementia
  • alcohol or drug abuse or dependence or a history of one of these
  • venous thromboembolism or are at risk of venous thromboembolism
  • lactose intolerance

Tell your doctor if you drink alcohol. Your doctor may advise you to avoid alcohol as it can magnify the side effects of this medicine.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking Tevaripiprazole.

Taking other medicines

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

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

  • medicines used to treat brain disorders such as, anxiety, depression, mood swings, epilepsy or seizures, Parkinson's disease or insomnia.
  • medicines used to treat high blood pressure
  • medicines used to treat fungal infections
  • medicines used to treat heart rhythm disturbances
  • medicines used to treat bacterial or viral infections
  • a medicine called cyclosporin (Cysporin®; Neoral®; Sandimmun®)
  • a medicine called cimetidine (Tagamet®; Magicul®; Sigmetadine®)

These medicines may be affected by Tevaripiprazole, or may affect how well it works. Your doctor may need to adjust your dose of Tevaripiprazole or of the other medicine.

Eating grapefruit or drinking grapefruit juice may affect how Tevaripiprazole works.

Your doctor or pharmacist may have more information on medicines to be careful with or avoid while taking Tevaripiprazole.

How to take Tevaripiprazole

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

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

The label put on the carton by the pharmacist will tell you how much you should take.

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

How to take it

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

Take Tevaripiprazole at about the same time each day.

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

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

It does not matter whether you take Tevaripiprazole with or without food.

If you forget to take it

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

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

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.

How long to take it

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

Tevaripiprazole helps to control your condition but does not cure it. Therefore you must take Tevaripiprazole every day. Improvement in symptoms may take several days to some weeks to occur. Even if you feel better do not stop taking Tevaripiprazole unless your doctor tells you to.

If you take too much (overdose)

Immediately telephone your doctor or pharmacist or the Poisons Information Centre (telephone 13 1126) or go to the Accident and Emergency Centre at your nearest hospital, if you or anyone else may have taken too much Tevaripiprazole. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking Tevaripiprazole

Things you must do

Tell any doctors, dentists or pharmacists who are treating you that you are taking Tevaripiprazole.

If you are about to be started on any new medicine, tell your doctor, dentist and pharmacist that you are taking Tevaripiprazole.

If you plan to have any kind of surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking Tevaripiprazole.

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

Be sure to keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

Do not give Tevaripiprazole to anyone else, even if their symptoms seem similar or they have the same condition as you.

Do not take Tevaripiprazole to treat any other complaints unless your doctor or pharmacist tells you to.

Do not stop taking Tevaripiprazole or lower the dosage, even if you are feeling better, without checking with your doctor. If you stop taking Tevaripiprazole suddenly your condition may worsen.

Do not take more of this medicine and do not take it more often than your doctor has ordered.

Things to be careful of

Make sure that you know how you react to Tevaripiprazole before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy or light headed or not alert.

Tevaripiprazole may cause some people to become drowsy or less alert than they are normally or cause light-headedness, dizziness or tiredness. If this occurs do not undertake the activity.

If Tevaripiprazole makes you feel light-headed, dizzy or faint, be careful when getting up from a sitting or lying position. Getting up slowly may help.

Be careful when drinking alcohol while taking Tevaripiprazole. Your doctor may suggest you avoid alcohol while you are being treated with Tevaripiprazole.

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

Tevaripiprazole 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:

  • wear light clothing
  • spend time in air-conditioned environments (or keep windows open and use electric fans)
  • drink plenty of water
  • 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 Tevaripiprazole.

Like other medicines Tevaripiprazole may cause some unwanted side effects. These are likely to vary from patient to patient. Tevaripiprazole is generally well-tolerated and the side effects are often hard to distinguish from disease symptoms. It is important that you tell your doctor as soon as possible about unwanted effects.

Ask your doctor or pharmacist to answer any questions you may have. Tell your doctor if you notice any of the following side effects and they worry you:

  • headache
  • indigestion
  • nausea
  • vomiting
  • insomnia
  • constipation
  • light-headedness
  • drowsiness
  • agitation
  • anxiety
  • inability to sit or stand still; restless movement of the arms and legs such as tapping, marching in places, rocking, crossing and uncrossing the legs.

These are the more common side effects of Tevaripiprazole

  • weight gain
  • weight loss
  • loss of appetite
  • excessive sweating
  • drowsiness

These side effects are very rare.

Tell your doctor if you notice the following side effects:

  • feeling dizzy especially when getting up from a lying or sitting position
    This side effect is not common.
  • high blood pressure
  • chest pain
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • bleeding or bruising more easily than normal
  • high blood sugar (excessive thirst, hunger and weakness) or the onset or worsening of diabetes
  • speech disorder
  • urinary incontinence
  • difficulty swallowing

These side effects are very rare.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • seizure, fits or convulsions.
  • fainting.
  • abnormal movements of the tongue or other uncontrolled movements of the tongue, mouth, cheeks or jaw which may progress to the arms and legs.
  • sudden increase in body temperature, sweating, fast heartbeat, muscle stiffness, high blood pressure and convulsions.
  • rash.
  • allergic reaction (rash, itching or hives on the skin; shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body).
  • muscle pain, muscle weakness or muscle stiffness
  • inflammation of the pancreas, severe upper stomach pain often with nausea and vomiting.
  • disorder of body temperature regulation resulting in low body temperature or high body temperature.
  • painful irreversible erection.
  • difficulty in passing urine.
  • yellowing of the skin and/or eyes, also called jaundice with or without nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching and dark coloured urine.
  • serious lung infection with fever, chills, shortness of breath, cough, chest pain and blood streaked phlegm
  • thoughts or talk about death or suicide; thoughts or talk about self-harm or doing harm to others; any recent attempts at self-harm; an increase in aggressive behaviour, irritability or agitation.
    If you or someone you know is showing these signs contact your doctor or a mental health advisor right away or go to the nearest hospital for treatment.

These are very serious side effects.

You may need urgent medical attention or hospitalisation.

All of these side effects are very rare.

Other side effects not listed above may occur in some patients.

Also, while taking aripiprazole, some elderly patients with dementia have suffered serious side effects such as a "mini" stroke, 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.

Do not be alarmed by this list of possible side effects.

You may not experience any or only some of them.

After using Tevaripiprazole

Storage

Store Tevaripiprazole in a cool place where the temperature stays below 25°C.

Do not store it or any other medicine in the bathroom. Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines. Do not keep outdated medicine or medicine no longer needed.

Disposal

If your doctor tells you to stop taking Tevaripiprazole or the medicine has passed its expiry date, ask your pharmacist what to do with any leftover medicine.

Be sure that any discarded medicine is out of the reach of children.

Product Description

What it looks like

Tevaripiprazole 5 mg uncoated tablet - Light yellow coloured round flat faced bevelled edge tablet debossed '5' on one side and plain on the other side.

Tevaripiprazole 10 mg uncoated tablet - Pink to light pink coloured, oblong tablet with debossed '10' on one side and breakline on the other side.

Tevaripiprazole 15 mg uncoated tablet - Light yellow coloured, round flat faced bevelled edged tablets with debossed '15' on one side and breakline on the other side.

Tevaripiprazole 20 mg uncoated tablet - White to off white or pale cream coloured, capsule shaped biconvex table with debossed '20' on one side and breakline on the other side.

Tevaripiprazole 30 mg uncoated tablet - Pink to light pink coloured, round biconvex tablets with debossed '30' on one side and breakline on the other side.

Aripiprazole tablets are packed in OPA/Al/PVC-Al blister in a carton. Each carton contains 30 tablets.

Ingredients

Active ingredient:

aripiprazole

Other Ingredients:

  • Lactose monohydrate
  • Maize starch
  • Microcrystalline cellulose
  • Hyprolose
  • Magnesium stearate
  • Croscarmellose sodium

The following colorants are also present in the tablets:

  • 5 mg - iron oxide yellow
  • 10 mg - iron oxide red
  • 15 mg - iron oxide yellow
  • 20 mg - no colourants
  • 30 mg - iron oxide red

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

Sponsored by

Teva Pharma Australia Pty Ltd
Level 2, 37 Epping Road
Macquarie Park NSW 2113
Australia
Toll Free Number: 1800 288 382

Australian Registration Numbers

5 mg tablets: AUST R 238013

10 mg tablets: AUST R 238014

15 mg tablets: AUST R 238032

20 mg tablets: AUST R 238033

30 mg tablets: AUST R 238034

Date of preparation: April 2020

Published by MIMS July 2020

BRAND INFORMATION

Brand name

Tevaripiprazole

Active ingredient

Aripiprazole

Schedule

S4

 

1 Name of Medicine

Aripiprazole.

