Aripiprazole 1mgml oral solution

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Aripiprazole
Available from:
Mylan
ATC code:
N05AX12
INN (International Name):
Aripiprazole
Dosage:
1mg/1ml
Pharmaceutical form:
Oral solution
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 04020100; GTIN: 5016695006925
Authorization number:
PL 04569/1667

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Package leaflet: Information for the patient

Aripiprazole 1 mg/ml oral solution

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Aripiprazole is and what it is used for

What you need to know before you take Aripiprazole

How to take Aripiprazole

Possible side effects

How to store Aripiprazole

Contents of the pack and other information

1.

What Aripiprazole is and what it is used for

Aripiprazole contains the active substance aripiprazole, which belongs to a group of medicines called

antipsychotics. It

is used to treat adults and adolescents aged 15 years and older who suffer from a

disease characterised by symptoms such as hearing, seeing or sensing things which are not there,

suspiciousness, mistaken beliefs, incoherent speech and behaviour and emotional flatness. People with

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

Aripiprazole is used to treat adults and adolescents aged 13 years and older who suffer from a

condition with symptoms such as feeling "high", having excessive amounts of energy, needing much

less sleep than usual, talking very quickly with racing ideas and sometimes severe irritability. In adults

it also prevents this condition from returning in patients who have responded to the treatment with

Aripiprazole.

2.

What you need to know before you take Aripiprazole

Do not take Aripiprazole:

if you are allergic to aripiprazole or any of the other ingredients of this medicine (listed in

section 6).

Warnings and precautions

Talk to your doctor or pharmacist before taking Aripiprazole if you suffer from or have ever suffered

from:

high blood sugar (characterised by symptoms such as excessive thirst, passing of large amounts

of urine, increase in appetite, and feeling weak) or family history of diabetes

seizures

involuntary, irregular muscle movements, especially in the face

heart diseases, family history of heart disease, heart failure, abnormal heart rhythm, stroke or

"mini" stroke

conditions which would lead to reduced blood pressure such as loss of fluid, reduced blood

volume and use of blood pressure lowering medicines

increased blood pressure

blood clots, or family history of blood clots, as antipsychotics have been associated with

formation of blood clots

past experience of excessive gambling

a condition known as Attention-deficit hyperactivity disorder (ADHD) (with symptoms such as

difficulty in maintaining focus on one task, struggle to follow instructions, hyperactive) and are

taking medicines to treat this condition.

During treatment

If you notice you are gaining weight, develop unusual movements, experience sleepiness that

interferes with normal daily activities, any difficulty in swallowing or allergic symptoms, please tell

your doctor.

Tell your doctor if you suffer from shaking, decreased heart rate, muscle stiffness and balance

disorders while on treatment with this medicine. These may be signs of a condition known as

parkinsonism.

If you are an elderly patient suffering from Alzheimer’s disease, dementia (loss of memory and other

mental abilities), you or your carer/relative should tell your doctor if you have ever had a stroke or

"mini" stroke.

Tell your doctor immediately if you are having any thoughts or feelings about hurting yourself.

Suicidal thoughts and behaviours have been reported during aripiprazole treatment.

Tell your doctor immediately if you suffer from muscle stiffness or inflexibility with high fever,

sweating, altered mental status, or very rapid or irregular heartbeat. Your doctor may consider

stopping your treatment with aripiprazole.

Children and adolescents

Aripiprazole is not recommended for use in children and adolescents under 13 years and for treating

schizophrenia in children under 15 years. Ask your doctor or pharmacist for advice before taking

Aripiprazole.

Other medicines and Aripiprazole

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines.

Blood pressure-lowering medicines: Aripiprazole may increase the effect of medicines used to lower

the blood pressure. Be sure to tell your doctor if you take a medicine to keep your blood pressure

under control.