6.7 Physicochemical Properties

Aripiprazole is a novel antipsychotic agent with unique pharmacologic properties and a chemical structure that differs from current antipsychotic agents.
Since aripiprazole is insoluble in water with its equilibrium solubility being about 0.00001% w/v, its pKa was established in 20% aqueous ethanol pKa = 7.6 (20% ethanol, at 25°C). The partition coefficients (Po/w) of aripiprazole range from 3.4 at pH 2.0 to > 1000 at pH 6.0.

Chemical structure.

The structural formula of aripiprazole is shown below:
Active ingredient: aripiprazole.
Chemical name: 7-[4-[4- (2, 3-dichlorophenyl)-1-piperazinyl] butoxy]-3, 4- dihydrocarbostyril.
Molecular formula: C23H27Cl2N3O2.
Molecular weight: 448.39.

CAS number.

129722-12-9.

2 Qualitative and Quantitative Composition

This product contains lactose (as lactose monohydrate).
Tevaripiprazole tablets contain 5, 10, 15, 20 or 30 mg of aripiprazole.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tevaripiprazole 5 mg uncoated tablet.

Light yellow coloured round flat faced bevelled edge tablet with debossed '5' on one side and plain on the other side.

Tevaripiprazole 10 mg uncoated tablet.

Pink to light pink coloured, oblong tablet with debossed '10' on one side and breakline on the other side.

Tevaripiprazole 15 mg uncoated tablet.

Light yellow coloured, round flat faced bevelled edge tablet with debossed '15' on one side and breakline on the other side.

Tevaripiprazole 20 mg uncoated tablet.

White to off white or pale cream coloured, capsule shaped biconvex tablet with debossed '20' on one side and breakline on the other side.

Tevaripiprazole 30 mg uncoated tablet.

Pink to light pink coloured, round biconvex tablet with debossed '30' on one side and breakline on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The mechanism of action of aripiprazole, as well as other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that the efficacy of aripiprazole is mediated through a combination of partial agonist activity at dopamine D2 and serotonin 5HT1A receptors and antagonist activity at serotonin 5HT2A receptors.
Aripiprazole activity is primarily due to the parent drug, aripiprazole.
Aripiprazole exhibited higher affinity binding in vitro for dopamine D2 and D3, serotonin 5HT1A and 5HT2A receptors (Ki values of 0.3, 0.8, 1.7, and 3.4 nanoM, respectively), than for dopamine D4, serotonin 5HT2C and 5HT7, alpha1-adrenergic and histamine H1 receptors (Ki values of 44, 15, 39, 57, and 61 nanoM, respectively) and the serotonin reuptake site (Ki value of 98 nanoM). Aripiprazole exhibited no appreciable affinity for muscarinic receptors (IC50 > 1000 nanoM).
The predominant metabolite in human plasma, dehydro-aripiprazole has been shown to have a similar affinity for dopamine D2 and D3 receptors (Ki values 0.4 and 0.5 nanoM, respectively) as the parent compound and a much lower affinity for the other receptor subtypes.
Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypoactivity.
Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.

Clinical trials.

Schizophrenia.

The efficacy of aripiprazole in the treatment of schizophrenia was evaluated in six short-term (4- and 6-week), placebo-controlled trials of inpatients, four of which also included an active control group consisting of either risperidone (one trial) or haloperidol (three trials). Studies were not powered to allow for a comparison of aripiprazole and the active comparators. Efficacy was also documented in two long-term trials, one of 52 weeks duration, which compared aripiprazole to haloperidol and one of 26 weeks duration, which compared aripiprazole to placebo. Patients in these trials met DSM-III/IV criteria for schizophrenia or schizo-affective disorder.
Several instruments were used for assessing psychiatric signs and symptoms. The Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) are both multi-item inventories of general psychopathology used to evaluate the effects of drug treatment in schizophrenia. The BPRS Psychosis Cluster (Core Score), a subset of the BPRS that can also be derived from the PANSS, is used to assess actively psychotic patients. The Clinical Global Impression (CGI) assessment reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.
Four short-term, fixed-dose trials were well controlled and powered to statistically demonstrate the efficacy of aripiprazole over placebo. The results of these trials are described below.

Trial 1.

In a 4-week, placebo-controlled trial (n=414) involving administration of 2 fixed doses of aripiprazole (15 or 30 mg/day) and haloperidol (10 mg/day) in acutely relapsed patients with a DSM-IV diagnosis of schizophrenia or schizo-affective disorder, aripiprazole 15 mg/day was superior to placebo with clinically meaningful changes in PANSS total, PANSS positive and negative subscales, CGI-severity, CGI-improvement, and PANSS-derived BPRS-core scores. The 30 mg dose was superior to placebo for all parameters except PANSS negative subscale.

Trial 2.

In a 4-week, placebo controlled trial (n=404) involving administration of 2 fixed doses of aripiprazole (20 or 30 mg/day) and risperidone (6 mg/day) in acutely relapsed patients with a DSM-IV diagnosis of schizophrenia or schizo-affective disorder, both doses of aripiprazole were superior to placebo with clinically meaningful changes in the PANSS total, PANSS positive and negative subscales, CGI-severity, CGI-improvement and PANSS-derived BPRS-core scores.

Trial 3.

In a 6-week, placebo-controlled trial (n=420) involving administration of 3 fixed doses of aripiprazole (10, 15, or 20 mg/day) in acutely relapsed patients with a DSM-IV diagnosis of schizophrenia, all aripiprazole dose groups were superior to placebo with clinically meaningful changes in the PANSS total score, the PANSS positive and negative subscales, the CGI severity and improvement scales, and the PANSS-derived BPRS core score.

Trial 4.

In a 6-week trial (n=367) comparing three fixed doses of aripiprazole (2, 5 or 10 mg/day) to placebo, in acutely relapsed patients with a DSM-IV diagnosis of schizophrenia, the 10 mg dose of aripiprazole was superior to placebo in the PANSS total score, the primary outcome measure of the study. In addition, the 10 mg dose was also superior to placebo in the PANSS positive subscale and the CGI severity score. Although the 5 mg dose of aripiprazole did not reach significance in the PANSS total score or the PANSS positive subscale, it was superior to placebo in the PANSS negative subscale and the CGI severity scale. The 2 mg1 dose did not reach significance in any of these outcome measures.
1Aripiprazole 2 mg table is unavailable in this brand however is available in other brands.
Two initial placebo-controlled trials were conducted to explore the efficacy of aripiprazole. The first one (Trial 5) was a placebo-controlled, 4-week ascending dose trial of aripiprazole (5 to 30 mg/day) in 103 patients diagnosed with schizophrenia according to the DSM-III-R criteria with acute schizophrenic relapse and a history of response to antipsychotic drugs. In this trial, aripiprazole differentiated from placebo in the PANSS total score, the PANSS positive subscale, and the CGI severity scale. The second one (Trial 6) was a placebo-controlled, 4-week, fixed-dose trial of aripiprazole (2, 10, or 30 mg/day) in 272 patients diagnosed with schizophrenia according to the DSM-IV criteria with acute schizophrenic relapse and a history of response to antipsychotic drugs. Statistical significance was reached only for the 30 mg dose on the PANSS total score, the PANSS positive subscale, and the CGI severity and improvement scales.
Thus, the efficacy of 10 mg, 15 mg, 20 mg and 30 mg was established in two studies for each dose. Among these doses there was no evidence that the higher dose groups offered any advantage over the lowest dose group. Broad efficacy was established across a variety of endpoints with an onset of action as early as Week 1 for positive symptoms at doses of 15 mg and higher.
Table 5 summarizes the results across all six trials.
A 52-week, haloperidol-controlled, long-term, maintenance trial (n=1294) was conducted in patients with acute relapse of chronic schizophrenia. In this trial involving the administration of aripiprazole 30 mg/day and haloperidol 10 mg/day, with a one-time option to decrease aripiprazole to 20 mg/day and haloperidol to 7 mg/day, aripiprazole was at least comparable to haloperidol in time-to-failure to maintain response in responders. Based on patients who responded at any time during the 52-week study (610/853, 72% in the aripiprazole group and 298/430, 69% in the haloperidol group), there was a 12% lower risk of subsequent failure with aripiprazole relative to haloperidol (relative risk: 0.881, 95% CI: 0.645 - 1.204). Aripiprazole was comparable to haloperidol in time-to-failure to maintain response in all randomized patients. Patients in the aripiprazole group had a 14% lower risk of failure compared with the haloperidol group (relative risk: 0.858, 95% CI: 0.721, 1.021). Aripiprazole was statistically superior to haloperidol in the analysis of the proportion of patients on treatment and in response at Weeks 8, 26, and 52 (pre-specified key time points). At Week 52, 40% of aripiprazole patients were still on-study and in response compared to 27% of haloperidol patients (p < 0.001). Aripiprazole-treated patients had a statistically significant lower risk (31%) of discontinuations due to lack of efficacy or adverse event relative to haloperidol treated patients (relative risk 0.692; 95% CI:0.573-0.837). There were no significant differences between aripiprazole and haloperidol groups in terms of change from baseline PANSS total scores, PANSS positive subscores, CGI-severity or improvement scores. Aripiprazole did result in a significantly greater improvement in the PANSS negative subscores at weeks 26 and 52 and the MADRS total score at Weeks 8, 26, and 52. [Mean change PANSS negative subscale score (week 26: p=0.029; 95% CI: -1.52, -0.08) (week 52: p=0.011; 95% CI: -1.73, -0.23). Mean change MADRS total score (week 8: p=0.027; 95% CI: -1.74, -0.11) (week 26: p=0.22; 95% CI:-1.95, -0.15) (week 52: p=0.031; 95% CI: -1.97, -0.09).]
To further demonstrate the maintenance effects of aripiprazole, a double-blind study was conducted in chronic, symptomatically stable schizophrenic patients (n=310) randomised to aripiprazole 15 mg or placebo and followed for 26 weeks. Patients were observed for "impending psychotic relapse", defined as CGI-improvement score ≥ 5 (minimally worse) or scores ≥ 5 (moderately severe) on the hostility or uncooperativeness items of the PANSS on two consecutive days or ≥ 20% increase in the PANSS Total Score. Patients in the placebo group experienced a higher relapse rate and/or relapsed sooner than those in the aripiprazole group. From 4 weeks onwards there were noticeably more relapses in the placebo group than the aripiprazole group. Kaplan Meier estimates showed that the estimated probability of not experiencing relapse prior to week 26 was 39% in the placebo group versus 63% in the aripiprazole group [relative risk aripiprazole: placebo = 0.50 (95% CI=0.35, 0.71, p ≤ 0.01)]. The number of relapses was significantly lower in the aripiprazole group compared to placebo (34% vs 57%, RR=0.59, 95% CI: 0.45, 0.75, p ≤ 0.01).
No trials have been conducted in patients with first episode schizophrenia or treatment-resistant schizophrenia. Thus, efficacy in these groups of patients has not been established.