If you are taking Aripiprazole with some other medicines, you may need to change your dose of

Aripiprazole. It is especially important to mention the following to your doctor:

quinidine (medicines to correct heart rhythm)

escitalopram, fluoxetine (antidepressant), cimetidine (used to treat stomach ulcers) or herbal

remedy used to treat depression and anxiety

ketoconazole, itraconazole (antifungal agents)

medicines that may cause changes in hearth rhythm which may be seen in tests (such as

alfuzosin, amiodarone, chloroquine)

medicines that may alter the level of blood salts (such as hydrocortisone, prednisolone,

furosemide)

certain medicines to treat HIV infection (such as ritonavir, indinavir, nelfinavir, efavirenz,

nevirapine)

diltiazem, carbamazepine, phenytoin, phenobarbital, primidone (anticonvulsants used to treat

epilepsy).

rifampicin and rifabutin ( antibiotic used to treat tuberculosis)

Medicines that increase the level of serotonin: triptans, tramadol, tryptophan, SSRIs (such as

paroxetine and fluoxetine), tricyclics (such as clomipramine, amitriptyline), pethidine, St John’s Wort

and venlafaxine. These medicines increase the risk of side effects; if you get any unusual symptoms

taking any of these medicines together with Aripiprazole, you should see your doctor.

Aripiprazole with alcohol

Alcohol should be avoided when taking Aripiprazole.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask

your doctor or pharmacist for advice before taking this medicine.

Pregnancy

The following symptoms may occur in newborn babies, of mothers that have used Aripiprazole in the

last trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness,

sleepiness, agitation, breathing problems, and difficulty in feeding. If your baby develops any of these

symptoms you may need to contact your doctor.

Breast-feeding

Be sure to tell your doctor immediately if you are breast-feeding. If you are taking Aripiprazole, you

should not breast-feed.

Driving and using machines

Do not drive or use any tools or machines until you know how Aripiprazole affects you.

3.

How to take Aripiprazole

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor

or pharmacist if you are not sure.

The recommended dose for adults is 10 ml or 15 ml solution (corresponding to 10 mg or 15 mg

aripiprazole) once a day.

However your doctor may prescribe a lower or higher dose to a maximum

of 30 ml (i.e. 30 mg) once a day.

Elderly

If you are elderly your doctor may start your treatment with a dose lower than the recommended dose.

Patients with liver problems

Tell your doctor if you are suffering from severe liver problems as your doctor may need to adjust the

dose of your medicine.

Use in children and adolescents

Aripiprazole may be started at a low dose with the oral solution (liquid) form. This should be given

using the 5 ml graduated oral syringe supplied in the carton. The dose may be gradually increased to

the recommended dose for adolescents of 10 ml once a day

However your doctor may prescribe a lower or higher dose to a maximum of 30 ml once a day.

Measuring dose

The dose of Aripiprazole oral solution must be measured using the graduated 30 ml cup or the 5 ml

graduated oral syringe supplied in the carton.

Open the bottle and make sure that the syringe is firmly inserted into the adaptor (Figure 1).

Turn the bottle upside down with the syringe still in place (Figure 2).

Pull the plunger down and fill the syringe with a quantity of solution slightly beyond the prescribed

dose (Figure 3).

If any bubbles appear in the syringe, keep the bottle upside down and slightly push in the plunger and

pull it back again. Repeat until there are no bubbles in the syringe (Figure 4).

Push the plunger in slowly to the graduation mark corresponding to the quantity in millilitres (ml)

prescribed by your doctor (Figure 5).

Turn the bottle the right way up and remove the syringe (Figure 6).

Wash the syringe and the cup with water after use and close the bottle with the plastic screw cap.

If you have the impression that the effect of Aripiprazole is too strong or too weak, talk to your doctor

or pharmacist.

Try to take the Aripiprazole oral solution at the same time each day.

It does not matter whether

you take it with or without food. However, you should not dilute with other liquids or mix with other

food prior to taking Aripiprazole oral solution.

Even if you feel better,

do not alter or discontinue the daily dose of Aripiprazole without first

consulting your doctor.

If you take more Aripiprazole than you should

If you realise you have taken more Aripiprazole oral solution than your doctor has recommended (or if

someone else has taken some of your Aripiprazole oral solution), contact your doctor right away. If

you cannot reach your doctor, go to the nearest hospital and take the pack with you. Signs and

symptoms of overdose may include unusual tiredness, increased blood pressure, feeling sleepy, fast

heart rate, feeling sick (nausea), diarrhoea and being sick (vomiting).