5.2 Pharmacokinetic Properties

Absorption.

Oral administration.

Aripiprazole is well absorbed after oral administration, with peak plasma concentrations occurring within 3-5 hours after dosing. The absolute oral bioavailability of the tablet formulation of aripiprazole is 87%. Aripiprazole can be administered without regard to meals. Following administration of a 15 mg aripiprazole tablet with a standard high-fat meal, the Cmax of aripiprazole and its active metabolite, dehydro-aripiprazole, increased by 11%. The AUC of aripiprazole was increased by 18% and that of the active metabolite by 14%. Food delayed Tmax by 3 hours for aripiprazole and 12 hours for the active metabolite. Aripiprazole accumulation is predictable from single dose pharmacokinetics. At steady state, the pharmacokinetics of aripiprazole are dose-proportional. There is no diurnal variation in the disposition of aripiprazole and its active metabolite, dehydro-aripiprazole.

Distribution.

Aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 L/kg. At therapeutic concentrations, aripiprazole is highly bound (88-97% to > 99%, as determined by polydimethylsiloxane-glass bead and equilibrium dialysis assays, respectively) to serum proteins, primarily albumin, in vitro. Aripiprazole did not alter the pharmacokinetics and pharmacodynamics of highly protein-bound warfarin, suggesting that protein displacement of warfarin did not occur.

Metabolism.

Aripiprazole undergoes minimal pre-systemic metabolism. Aripiprazole is extensively metabolized by the liver primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are primarily responsible for dehydrogenation and hydroxylation of aripiprazole, while N-dealkylation is primarily catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in systemic circulation. At steady state, dehydro-aripiprazole, the active metabolite, represented about 39% of aripiprazole AUC in plasma. Approximately 8% of Caucasians lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are extensive metabolizers (EM). PMs have about an 80% increase in aripiprazole exposure and about a 30% decrease in exposure to the active metabolite compared to EMs, resulting in about a 60% higher exposure to the total active moieties from a given dose of aripiprazole compared to EMs. Subjects were entered into clinical studies without knowledge of their metabolizer status and, therefore, the safety profile reflects experience in both EMs and PMs.

Excretion.

Following a single, oral dose of [14C]-labeled aripiprazole, approximately 27% and 60% of the administered radioactivity was recovered in the urine and faeces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the faeces. The total body clearance of aripiprazole is 0.7 mL/min/kg, which is primarily hepatic.
In a bioavailability study comparing fasted and fed subjects at a dose of 15 mg, the elimination half-life of aripiprazole from human plasma was found to be 75 hours mean, range 32-146 hours, n=58, in fasted subjects and 84 hours mean, range 32-157 hours, n=57 in subjects taking a high-fat meal immediately before drug administration. Steady-state concentrations are attained within 14 days of dosing. The plasma elimination half-life of the chief metabolite, dehydro-aripiprazole, from human plasma was found to be approx. 100 hours.

Elderly.

There were no differences in the pharmacokinetics of aripiprazole between healthy elderly and younger adult subjects nor was there any detectable effect of age in a population pharmacokinetic analysis in schizophrenic patients. In formal single-dose pharmacokinetic studies (with aripiprazole given in a single dose of 15 mg), aripiprazole clearance was 20% lower in elderly (≥ 65 years) subjects compared to younger adult subjects (18-64 years). There was no detectable age effect, however, in the population pharmacokinetic analysis in schizophrenia patients. Also, the pharmacokinetics of aripiprazole after multiple doses in elderly patients appeared similar to that observed in young healthy subjects. No dosage adjustment is recommended for elderly patients. (See Section 4.4 Special Warnings and Precautions for Use, Increased mortality in elderly patients with dementia-related psychosis, Use in the elderly).

Gender.

There were no differences in the pharmacokinetics of aripiprazole between healthy male and female subjects nor was there any detectable effect of gender in a population pharmacokinetic analysis in schizophrenic patients. Cmax and AUC of aripiprazole and its active metabolite, dehydro-aripiprazole, are 30 to 40% higher in women than in men, and correspondingly, the apparent oral clearance of aripiprazole is lower in women. These differences, however, are largely explained by differences in body weight (25%) between men and women. No dosage adjustment is recommended based on gender.

Race.

Population pharmacokinetic evaluation has revealed no evidence of clinically significant race-related differences in the pharmacokinetics of aripiprazole.

Smoking.

Population pharmacokinetic evaluation has revealed no evidence of clinically significant effects of smoking on the pharmacokinetics of aripiprazole. Based on studies utilizing human liver enzymes in vitro, aripiprazole is not a substrate for CYP1A2 and also does not undergo direct glucuronidation. Smoking should, therefore, not have an effect on the pharmacokinetics of aripiprazole. Consistent with these in vitro results, population pharmacokinetic evaluation did not reveal any significant pharmacokinetic differences between smokers and non-smokers. No dosage adjustment is recommended based on smoking status.

Renal impairment.

The pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were found to be similar in patients with severe renal disease compared to young healthy subjects. In patients with severe renal impairment (creatinine clearance < 30 mL/min), Cmax of aripiprazole (given in a single dose of 15 mg) and dehydro-aripiprazole increased by 36% and 53%, respectively, but AUC was 15% lower for aripiprazole and 7% higher for dehydro-aripiprazole. Renal excretion of both unchanged aripiprazole and dehydro-aripiprazole is less than 1% of the dose. No dosage adjustment is required in subjects with renal impairment.

Hepatic impairment.

A study in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydro-aripiprazole. In a single-dose study (15 mg of aripiprazole) in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C), the AUC of aripiprazole, compared to healthy subjects, increased 31% in mild HI, increased 8% in moderate HI, and decreased 20% in severe HI. None of these differences would require dose adjustment.

5.3 Preclinical Safety Data

Choleliths (gallsand and/or gallstones) were observed in the bile of monkeys given aripiprazole orally for 4 - 52 weeks at doses of 25 -125 mg/kg/day (1 - 3 times the MRHD based on plasma AUC and 15 -76 times the MRHD based on mg/m2) and were attributed to precipitation of sulfate conjugates of hydroxy metabolites, which exceeded their solubility limits in bile. Human biliary concentrations of these sulfate conjugates after repeated daily administration of the MRHD are substantially lower (0.2 - 14% of their in vitro solubility limits).
Bilateral retinal degeneration was observed in albino rats given oral aripiprazole for 6 months or two years at exposures of 6-13 times the clinical exposure at the MRHD (based on plasma AUC). The exposure at the NOEL dose was 3 times that at the MRHD. A subsequent 18-month study reported this finding in albino but not pigmented rats, possibly due to lack of photoprotective ocular melanin in the albino rats, although it is unknown whether pigmentation prevented or merely delayed retinal degeneration in the pigmented rats. The clinical relevance of this finding is uncertain.

Genotoxicity.