If you forget to take Aripiprazole

If you miss a dose, take the missed dose as soon as you remember but do not take a double dose to

make up for a forgotten dose.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop taking Aripiprazole and contact your doctor immediately or go to your nearest hospital

emergency room if you have any of the following:

Not known

(frequency cannot be estimated from the available data):

changes in the levels of some blood cells, which can be seen on a blood test and lead to getting

more infections than normal

heart attack

unusual heart beat or abnormal heart rhythm which may be seen in tests

allergic reaction (e.g. swelling in the mouth, tongue, face and throat, difficulty in breathing and

swallowing, itching, rash)

ketoacidosis (ketones in the blood and urine) or coma

suicide, thoughts of suicide, suicide attempt

seizures

serotonin syndrome (a reaction which may cause feelings of great happiness, drowsiness,

clumsiness, restlessness, feeling of being drunk, fever, sweating or rigid muscles)

combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness and

sudden changes in blood pressure and heart rate

blood clots in the veins especially in the legs (symptoms include swelling, pain and redness in the

leg), which may travel through blood vessels to the lungs causing chest pain and difficulty in

breathing

accidental inhalation of food with risk of pneumonia

inflammation of the pancreas

difficulty in passing urine (urinary retention)

liver failure, inflammation of the liver, yellowing of the skin and white part of eyes

muscle weakness, tenderness or pain and particularly, if at the same time, you feel unwell or have

a high temperature it may be caused by an abnormal muscle breakdown which can be life-

threatening and lead to kidney problems.

Other possible side effects:

Common (may affect up to 1 in 10 people)

uncontrollable twitching, jerking or writhing movements, restless legs

feeling restless and unable to keep still, difficulty sitting still

headache

light-headedness

sleepiness

shaking

tiredness

diabetes mellitus

feeling sick (nausea), being sick (vomiting), indigestion, constipation, increased production of

saliva

trouble sleeping, feeling anxious

blurred vision.

Uncommon (may affect up to 1 in 100 people)

some people may feel dizzy, especially when getting up from a lying or sitting position

may experience a fast heart rate or double vision

some people may feel depressed

increased or altered sexual interest

increased levels of the hormone prolactin

decreased blood pressure

high blood sugar which may be seen in blood tests

muscle disorder causing twisting movements (dystonia)

uncontrollable movements of the mouth tongue and limbs (tardive dyskinesia)

hiccups.

The following side effects have been reported since the marketing of aripiprazole but the frequency for

them to occur is not known (frequency cannot be estimated from the available data):

sudden unexplained death

decreased heart rate

low sodium level in the blood

weight gain, weight loss, loss of appetite (anorexia)

nervousness, agitation, aggression, excessive gambling, speech disorder

fainting, high blood pressure

spasm of the muscles around the voice box, difficulty in swallowing

reduction in blood platelets resulting in bleeding or bruising more easily than normal

reports of abnormal liver test values, abdominal and stomach discomfort, diarrhoea

skin rash and sensitivity to light, unusual hair loss or thinning, excessive sweating; stiffness or

cramps, muscle pain

involuntary loss of urine

prolonged and/or painful erection

difficulty controlling core body temperature or overheating, chest pain, and swelling of hands,

ankles or feet

increased or fluctuating blood sugar and other changes which may be seen in blood tests.

In elderly patients with dementia, more fatal cases have been reported while taking aripiprazole. In

addition, cases of stroke or "mini" stroke have been reported.

Additional side effects in children and adolescents

Adolescents aged 13 years and older experienced side effects that were similar in frequency and type

to those in adults except that sleepiness, uncontrollable twitching or jerking movements, restlessness,

and tiredness were very common (greater than 1 in 10 patients) and upper abdominal pain, dry mouth,

increased heart rate, weight gain, increased appetite, muscle twitching, uncontrolled movements of the

limbs, and feeling dizzy, especially when getting up from a lying or sitting position, were common

(greater than 1 in 100 patients).

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on

the safety of this medicine.

5.

How to store Aripiprazole

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the bottle and on the carton after

EXP. The expiry date refers to the last day of that month.

After first opening: Use within 6 months.

Do not refrigerate or freeze. Store in the original package in order to protect from light.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Aripiprazole contains

The active substance is aripiprazole. Each ml contains 1 mg of aripiprazole.

The other ingredients are disodium edetate; erythritol (E 968); hypromellose; macrogol 4000;

phosphoric acid, concentrated; propylene glycol (E 1520); sodium benzoate (E 211); sucralose

(E 955); water, purified, grape flavour.

What Aripiprazole looks like and contents of the pack

Aripiprazole 1 mg/ml oral solution is a clear, colourless liquid.

Aripiprazole is supplied in amber glass or plastic bottles with child-resistant caps. Each bottle contains

150 ml of Aripiprazole, and is placed in a cardboard carton. Each carton also contains a 5 ml syringe

(graduated at every 0.5 ml) and a 30 ml measuring cup (graduated at every 5 ml).

Marketing Authorisation Holder

Mylan, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom.

Manufacturer

Balkanpharma – Troyan AD, 1 Krayrechna Str., Troyan, 5600, Bulgaria.

This leaflet was last revised in 08/2017

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Object 1

Aripiprazole 1 mg/ml oral solution

Summary of Product Characteristics Updated 21-May-2018 | Generics UK T/A Mylan

1. Name of the medicinal product

Aripiprazole 1 mg/ml oral solution

2. Qualitative and quantitative composition

Each ml contains 1 mg of aripiprazole.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Oral solution.

A clear, colourless liquid.

4. Clinical particulars

4.1 Therapeutic indications

Aripiprazole is indicated for the treatment of schizophrenia in adults and in adolescents aged 15 years and

older.

Aripiprazole is indicated for the treatment of moderate to severe manic episodes in Bipolar I Disorder and

for the prevention of a new manic episode in adults who experienced predominantly manic episodes and

whose manic episodes responded to aripiprazole treatment (see section 5.1).

Aripiprazole is indicated for the treatment up to 12 weeks of moderate to severe manic episodes in

Bipolar I Disorder in adolescents aged 13 years and older (see section 5.1).

4.2 Posology and method of administration

Posology

Adults

Schizophrenia: the recommended starting dose for Aripiprazole is 10 or 15 mg/day (i.e. 10 or 15 ml

solution/day) with a maintenance dose of 15 mg/day administered on a once-a-day schedule without

regard to meals. Aripiprazole is effective in a dose range of 10 to 30 mg/day (i.e. 10 to 30 ml

solution/day). Enhanced efficacy at doses higher than a daily dose of 15 mg has not been demonstrated

although individual patients may benefit from a higher dose. The maximum daily dose should not exceed

30 mg.

Manic episodes in Bipolar I Disorder: the recommended starting dose for Aripiprazole is 15 mg (i.e. 15

ml solution/day) administered on a once-a-day schedule without regard to meals as monotherapy or

combination therapy (see section 5.1). Some patients may benefit from a higher dose. The maximum

daily dose should not exceed 30 mg (i.e. 30 ml solution/day).

Recurrence prevention of manic episodes in Bipolar I Disorder: for preventing recurrence of manic

episodes in patients who have been receiving aripiprazole as monotherapy or combination therapy,

continue therapy at the same dose. Adjustments of daily dosage, including dose reduction should be

considered on the basis of clinical status.

Aripiprazole oral solution may be used as an alternative to aripiprazole tablets for patients who have

difficulty swallowing aripiprazole tablets (see section 5.2).

Special population

Paediatric population

Schizophrenia in adolescents aged 15 years and older: the recommended dose for Aripiprazole is 10

mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2

mg (using Aripiprazole oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach

the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be

administered in 5 mg increments without exceeding the maximum daily dose of 30 mg (see section 5.1).