Aripiprazole was tested in a standard range of assays for gene mutation, chromosomal damage, and DNA damage and repair. Aripiprazole was non-genotoxic in the in vitro bacterial reverse-mutation assay, the in vitro forward gene mutation assay in mouse lymphoma cells, in vitro bacterial DNA repair assay, and the unscheduled DNA synthesis assay in rat hepatocytes. However, aripiprazole and its minor metabolite 2,3-DCPP were clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells in both the presence and absence of metabolic activation. A positive response for aripiprazole in 1 of 6 in vivo mouse micronucleus tests was attributed to drug-induced hypothermia.

Carcinogenicity.

Lifetime carcinogenicity studies were conducted in ICR mice and in Sprague-Dawley (SD) and Fischer (F344) rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2 to 5 and 0.3 to 3 times the maximum recommended human dose [MRHD] based on mg/m2, respectively). SD rats were dosed orally by gavage for 2 years at 10, 20, 40, and 60 mg/kg/day (3 to 18 times the MRHD based on mg/m2). There was no evidence of tumorigenesis in male mice or rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.1 to 0.9 times MRHD based on AUC and 0.5 to 5 times the MRHD based on mg/m2). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (< 0.1 times MRHD based on AUC and 3 times the MRHD based on mg/m2); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral gavage dose of 60 mg/kg/day (10 times the MRHD based on AUC and 18 times MRHD based on mg/m2). In male rats, the incidence of benign and combined benign/malignant phaeochromocytomas were also increased at an oral gavage dose of 60 mg/kg/day (10 times the MRHD based on AUC and 18 times the MRHD based on mg/m2).
Proliferative changes in the pituitary and mammary gland of rodents have been observed following chronic administration of other antipsychotic agents and are considered prolactin-mediated. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. Hyperprolactinaemia was observed in female mice in a 13-week dietary study at doses associated with mammary gland and pituitary tumours, but not in female rats in 4- and 13-week dietary studies at doses associated with mammary gland tumours. Hyperprolactinaemia was observed in female rats after 5 and 13 weeks of oral administration at doses up to that associated with adrenocortical tumours, but serum prolactin was decreased at this dose in male rats. The relationship between tumourigenic findings with aripiprazole and prolactin is unclear and the relevance for human risk of prolactin-mediated endocrine tumours is unknown. The adrenocortical response in female rats is considered a consequence of increased adrenocortical cell proliferation secondary to chronic drug-related adrenocortical cytotoxicity; the no-effect exposure (plasma AUC) was about fold 7 clinical exposure at the MRHD.

4 Clinical Particulars

4.1 Therapeutic Indications

Tevaripiprazole is indicated for the treatment of schizophrenia including maintenance of clinical improvement during continuation therapy.

4.3 Contraindications

Tevaripiprazole is contraindicated in patients who are hypersensitive to aripiprazole or any of the excipients (see Section 6.1 List of Excipients).
For specific information about the contraindications of mood stabilisers see Section 4.3 Contraindications when combination with lithium or valproate is indicated.

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 atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen 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 the placebo group. Although the causes of death varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature.
In three placebo-controlled trials of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease, cerebrovascular adverse events (e.g. stroke, transient ischaemic attack), including fatalities, occurred in 1.3% (8/595) of aripiprazole-treated patients compared with 0.6% (2/343) of placebo-treated patients during the 10-week double-blind period or within 30 days of the last dose for those who discontinued the study during the double-blind phase. The all-cause mortality rate in the same trials over the same period was 3.5% (21/595) in aripiprazole-treated patients and 1.7% (6/343) in the placebo group.
Aripiprazole is not approved for the treatment of patients with dementia-related psychosis.

Falls.

Aripiprazole may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls. Caution should be taken when treating patients at higher risk, and a lower starting dose should be considered (e.g. elderly or debilitated patients) (see Section 4.2 Dose and Method of Administration).

General.

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored during this period.

Suicide.

The possibility of a suicide attempt is inherent in psychotic illnesses and close supervision of high-risk patients should accompany drug therapy. Prescriptions for aripiprazole should be written for the smallest quantity consistent with good patient management, in order to reduce the risk of overdose.

Tardive dyskinesia.

The risk of tardive dyskinesia increases with long-term exposure to antipsychotic treatment. If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, a dose reduction or drug discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.

Neuroleptic malignant syndrome.

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs including aripiprazole. Rare cases of NMS occurred during aripiprazole treatment in the worldwide clinical database. 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 kinase, 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 aripiprazole must be discontinued.

Seizure.

In short-term, placebo controlled trials, seizures occurred in 0.1% (3/2467) of adult patients treated with aripiprazole.
As with other antipsychotic drugs, aripiprazole should be used cautiously in patients who have a history of seizure disorder or have conditions associated with seizures.

Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis.

In placebo-controlled clinical studies (2 flexible dose and 1 fixed dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse events (e.g. stroke, transient ischemic attack), including fatalities, in aripiprazole-treated patients (mean age: 84 years; range: 78-88 years). In the fixed dose study, there was a statistically significant dose response relationship for cerebrovascular adverse events in patients treated with aripiprazole. Aripiprazole is not approved for the treatment of patients with dementia-related psychosis. (Also see Section 4.4 Special Warnings and Precautions for Use, Increased mortality in elderly patients with dementia-related psychosis, Use in patients with concomitant illness, Safety experience in elderly patients with psychosis associated with Alzheimer's disease.)

Hyperglycaemia and diabetes mellitus.

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients with atypical antipsychotics including aripiprazole. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increase background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycaemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycaemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycaemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
In patients with significant treatment-emergent hyperglycaemia, discontinuation of aripiprazole should be considered.

Cardiovascular adverse events.

Potentially due to its α1-adrenergic receptor antagonism, aripiprazole may be associated with orthostatic hypotension.
The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral aripiprazole (n=2467) included (aripiprazole incidence, placebo incidence): orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%).
Orthostatic hypotension occurred in 0.8% (112/13,543) of oral aripiprazole-treated patients during clinical trials.
As with other atypical antipsychotics, aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischaemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolaemia, and treatment with antihypertensive medications).
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 treatment with aripiprazole and preventive measures undertaken.

Body temperature regulation.

Disruption of the body's ability to increase or reduce core body temperature has been attributed to antipsychotic agents, including aripiprazole. Appropriate care is advised when prescribing aripiprazole for patients who will be experiencing conditions which 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.
Patients should be advised regarding appropriate care in avoiding overheating and dehydration.

Dysphagia.

Oesophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk of aspiration pneumonia (e.g. elderly patients).

Akathisia.

Class effect.

The presentation of akathisia may be variable and comprises subjective complaints of restlessness and an overwhelming urge to move and either distress or motor phenomena such as pacing, swinging of the legs while seated, rocking from foot to foot, or both. Particular attention should be paid to the monitoring for such symptoms and signs as, left untreated, akathisia is associated with poor compliance and an increased risk of relapse.

Leucopenia, neutropenia and agranulocytosis.

Class effect.

In clinical trial and/or postmarketing experience, events of leucopenia/neutropenia have been reported temporally related to antipsychotic agents, including aripiprazole. Agranulocytosis has also been reported.
Possible risk factors for leucopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leucopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug-induced leucopenia/neutropenia should have their complete blood cell (CBC) monitored frequently during the first few months of therapy and discontinuation of aripiprazole should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant 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 aripiprazole and have their WBC followed until recovery.

Potential for cognitive and motor impairment.

Aripiprazole, like other antipsychotics, may have the potential to impair judgment, thinking, or motor skills. In short-term, placebo-controlled trials, somnolence (including sedation) was reported as follows (aripiprazole incidence, placebo incidence): in adult patients (n=2467) treated with oral aripiprazole (11%, 6%). Somnolence (including sedation) led to discontinuation in 0.3% (8/2467) of adult patients on oral aripiprazole in short-term, placebo-controlled trials.
Despite the relatively modest increased incidence of these events compared to placebo, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with aripiprazole does not affect them adversely.

Pathological gambling and impulse-control disorders.

Patients can experience increased urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other urges, reported include: increased sexual urges, compulsive spending, binge or compulsive eating, and other impulsive and compulsive behaviours. It is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, compulsive spending, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder; however, in some cases urges were reported to have stopped when the dose was reduced or the medication was discontinued. Impulse control disorders may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges while taking aripiprazole. (See Section 4.8 Adverse Effects (Undesirable Effects)).

Lactose.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency of glucose-galactose malabsorption should not take this medicine.

Use in patients with concomitant illness.

Clinical experience with aripiprazole in patients with certain concomitant systemic illnesses is limited. (See Section 5.2 Pharmacokinetic Properties, Renal impairment, Hepatic impairment). Aripiprazole has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies.

Safety experience in elderly patients with psychosis associated with Alzheimer's disease.

In three, 10-week, placebo-controlled studies of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease (n=938; mean age: 82.4 years; range: 56-99 years), the treatment-emergent adverse events that were reported at an incidence of ≥ 5% and aripiprazole incidence at least twice that for placebo were lethargy [placebo 2%, aripiprazole 5%], somnolence (including sedation) [placebo 3%, aripiprazole 8%] and incontinence (primarily, urinary incontinence) [placebo 1%, aripiprazole 5%].
The safety and efficacy of aripiprazole in the treatment of patients with psychosis associated with dementia have not been established. Aripiprazole is not indicated for the treatment of psychosis associated with Alzheimer's disease. (Also see Section 4.4 Special Warnings and Precautions for Use, Increased mortality in elderly patients with dementia-related psychosis, Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis.)

Concomitant medication.

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. (See Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.2 Dose and Method of Administration, Concomitant medications).

Use in hepatic impairment.

See Section 5.2 Pharmacokinetic Properties.

Use in renal impairment.

See Section 5.2 Pharmacokinetic Properties.

Use in the elderly.

Placebo-controlled studies of aripiprazole in schizophrenia or Bipolar Mania did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 13,543 patients treated with oral aripiprazole in clinical trials, 1073 (8%) were ≥ 65 years old and 799 (6%) were ≥ 75 years old. The majority (81%) of the 1073 patients were diagnosed with Dementia of the Alzheimer's Type.
Studies of elderly patients with psychosis associated with Alzheimer's disease have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia (see Section 4.4 Special Warnings and Precautions for Use, Increased mortality in elderly patients with dementia-related psychosis, Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis, Use in patients with concomitant illness). The safety and efficacy of aripiprazole in the treatment of patients with psychosis associated with Alzheimer's disease has not been established. Aripiprazole is not indicated for the treatment of psychosis associated with Alzheimer's disease.
Of the 749 patients treated with aripiprazole injection in clinical trials, 99 (13%) were ≥ 65 years old and 78 (10%) were ≥ 75 years old. Almost all of the use in the elderly was in clinical trials for an indication for which registration has not been requested. Placebo-controlled studies of aripiprazole injection in patients with agitation associated with schizophrenia did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
There was no effect of age on the pharmacokinetics of a single, 15 mg dose of aripiprazole. Aripiprazole clearance was decreased by 20% in elderly subjects (> 65 years) compared to younger adult subjects (18 to 64 years), but there was no detectable effect of age in the population pharmacokinetic analysis in schizophrenia patients.

Paediatric use.

The safety and efficacy of aripiprazole in patients less than 18 years of age have not been established.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Laboratory test abnormalities.

4.5 Interactions with Other Medicines and Other Forms of Interactions

CNS drugs (including alcohol).

Given the primary CNS effects of aripiprazole, caution should be used when aripiprazole is taken in combination with other centrally acting drugs and alcohol.
Patients should be advised to avoid alcohol while taking aripiprazole.
Co-administration of lithium titrated upwards from a starting dose of 900 mg until serum lithium concentrations near the upper end of the lithium therapeutic concentration range (1.0-1.4 mmol/L) were achieved and maintained for at least 5 days or until dose-limiting adverse events were observed and valproate (divalproex sodium) titrated upwards from a starting dose of 250 mg twice daily to achieve serum concentrations within the therapeutic range of 50-125 microgram/mL for at least 14 days, with 30 mg aripiprazole once daily had no clinically significant effects on the pharmacokinetics of aripiprazole. Nor was there any clinically significant change in valproic acid or lithium pharmacokinetics when aripiprazole 30 mg once daily was administered concomitantly for 7 days with either divalproex sodium 500 mg every 12 hours or controlled release lithium 450 mg every 12 hours.
When aripiprazole was administered concomitantly with either valproate, lithium or lamotrigine, there was no clinically important change in valproate, lithium or lamotrigine concentrations.

Antihypertensive agents.

Due to its α1-adrenergic receptor antagonist activity, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.

Medicines which cause QT prolongation or electrolyte imbalance.

If aripiprazole is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used.

Inhibitors and inducers of CYP2D6 and CYP3A4.

Aripiprazole is metabolized by multiple pathways primarily involving the CYP2D6 and CYP3A4 enzymes. In clinical studies with healthy subjects, potent inhibitors of CYP2D6 (quinidine) and 3A4 (ketoconazole) decreased oral clearance of aripiprazole by 52% and 38%, respectively. Other potent inhibitors of CYP3A4 and CYP2D6 may be expected to have similar effects. When concomitant administration of quinidine or ketoconazole with aripiprazole occurs, the aripiprazole dose should be halved. When the inhibitor is withdrawn from the combination therapy, the aripiprazole dose should then be increased. (See Section 4.2 Dose and Method of Administration, Concomitant medications).
No data are available for use of aripiprazole with other inhibitors of CYP3A4 or CYP2D6. Examples of medicines or substances that have the potential to inhibit CYP3A4 or CYP2D6 include, but are not limited to, clarithromycin, erythromycin, itraconazole, fluconazole, ritonavir, indinavir, nefazodone, cyclosporin, amiodarone, cimetidine, fluoxetine, paroxetine and grapefruit juice.
Dose reduction of aripiprazole should be applied with concomitant administration of potent CYP3A4 inhibitors such as itraconazole, clarithromycin and HIV protease inhibitors, as similar effects to that seen in the clinical studies with ketoconazole may be expected. Dose reduction of aripiprazole should be applied with concomitant administration of potent CYP2D6 inhibitors such as fluoxetine and paroxetine as similar effects to that seen in the clinical studies with quinidine may be expected (see Section 4.2 Dose and Method of Administration, Concomitant medications).
In a clinical study in patients with schizophrenia or schizo-affective disorder, co-administration of carbamazepine (200 mg twice daily), a potent CYP3A4 inducer, with aripiprazole (30 mg daily) resulted in an approximate 70% decrease in AUC values of both aripiprazole and its active metabolite, dehydro-aripiprazole. Other potent inducers of CYP3A4 and CYP2D6 may be expected to have similar effects. When a potent inducer like carbamazepine is added to aripiprazole therapy, the aripiprazole dose should be increased. Other potent inducers of CYP3A4 include, but are not limited to, St. John's Wort, phenytoin, rifampicin, efavirenz, and nevirapine. Additional dose increases should be based on clinical evaluation. When the inducer is withdrawn from the combination therapy, the aripiprazole dose should then be reduced. (See Section 4.2 Dose and Method of Administration, Dosage adjustment for patients taking aripiprazole concomitantly with potential CYP3A4 inducers).

Inhibitors and inducers of CYP1A1, CYP1A2, CYP2C9, and CYP2C19.

Aripiprazole is not metabolized by CYP1A1, CYP1A2, CYP2C9, and CYP2C19 in vitro, suggesting that interactions with medications or other factors (e.g. smoking), which are inhibitors or inducers of these enzymes, are unlikely.

Effects of aripiprazole on substrates for CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP1A2.

Aripiprazole and dehydro-aripiprazole were weak inhibitors of CYP2C9, CYP2C19, CYP2D6, and CYP3A4-mediated metabolism in vitro (IC50 values 2.4-25 microM). Neither aripiprazole nor dehydro-aripiprazole inhibited CYP1A2-mediated metabolism in vitro (IC50 value > 50-66 microM).
In clinical studies, 10-30 mg/day doses of aripiprazole had no significant effect on metabolism of substrates of CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and CYP3A4 (dextromethorphan). Thus, aripiprazole is unlikely to cause clinically important drug interactions mediated by these enzymes.

Famotidine.

There was no significant effect of the H2 antagonist famotidine, a potent gastric acid blocker, on the pharmacokinetics of aripiprazole.

Food.

Aripiprazole can be administered without regard to meals. Following administration of a 15 mg aripiprazole tablet with a standard high-fat meal, the Cmax of aripiprazole and its active metabolite, dehydro-aripiprazole, increased by 11%. The AUC of aripiprazole was increased by 18% and that of the active metabolite by 14%. Food delayed Tmax by 3 hours for aripiprazole and 12 hours for the active metabolite.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Aripiprazole had no effect on fertility in female rats treated orally with 2, 6, and 20 mg/kg/day (0.6, 2, and 6 times the MRHD based on mg/m2) for 2 weeks prior to mating through gestation day 7. Drug-related effects (persistent dioestrus and increased mating time pre-implantation losses, and corpora lutea) observed at all doses were considered the result of perturbed oestrous cyclicity secondary to drug-mediated hyperprolactinaemia.
Aripiprazole had no effect on fertility in male rats treated with PO doses of 20, 40, and 60 mg/kg/day (6, 12, and 18 times the MRHD based on mg/m2) for 9 weeks prior to mating through mating. Disturbances of spermatogenesis were seen at 60 mg/kg/day and prostatic atrophy was seen at 40 and 60 mg/kg/day.
(Category C)
Congenital anomalies have been reported; however, a causal relationship with aripiprazole could not be established. In animal studies aripiprazole demonstrated developmental toxicity, including possible teratogenic effects, in rats and rabbits.
Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 9 times the MRHD on a mg/m2 basis) of aripiprazole during the period of organogenesis. At 30 mg/kg, treatment was associated with slightly prolonged gestation, and a slight delay in foetal development as evidenced by decreased foetal weight, undescended testes, and delayed skeletal ossification. There were no adverse effects on embryofoetal or pup survival. Delivered offspring had increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia at 30 mg/kg (the other doses were not examined for these findings).
(A low incidence of diaphragmatic hernia was also seen in the foetuses exposed to 30 mg/kg). Postnatally, decreased pup weight (persisting into adulthood) was seen at 30 mg/kg, delayed vaginal opening was seen at 10 and 30 mg/kg, and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, and live foetuses, and increased post-implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg. Maternal toxicity was seen at 30 mg/kg, which was similar to doses eliciting embryotoxicity.
Pregnant rabbits were treated with oral doses of 10, 30, and 100 mg/kg/day (2, 3, and 11 times human exposure at MRHD based on AUC and 8, 24, and 81 times the MRHD based on mg/m2) of aripiprazole during the period of organogenesis. Decreased maternal food consumption, and increased abortions were seen at 100 mg/kg. Treatment caused increased foetal mortality (100 mg/kg), decreased foetal weight (30 mg and 100 mg/kg), increased incidence of a skeletal abnormality (fused sternebrae at 100 mg/kg) and minor skeletal variations (100 mg/kg).
Rats were treated with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 9 times the MRHD on a mg/m2 basis) of aripiprazole from late gestation through weaning. At 30 mg/kg, maternal toxicity, slightly prolonged gestation, an increase in stillbirths, poor postnatal care/nursing, and decreases in pup weight (persisting into adulthood) and survival were seen.