Aripiprazole is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a

daily dose of 10 mg has not been demonstrated although individual patients may benefit from a higher

dose.

Aripiprazole is not recommended for use in patients with schizophrenia below 15 years of age due to

insufficient data on safety and efficacy (see sections 4.8 and 5.1).

Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older: the recommended dose for

Aripiprazole is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment

should be initiated at 2 mg (using Aripiprazole oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2

additional days to reach the recommended daily dose of 10 mg. The treatment duration should be the

minimum necessary for symptom control and must not exceed 12 weeks. Enhanced efficacy at doses

higher than a daily dose of 10 mg has not been demonstrated, and a daily dose of 30 mg is associated with

a substantially higher incidence of significant undesirable effects including EPS related events,

somnolence, fatigue and weight gain (see section 4.8). Doses higher than 10 mg/day should therefore only

be used in exceptional cases and with close clinical monitoring (see sections 4.4, 4.8 and 5.1).

Younger patients are at increased risk of experiencing adverse events associated with aripiprazole.

Therefore, aripiprazole is not recommended for use in patients below 13 years of age (see sections 4.8 and

5.1).

Irritability associated with autistic disorder: the safety and efficacy of aripiprazole in children and

adolescents aged below 18 years have not yet been established. Currently available data are described in

section 5.1 but no recommendation on a posology can be made.

Tics associated with Tourette's disorder: the safety and efficacy of aripiprazole in children and

adolescents 6 to 18 years of age have not yet been established. Currently available data are described in

section 5.1 but no recommendation on a posology can be made.

Hepatic impairment

No dosage adjustment is required for patients with mild to moderate hepatic impairment. In patients with

severe hepatic impairment, the data available are insufficient to establish recommendations. In these

patients dosing should be managed cautiously. However, the maximum daily dose of 30 mg should be

used with caution in patients with severe hepatic impairment (see section 5.2).

Renal impairment

No dosage adjustment is required in patients with renal impairment.

Elderly

The effectiveness of aripiprazole in the treatment of schizophrenia and Bipolar I Disorder in patients aged

65 years and older has not been established. Owing to the greater sensitivity of this population, a lower

starting dose should be considered when clinical factors warrant (see section 4.4).

Gender

No dosage adjustment is required for female patients as compared to male patients (see section 5.2).

Smoking status

According to the metabolic pathway of aripiprazole no dosage adjustment is required for smokers (see

section 4.5).

Dose adjustments due to interactions

When concomitant administration of potent CYP3A4 or CYP2D6 inhibitors with aripiprazole occurs, the

aripiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the

combination therapy, aripiprazole dose should then be increased (see section 4.5).

When concomitant administration of potent CYP3A4 inducers with aripiprazole occurs, the aripiprazole

dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the

aripiprazole dose should then be reduced to the recommended dose (see section 4.5).

Method of administration

Aripiprazole oral solution is for oral use.

A 30 ml graduated measuring cup and a graduated 5 ml oral syringe are included in the carton.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to

some weeks. Patients should be closely monitored throughout this period.

Suicidality

The occurrence of suicidal behaviour is inherent in psychotic illnesses and mood disorders and in some

cases has been reported early after initiation or switch of antipsychotic treatment, including treatment

with aripiprazole (see section 4.8). Close supervision of high-risk patients should accompany

antipsychotic therapy.

Results of an epidemiological study suggested that there was no increased risk of suicidality with

aripiprazole compared to other antipsychotics among adult patients with schizophrenia or bipolar

disorder. There are insufficient paediatric data to evaluate this risk in younger patients (below 18 years of

age), but there is evidence that the risk of suicide persists beyond the first 4 weeks of treatment for

atypical antipsychotics, including aripiprazole.

Cardiovascular disorders

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, conditions which would predispose patients to hypotension (dehydration,

hypovolemia, and treatment with antihypertensive medicinal products) or hypertension, including

accelerated or malignant.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products.

Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible

risk factors for VTE should be identified before and during treatment with aripiprazole and preventive

measures undertaken.

QT prolongation

In clinical trials of aripiprazole, the incidence of QT prolongation was comparable to placebo. As with

other antipsychotics, aripiprazole should be used with caution in patients with a family history of QT

prolongation (see section 4.8).

Tardive dyskinesia

In clinical trials of one year or less duration, there were uncommon reports of treatment emergent

dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a

patient on aripiprazole, dose reduction or discontinuation should be considered (see section 4.8). These

symptoms can temporally deteriorate or can even arise after discontinuation of treatment.

Other extrapyramidal symptoms

In paediatric clinical trials of aripiprazole akathisia and parkinsonism were observed. If signs and

symptoms of other EPS appear in a patient taking aripiprazole, dose reduction and close clinical

monitoring should be considered.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially fatal symptom complex associated with antipsychotic medicinal products. In clinical

trials, rare cases of NMS were reported during treatment with aripiprazole. Clinical manifestations of

NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability

(irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs

may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS,

have also been reported. If a patient develops signs and symptoms indicative of NMS, or presents with

unexplained high fever without additional clinical manifestations of NMS, all antipsychotic active

substances, including aripiprazole, must be discontinued.

Seizure

In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore,

aripiprazole should be used with caution in patients who have a history of seizure disorder or have

conditions associated with seizures (see section 4.8).

Elderly patients with dementia-related psychosis

Increased mortality

In three placebo-controlled trials (n = 938; mean age: 82.4 years; range: 56to 99 years) of aripiprazole in

elderly patients with psychosis associated with Alzheimer's disease, patients treated with aripiprazole

were at increased risk of death compared to placebo. The rate of death in aripiprazole-treated patients was

3.5 % compared to 1.7 % in the placebo group. Although the causes of deaths were varied, most of the

deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g.

pneumonia) in nature (see section 4.8).

Cerebrovascular adverse reactions

In the same trials, cerebrovascular adverse reactions (e.g. stroke, transient ischaemic attack), including

fatalities, were reported in patients (mean age: 84 years; range: 78 to 88 years). Overall, 1.3 % of

aripiprazole-treated patients reported cerebrovascular adverse reactions compared with 0.6 % of placebo-

treated patients in these trials. This difference was not statistically significant. However, in one of these

trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse

reactions in patients treated with aripiprazole (see section 4.8).

Aripiprazole is not indicated for the treatment of dementia-related psychosis.

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death,

has been reported in patients treated with atypical antipsychotic medicinal products, including

aripiprazole. Risk factors that may predispose patients to severe complications include obesity and family

history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the

incidence rates of hyperglycaemia-related adverse reactions (including diabetes) or in abnormal

glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related

adverse reactions in patients treated with aripiprazole and with other atypical antipsychotic medicinal

products are not available to allow direct comparisons. Patients treated with any antipsychotic medicinal

products, including aripiprazole, should be observed for signs and symptoms of hyperglycaemia (such as

polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for

diabetes mellitus should be monitored regularly for worsening of glucose control (see section 4.8).

Hypersensitivity

As with other medicinal products, hypersensitivity reactions, characterised by allergic symptoms, may

occur with aripiprazole (see section 4.8).

Weight gain

Weight gain is commonly seen in schizophrenic and bipolar mania patients due to co-morbidities, use of

antipsychotics known to cause weight gain, poorly managed life-style, and might lead to severe

complications. Weight gain has been reported post-marketing among patients prescribed aripiprazole.

When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder

or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant

weight gain in adults (see section 5.1). In clinical trials of adolescent patients with bipolar mania,

aripiprazole has been shown to be associated with weight gain after 4 weeks of treatment. Weight gain

should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant,

dose reduction should be considered (see section 4.8).

Dysphagia

Oesophageal dysmotility and aspiration have been associated with antipsychotic medicinal product use,

including aripiprazole. Aripiprazole and other antipsychotic active substances should be used cautiously

in patients at risk for aspiration pneumonia.

Pathological gambling

Post-marketing reports of pathological gambling have been reported among patients prescribed

aripiprazole, regardless of whether these patients had a prior history of gambling. Patients with a prior

history of pathological gambling may be at increased risk and should be monitored carefully (see section

4.8).