Non-teratogenic class effect.

Neonates exposed to antipsychotic drugs (including aripiprazole) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been postmarket 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 additional medical treatment or monitoring.
Aripiprazole should be used during pregnancy only if the anticipated benefit outweighs the risk and the administered dose and duration of treatment should be as low and as short as possible.
Patients should be advised to notify their doctors if they become pregnant or intend to become pregnant.

Use in labour and delivery.

The effect of aripiprazole on labour and delivery has not been studied.
Aripiprazole and/or its metabolites have been found in the milk of lactating rats. Aripiprazole is excreted in breast milk. Patients should be advised not to breast-feed if they are taking aripiprazole.

4.8 Adverse Effects (Undesirable Effects)

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.
Aripiprazole has been evaluated for safety in 13,543 patients who participated in multiple-dose clinical trials in Schizophrenia (including schizo-affective disorder), Bipolar I Disorder, Major Depressive Disorder, Dementia of the Alzheimer's type, Parkinson's disease, and alcoholism, and who had approximately 7619 patient-years of exposure to oral aripiprazole and 749 patients with exposure to aripiprazole injection. A total of 3390 patients were treated with oral aripiprazole for at least 180 days and 1933 patients treated with oral aripiprazole had at least 1 year of exposure.
The conditions and duration of treatment with aripiprazole (monotherapy and in combination treatment with lithium or valproate) included (in overlapping categories) double-blind, comparative and non-comparative open-label studies, inpatient and outpatient studies, fixed- and flexible-dose studies, and short- and longer-term exposure.
Adverse events during exposure were obtained by collecting voluntarily reported adverse events, as well as results of physical examinations, vital signs, weights, laboratory analyses, and ECG. Adverse experiences were recorded by clinical investigators using terminology of their own choosing. In the tables and tabulations that follow, MedDRA dictionary terminology has been used initially to classify reported adverse events into a smaller number of standardized event categories, in order to provide a meaningful estimate of the proportion of individuals experiencing adverse events.
The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatment uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse event incidence in the population studied.

Oral administration.

Adult patients with schizophrenia.

Adverse events associated with discontinuation of treatment in short-term, placebo-controlled trials of patients with schizophrenia.

Based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which aripiprazole was administered to acutely relapsed patients with schizophrenia in doses ranging from 2 to 30 mg/day, there was no difference in the incidence of discontinuation due to adverse events between aripiprazole-treated (7%) and placebo-treated (9%) patients. The types of adverse events that led to discontinuation were similar between the aripiprazole- and placebo-treated patients.

Adult patients with bipolar I disorder.

Monotherapy.

The following findings are based on a pool of 3-week, placebo-controlled, Bipolar I Disorder trials in which oral aripiprazole was administered at doses of 15 mg/day or 30 mg/day.

Adverse reactions associated with discontinuation of treatment.

Overall, in patients with Bipolar I Disorder, there was little difference in the incidence of discontinuation due to adverse reactions between aripiprazole-treated (11%) and placebo-treated (10%) patients. The types of adverse reactions that led to discontinuation were similar between aripiprazole-treated and placebo-treated patients.

Commonly observed adverse reactions.

Commonly observed adverse reactions associated with the use of aripiprazole in patients with Bipolar I Disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 1.

Less common adverse reactions in adults. Adverse events occurring at an incidence of at least 2% among aripiprazole-treated patients in short-term placebo-controlled trials.

Table 2 enumerates the pooled incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy (up to 6 weeks in Schizophrenia and up to 3 weeks in Bipolar Mania), 2 or more of patients treated with aripiprazole (doses ≥ 2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo in the combined dataset.
An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race.

Adult patients with adjunctive therapy with bipolar I disorder.

The following findings are based on a placebo-controlled trial of adult patients with Bipolar I Disorder in which aripiprazole was administered at doses of 15 mg/day or 30 mg/day in combination with lithium or valproate.

Adverse reactions associated with discontinuation of treatment.

In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 12% for patients treated with adjunctive aripiprazole compared with 6% for patients treated with adjunctive placebo. The most common adverse drug reactions associated with discontinuation in the adjunctive aripiprazole-treated compared to placebo-treated patients were akathisia (5% and 1%, respectively) and tremor (2% and 1%, respectively).

Commonly observed adverse reactions.

The commonly observed adverse reactions associated with adjunctive aripiprazole and lithium or valproate in patients with Bipolar I Disorder (incidence of 5% or greater and incidence at least twice that for adjunctive placebo) were: akathisia, insomnia, and extrapyramidal disorder.

Less common adverse reactions in adults with adjunctive therapy in bipolar I disorder.

Table 3 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute treatment (up to 6 weeks), including only those reactions that occurred in 2% or more of patients treated with adjunctive aripiprazole (doses of 15 mg/day or 30 mg/day) and lithium or valproate and for which the incidence in patients treated with this combination was greater than the incidence in patients treated with placebo plus lithium or valproate.

Dose-related adverse events in short-term, placebo-controlled trials in schizophrenia.

Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials comparing fixed doses (2, 10, 15, 20, and 30 mg/day) of aripiprazole to placebo. This analysis, stratified by study, indicated that the only adverse event to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence (including sedation) [placebo, 7.1%; 10 mg, 8.5%, 15 mg, 8.7 %; 20 mg, 7.5%; 30 mg, 12.6%].

Adverse events occurring in long-term controlled trials.

The adverse events reported in a 26-week, double-blind trial comparing aripiprazole and placebo in patients with schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for aripiprazole vs. 2% (3/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity (8/12 mild and 4/12 moderate), occurred early in therapy (9/12 ≤ 49 days), and were of limited duration (7/12 ≤ 10 days). Tremor infrequently led to discontinuation (< 1%) of aripiprazole. In addition, in a long-term (52-week), active-controlled study, the incidence of tremor for aripiprazole was 5% (40/859). A similar profile was observed in a long-term study in Bipolar I Disorder.

Weight gain.

In placebo-controlled trials, there was a slight difference in mean weight change between aripiprazole and placebo patients (+0.7 kg vs -0.05 kg, respectively, in short-term studies; p ≤ 0.01, and -1.3 kg vs -0.9 kg, respectively, in 26 week study; p=n.s.) and also a difference in the proportion of patients meeting the significant weight gain criterion of ≥ 7% of body weight (aripiprazole 8% compared to placebo 3% in short-term studies; p ≤ 0.01; and aripiprazole 6% compared to placebo 4% in long-term studies; p = n.s.).
In 3-week trials in adults with Bipolar I Disorder with monotherapy aripiprazole, the mean weight gain for aripiprazole and placebo patients was 0.1 kg versus 0.0 kg, respectively. The proportion of patients meeting a weight gain criterion of ≥ 7% of body weight was aripiprazole (2%) compared to placebo (3%). In the 6-week trial in Bipolar I Disorder with aripiprazole as adjunctive therapy with either lithium or valproate, the mean weight gain for aripiprazole and placebo patients was 0.6 kg versus 0.2 kg, respectively. The proportion of patients meeting a weight gain criterion of ≥ 7% of body weight with adjunctive aripiprazole was 3% compared to adjunctive placebo 4%.
In long-term, double-blind, active-comparator trials in schizophrenia, aripiprazole was associated with a higher incidence of significant weight gain (≥ 7% above baseline) compared with haloperidol (20% vs 13%, respectively; p ≤ 0.01; 1.1 kg vs 0.4 kg, respectively; p = n.s.) but a lower incidence of significant weight gain compared to olanzapine (aripiprazole 13% vs olanzapine 33%; p < 0.001; -0.9 kg vs 3.4 kg; p < 0.001 in a double-blind study).
Weight change results (see Table 4) from long-term, double-blind, controlled trials in schizophrenia showed that patients with high body mass index (BMI) (> 27) were less likely to have significant weight gain on aripiprazole than those with low BMI (< 23).