Patients with ADHD comorbidity

Despite the high comorbidity frequency of Bipolar I Disorder and ADHD, very limited safety data are

available on concomitant use of aripiprazole and stimulants; therefore, extreme caution should be taken

when these medicinal products are co-administered.

4.5 Interaction with other medicinal products and other forms of interaction

Due to its α

-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of

certain antihypertensive agents.

Given the primary CNS effects of aripiprazole, caution should be used when aripiprazole is taken in

combination with alcohol or other CNS medicinal products with overlapping adverse reactions such as

sedation (see section 4.8).

If aripiprazole is administered concomitantly with medicinal products known to cause QT prolongation or

electrolyte imbalance, caution should be used.

Potential for other medicinal products to affect aripiprazole

A gastric acid blocker, the H2 antagonist famotidine, reduces aripiprazole rate of absorption but this

effect is deemed not clinically relevant.

Aripiprazole is metabolised by multiple pathways involving the CYP2D6 and CYP3A4 enzymes but not

CYP1A enzymes. Thus, no dosage adjustment is required for smokers.

Quinidine and other CYP2D6 inhibitors

In a clinical trial in healthy subjects, a potent inhibitor of CYP2D6 (quinidine) increased aripiprazole

AUC by 107 %, while C

was unchanged. The AUC and C

of dehydro-aripiprazole, the active

metabolite, decreased by 32 % and 47 % respectively. Aripiprazole dose should be reduced to

approximately one-half of its prescribed dose when concomitant administration of aripiprazole with

quinidine occurs. Other potent inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected

to have similar effects and similar dose reductions should therefore be applied.

Ketoconazole and other CYP3A4 inhibitors

In a clinical trial in healthy subjects, a potent inhibitor of CYP3A4 (ketoconazole) increased aripiprazole

AUC and C

by 63 % and 37 %, respectively. The AUC and C

of dehydro-aripiprazole increased by

77 % and 43 %, respectively. In CYP2D6 poor metabolisers, concomitant use of potent inhibitors of

CYP3A4 may result in higher plasma concentrations of aripiprazole compared to that in CYP2D6

extensive metabolizers. When considering concomitant administration of ketoconazole or other potent

CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the potential risks to the patient.

When concomitant administration of ketoconozole with aripiprazole occurs, aripiprazole dose should be

reduced to approximately one-half of its prescribed dose. Other potent inhibitors of CYP3A4, such as

itraconazole and HIV protease inhibitors, may be expected to have similar effects and similar dose

reductions should therefore be applied.

Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dosage of aripiprazole should be

increased to the level prior to the initiation of the concomitant therapy.

When weak inhibitors of CYP3A4 (e.g. diltiazem or escitalopram) or CYP2D6 are used concomitantly

with aripiprazole, modest increases in aripiprazole concentrations might be expected.

Carbamazepine and other CYP3A4 inducers

Following concomitant administration of carbamazepine, a potent inducer of CYP3A4, the geometric

means of C

and AUC for aripiprazole were 68 % and 73 % lower, respectively, compared to when

aripiprazole (30 mg) was administered alone. Similarly, for dehydro-aripiprazole the geometric means of

and AUC after carbamazepine co-administration were 69 % and 71 % lower, respectively, than

those following treatment with aripiprazole alone.

Aripiprazole dose should be doubled when concomitant administration of Aripiprazole occurs with

carbamazepine. Other potent inducers of CYP3A4 (such as rifampicin, rifabutin, phenytoin,

phenobarbital, primidone, efavirenz, nevirapine and St. John's Wort) may be expected to have similar

effects and similar dose increases should therefore be applied. Upon discontinuation of potent CYP3A4

inducers, the dosage of aripiprazole should be reduced to the recommended dose.

Valproate and lithium

When either valproate or lithium were administered concomitantly with aripiprazole, there was no

clinically significant change in aripiprazole concentrations.

Serotonin syndrome

Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and

symptoms for this condition can occur especially in cases of concomitant use with other serotonergic

medicinal products, such as SSRI/SNRI, or with medicinal products that are known to increase

aripiprazole concentrations (see section 4.8).