Extrapyramidal symptoms.

In the short-term, placebo-controlled trials of schizophrenia in adults, the incidence of reported EPS-related events excluding events related to akathisia for aripiprazole-treated patients was 13% vs. 12% for placebo. The incidence of akathisia-related events for aripiprazole-treated patients was 8% vs 5% for placebo-treated patients.
In the short-term, placebo-controlled trials in Bipolar I Disorder in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for monotherapy aripiprazole-treated patients was 16% versus 8% for placebo and the incidence of akathisia-related events for monotherapy aripiprazole-treated patients was 13% versus 4% for placebo. In the 6-week, placebo-controlled trial in Bipolar I Disorder for combination therapy with lithium or valproate, the incidence of reported EPS-related events, excluding events related to akathisia for patients treated with aripiprazole in combination with lithium or valproate was 15% versus 8% for patients treated with aripiprazole and placebo and the incidence of akathisia-related events for patients treated with aripiprazole in combination with lithium or valproate was 19% versus 5% for patients treated with aripiprazole and placebo.
Objectively collected data from those trials on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias) did not show a difference between aripiprazole and placebo, with the exception of the Barnes Akathisia Scale (aripiprazole, 0.08; placebo, -0.05).
In the adult Bipolar I Disorder trials with monotherapy aripiprazole, The Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0.50; placebo, -0.01 and aripiprazole, 0.21; placebo, -0.05). Changes in the Assessment of Involuntary Movement Scales were similar for the aripiprazole and placebo groups. In the Bipolar I Disorder trials with aripiprazole in combination with either lithium or valproate, The Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive aripiprazole and combination therapy placebo (aripiprazole, 0.73; placebo, 0.07 and aripiprazole, 0.30; placebo, 0.11). Changes in the Assessment of Involuntary Movement Scales were similar for adjunctive aripiprazole and combination therapy placebo.
In a long-term, double-blind, haloperidol-controlled study in schizophrenia, the incidence of haloperidol-treated patients showing at least one EPS-related adverse event, including dystonia, was significantly greater than that of the aripiprazole group (57% vs 26%; p < 0.001). In a long-term, double-blind, olanzapine-controlled study, the incidence of olanzapine-treated patients showing at least one EPS-related adverse event was comparable to aripiprazole-treated patients (15% vs 15%, respectively; p = n.s.).

Dystonia.

Class effect.

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

ECG changes.

Between group comparisons for pooled, acute, placebo-controlled trials in patients with schizophrenia or Bipolar I Disorder revealed no significant differences between oral aripiprazole and placebo in the proportion of patients experiencing potentially important changes in ECG parameters. In fact, within the dose range of 10 to 30 mg/day, aripiprazole tended to slightly shorten the QTc interval. Aripiprazole was associated with a median increase in heart rate of two beats per minute compared to no increase among placebo patients.
In a 26-week, placebo-controlled trial in schizophrenia, there were no significant differences between aripiprazole and placebo in the proportion of patients experiencing potentially important changes in ECG parameters.

Laboratory test abnormalities.

A between group comparison for acute, 3 to 6-week, placebo-controlled trials in adults revealed no medically important differences between the aripiprazole and placebo groups in the proportions of patients experiencing potentially clinically significant changes in routine serum chemistry, haematology, or urinalysis parameters. Similarly, there were no aripiprazole/placebo differences in the incidence of discontinuations for changes in serum chemistry, haematology, or urinalysis in adult patients.
In a long-term (26-week), placebo-controlled trial, there were no statistically significant differences between the aripiprazole and placebo patients in the mean change from baseline in fasting glucose, triglyceride, LDL, and total cholesterol measurements.

Adverse reactions observed during the premarketing evaluation of oral aripiprazole.

The following is a list of MedRA terms that reflect adverse reactions reported by adult patients treated with oral aripiprazole at multiple doses ≥ 2 mg/day during any phase of a trial within a database of 13,543 adult patients. The listing does not show adverse events mentioned in Table 1, 2 and 3 or in other sections of this prescribing information. It is important to emphasise that although the events reported occurred with treatment they are not necessarily caused by it. The adverse reactions are classified by system organ class and are according to the following definitions: common adverse reactions are those occurring in at least 1/100 patients; uncommon adverse reactions are those occurring in at least 1/1000, but less than 1/100 patients; rare adverse reactions are those occurring in less than 1/1000 patients.

Blood and lymphatic system disorders.

Uncommon: leukopenia, neutropenia, thrombocytopenia; rare - eosinophilia, lymphadenopathy.

Cardiac disorders.

Uncommon - bradycardia, palpitations; cardiopulmonary failure, myocardial infarction, cardio-respiratory arrest, atrioventricular block, extrasystoles, sinus tachycardia, atrial fibrillation, angina pectoris, myocardial ischaemia; rare - atrial flutter, supraventricular tachycardia, ventricular tachycardia.

Ear and labyrinth disorders.

Rare - ear canal erythema, hypoacusis, vertigo positional, tinnitus.

Endocrine disorders.

Rare - early menarche.

Eye disorders.

Uncommon - dry eye; photophobia, diplopia, eyelid oedema, photopsia; rare - eye redness, chromotopsia, conjunctivitis, eye disorder, eye movement disorder, gaze palsy, lacrimation increased.

Gastrointestinal disorders.

Uncommon - diarrhoea, gastritis, dysphagia, gastroesophageal reflux disease, swollen tongue, oesophagitis, hypoaesthesia oral; rare - abdominal distension, abnormal faeces, eructation, faeces discoloured, constipation, gastrointestinal disorder, gastrointestinal pain, glossitis, lip dry, parotid gland enlargement, pruritus ani, tongue discolouration, pancreatitis.

General disorders and administration site conditions.

Common - asthenia, peripheral oedema, irritability, chest pain; uncommon - face oedema, angiodema, gait disturbance, adverse event, chills, discomfort, feeling abnormal, mobility decreased; rare - difficulty in walking, facial pain, swelling, malaise, thirst, chest discomfort, cyst, energy increased, feeling cold, generalised oedema, local swelling, oedema, tenderness, xerosis, hypothermia.

Hepatobiliary disorders.

Rare - hepatitis, jaundice.

Immune system disorders.

Rare - decreased immune responsiveness, hypersensitivity.

Infections and infestations.

Rare - sinusitis, urinary tract infection, body tinea, gastroenteritis viral, herpes simplex, localized infection, lower respiratory tract infection, oral candidiasis, parotitis, gastroenteritis.

Injury, poisoning, and procedural complications.

Common - fall; uncommon - self mutilation; rare - heat stroke, injury, muscle strain, clavicle fracture, femoral neck fracture, hip fracture, humerus fracture, mouth injury, open wound.

Investigations.

Common - weight decreased, creatinine phosphokinase increased; uncommon - weight increased, blood creatinine increased, heart rate increased, blood glucose increased, pyrexia, blood prolactin increased, blood urea increased, electrocardiogram QT prolonged, blood bilirubin increased, hepatic enzyme increased; rare - electrocardiogram abnormal, urine output increased, blood creatine phosphokinase abnormal, orthostatic hypotension, blood urine present, electrocardiogram PR prolongation, electrocardiogram T wave inversion, eosinophil count increased, head lag abnormal, heart rate irregular, physical examination, urine ketone body present, white blood cell count increased, blood lactate dehydrogenase increased, glycosylated haemoglobin increased, gamma-glutamyl transferase increased.

Metabolism and nutrition disorders.

Uncommon - hyperlipidaemia, anorexia, diabetes mellitus (including blood insulin increased, carbohydrate tolerance decreased, diabetes mellitus non-insulin-dependent, glucose tolerance impaired, glycosuria, glucose urine, glucose urine present), hyperglycaemia, hypokalaemia, hypoglycaemia, polydipsia; increased appetite, dehydration, hyponatraemia; rare - diabetic ketoacidosis, hyperuricaemia.

Musculoskeletal and connective tissue disorders.

Uncommon -muscle rigidity, musculoskeletal rigidity, muscle tightness, muscle spasms, muscular weakness, mobility decreased; rare - bone pain, nuchal rigidity, sensation of heaviness, flank pain, jaw disorder, kyphosis, osteoarthritis, rhabdomyolysis.

Neoplasms benign, malignant and unspecified (including cysts and polyps).

Rare - oral neoplasm, skin papilloma.

Nervous system disorders.

Common - coordination abnormal; uncommon - memory impairment, cerebrovascular accident, hypokinesia, hypotonia, myoclonus, hypertonia, akinesia, bradykinesia, drooling, cogwheel rigidity, dystonia, disturbance in attention, dizziness postural, dysarthria, paraesthesia, parkinsonism, psychomotor hyperactivity, hypoaesthesia, speech disorder, tardive dyskinesia; rare - burning sensation, convulsion, depressed level of consciousness, dysgeusia, akinaesthesia, ataxia, bradykinesia, coma, dysphasia, facial palsy, judgement impaired, loss of consciousness, migraine, neuroleptic malignant syndrome, paraesthesia circumoral, sleep phase rhythm disturbance, Grand Mal convulsion, choreoathetosis, unresponsive to verbal stimuli.

Psychiatric disorders.

Common - suicidal ideation; uncommon - aggression, loss of libido, suicide attempt, hostility, libido increased, anger, anorgasmia, delirium, intentional self injury, completed suicide, tic, homicidal ideation, depression, confusional state, nightmare, mania, abnormal dreams, hallucination auditory, nervousness, hallucination, apathy, thinking abnormal, bruxism; rare - catatonia, sleep walking, bradyphrenia, delirium, depressed mood, disorientation, euphoric mood, logorrhea, mental status changes, mood altered, panic attack, sleep disorder, blunted affect, cognitive deterioration, delusional perception, insomnia, eating disorder, emotional distress, impulsive behaviour, asthenia, mood swings, psychomotor retardation, somatoform disorder.

Renal and urinary disorders.

Uncommon - nocturia, polyuria, pollakiuria, incontinence, urinary retention; rare - proteinuria, bladder discomfort, chromaturia, enuresis, micturition urgency, oliguria, urethral discharge, urinary hesitation.

Reproductive system and breast disorders.

Uncommon - erectile dysfunction, amenorrheaf, breast pain, menstruation irregularf; rare - genital pruritus femalef, vulvovaginal discomfortf, pelvic pain, breast discharge, sexual dysfunction, gynaecomastia, priapism.

Respiratory, thoracic and mediastinal disorders.

Common - nasal congestion, dyspnea, pneumonia aspiration; uncommon - hiccups, epistaxis; rare - dry throat, rhinorrhoea, sinus congestion, hoarseness, nasal dryness, painful respiration, paranasal sinus hypersecretion.

Skin and subcutaneous tissue disorders.

Common - rash (including erythematous, exfoliative, generalised, macular, maculopapular, popular rash, acneiform, allergic contact, exfoliative seborrheic dermatitis, neurodermatitis, and drug eruption), hyperhydrosis; uncommon - pruritus, photosensitivity reaction, alopecia, urticaria; rare - decubitus ulcer, face oedema, pemphigus, psoriasis, dry skin.

Social circumstances.

Rare - smoker.

Vascular disorders.

Common - hypertension; uncommon - hypotension, hot flush, rare - flushing, hyperaemia.
f(female) Indicates incidence based on gender total.

Postmarketing experience.

The following adverse reactions have been identified during post-approval use of aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angiodema, laryngospasm, pruritis/urticaria, or oropharyngeal spasm), and blood glucose fluctuation. Very rare occurrences of increased AST and increased ALT and hiccups have been reported.

Psychiatric disorders.

Uncommon - hypersexuality; unknown - pathological gambling, impulse-control disorders, obsessive-compulsive disorders, eating disorders.

Eye disorders.

Not known - Oculogyric crisis.

Drug abuse and dependence.

Aripiprazole has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. In self-administration studies in rats and monkeys, aripiprazole demonstrated marginal to no abuse potential. In physical dependence studies in rats and monkeys, modest withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behaviour, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse and such patients should be observed closely for signs of aripiprazole misuse or abuse (e.g. development of tolerance, increases in dose, drug-seeking behaviour).

4.2 Dose and Method of Administration

Tevaripiprazole is available as 5 mg, 10 mg, 15 mg, 20 mg and 30 mg tablets for oral administration.

Recommended dosage.

Schizophrenia.

Adults.

The recommended starting dose for aripiprazole tablets is 10 or 15 mg/day administered on a once-a-day schedule without regard to meals. Doses in the range of 10 to 30 mg/day have been effective in clinical trials. Daily dosage may be adjusted on the basis of individual clinical status within the range of 10-30 mg daily. Dosage increases should not be made before 2 weeks, the time needed to achieve steady state. There is no evidence that doses higher than 15 mg/day are more effective than the recommended starting dose of 10-15 mg.
The maintenance dose for aripiprazole tablets is 15 mg/day.

Renal impairment.

No dosage adjustment is required in adult patients with renal impairment.

Hepatic impairment.

No dosage adjustment is required for adult patients with hepatic impairment (Child-Pugh Class A, B or C).

Elderly.

No dosage adjustment is required for patients ≥ 65 years of age.

Gender.

No dosage adjustment is required for female adult patients relative to male adult patients.

Concomitant medications.

Dosage adjustment for patients taking aripiprazole concomitantly with potential CYP3A4 inhibitors.

When concomitant administration of a potent CYP3A4 inhibitor such as ketoconazole, itraconazole, clarithromycin and HIV protease inhibitors with aripiprazole occurs, the aripiprazole dose should be decreased. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should then be increased.

Dosage adjustment for patients taking aripiprazole concomitantly with potential CYP2D6 inhibitors.

When concomitant administration of potential CYP2D6 inhibitors such as quinidine, fluoxetine, or paroxetine with aripiprazole occurs, the aripiprazole dose should be halved. When the CYP2D6 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should then be increased.

Dosage adjustment for patients taking aripiprazole concomitantly with multiple medications that inhibit CYP3A4 and CYP2D6.

Although no clinical studies have been conducted in which aripiprazole was taken together with multiple drugs that inhibit CYP3A4 and CYP2D6, consideration should be given to reducing the daily dose of aripiprazole in individual circumstances.

Dosage adjustment for patients taking aripiprazole concomitantly with potential CYP3A4 inducers.

When a potent CYP3A4 inducer such as carbamazepine is added to aripiprazole therapy, the aripiprazole dose should be increased. Additional dose increases should be based on clinical evaluation. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should then be reduced.

Smoking status.

No dosage adjustment is required for smoking patients relative to non-smoking patients.

Switching from other antipsychotics.

Data was prospectively and systematically collected to address the safety of switching from other antipsychotics to aripiprazole (30 mg/day). These data indicate that any of the following methods can be used safely for switching patients to aripiprazole from another antipsychotic monotherapy:
immediate discontinuation of the patient's current antipsychotic regimen and immediate initiation of aripiprazole;
immediate initiation of aripiprazole while tapering off the current antipsychotic regimen over a 2-week period;
upward titration of aripiprazole over a 2-week period and simultaneous tapering off of the patient's current antipsychotic regimen over the same 2-week period.

4.7 Effects on Ability to Drive and Use Machines

As with other antipsychotics, patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that aripiprazole does not affect them adversely.

4.9 Overdose

Human experience.

In clinical studies, and postmarketing experience accidental or intentional acute overdosage of aripiprazole alone was identified in adult patients with estimated doses up to 1260 mg with no fatalities. The potentially medically important signs and symptoms observed in adult patients who overdosed with aripiprazole alone at doses up to 1260 mg included lethargy, blood pressure increased, somnolence, tachycardia and vomiting. In addition, reports of accidental overdose with aripiprazole alone (up to 195 mg) in children have been received. The potentially medically serious signs and symptoms reported include somnolence, and transient loss of consciousness. In the patients who were evaluated in hospital settings, there were no reported observations indicating a clinically significant adverse change in vital signs, laboratory assessments, or ECG.

Management of overdosage.

No specific information is available on the treatment of overdose with aripiprazole. The possibility of multiple drug involvement should be considered. Therefore cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. 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.

Charcoal.

In the event of an overdose of aripiprazole, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole. In a single-dose study in which 15 mg of aripiprazole was administered to fully compliant, fully conscious, healthy, male volunteers and followed by activated charcoal (50 g), administered one hour after aripiprazole, aripiprazole AUC and Cmax was decreased by 51 and 41%, respectively, compared to historic controls, suggesting that charcoal may be effective for overdose management.

Haemodialysis.

Although there is no information on the effect of haemodialysis in treating an overdose with aripiprazole, haemodialysis is unlikely to be useful in overdose management, since aripiprazole is not eliminated unchanged by the kidneys and is highly bound to plasma proteins.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).

6 Pharmaceutical Particulars

6.1 List of Excipients

The inactive ingredients in the tablets are: lactose monohydrate, maize starch, microcrystalline cellulose, hyprolose, magnesium stearate and croscarmellose sodium. The following colorants are also contained in the tablets: 5 mg tablets - iron oxide yellow; 10 mg tablets - iron oxide red; 15 mg tablets - iron oxide yellow; 20 mg tablets - nil; 30 mg tablets - iron oxide red.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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 25°C.

6.5 Nature and Contents of Container

Tevaripiprazole tablets are available in OPA/Al/PVC-Al blister in cartons in a pack size of 30 tablets.

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