Potential for aripiprazole to affect other medicinal products

In clinical studies, 10 to 30 mg/day doses of aripiprazole had no significant effect on the metabolism of

substrates of CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), CYP2C9 (warfarin), CYP2C19

(omeprazole), and CYP3A4 (dextromethorphan). Additionally, aripiprazole and dehydroaripiprazole did

not show potential for altering CYP1A2-mediated metabolism in vitro. Thus, aripiprazole is unlikely to

cause clinically important medicinal product interactions mediated by these enzymes.

When aripiprazole was administered concomitantly with either valproate, lithium or lamotrigine, there

was no clinically important change in valproate, lithium or lamotrigine concentrations.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies

have been reported; however, causal relationship with aripiprazole could not be established. Animal

studies could not exclude potential developmental toxicity (see section 5.3). Patients should be advised to

notify their physician if they become pregnant or intend to become pregnant during treatment with

aripiprazole. Due to insufficient safety information in humans and concerns raised by animal reproductive

studies, this medicinal product should not be used in pregnancy unless the expected benefit clearly

justifies the potential risk to the foetus.

Newborn infants exposed to antipsychotics (including aripiprazole) during the third trimester of

pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that

may vary in severity and duration following delivery. There have been reports of agitation, hypertonia,

hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborn infants

should be monitored carefully.

Breast-feeding

Aripiprazole is excreted in human milk. Patients should be advised not to breast-feed if they are taking

aripiprazole.

4.7 Effects on ability to drive and use machines

As with other antipsychotics, patients should be cautioned about operating hazardous machines, including

motor vehicles, until they are reasonably certain that aripiprazole does not affect them adversely. Some

paediatric patients with Bipolar I Disorder have an increased incidence of somnolence and fatigue (see

section 4.8).

4.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions in placebo-controlled trials are akathisia and nausea each

occurring in more than 3 % of patients treated with oral aripiprazole.

Tabulated list of adverse reactions

All ADRs are listed by system organ class and frequency; very common (≥ 1/10), common (≥ 1/100 to <

1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not

known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions

are presented in order of decreasing seriousness.

The frequency of adverse reactions reported during post-marketing use cannot be determined as they are

derived from spontaneous reports. Consequently, the frequency of these adverse events is qualified as

"not known"

Common

Uncommon

Not known

Blood and lymphatic

system disorders

Leukopenia

Neutropenia

Thrombocytopenia

Immune system

disorders

Allergic reaction (e.g.

anaphylactic reaction,

angioedema including

swollen tongue, tongue

oedema, face oedema,

pruritus or urticaria)

Endocrine disorders

Hyperprolactinaemia

Diabetic hyperosmolar

coma

Diabetic ketoacidosis

Metabolism and

nutrition disorders

Diabetes mellitus

Hyperglycaemia

Hyponatremia

Anorexia

Weight decreased

Weight gain

Psychiatric disorders

Insomnia

Anxiety

Restlessness

Depression,

Hypersexuality

Suicide attempt, suicidal

ideation and completed

suicide (see section 4.4)

Pathological gambling

Aggression

Agitation

Nervousness

Nervous system

disorders

Akathisia

Extrapyramidal disorder

Tremor

Headache

Sedation

Somnolence

Dizziness

Tardive dyskinesia

Dystonia

Neuroleptic Malignant

Syndrome (NMS)

Grand mal convulsion

Serotonin syndrome

Speech disorder

Eye disorders

Vision blurred

Diplopia

Cardiac disorders

Tachycardia

Sudden unexplained death

Torsades de pointes

QT prolongation

Ventricular arrhythmias

Cardiac arrest

Bradycardia

Vascular disorders

Orthostatic

hypotension

Venous thromboembolism

(including pulmonary

embolism and deep vein

thrombosis)

Hypertension

Syncope

Respiratory, thoracic

and mediastinal

Hiccups

Aspiration pneumonia

disorders

Laryngospasm

Oropharyngeal spasm

Gastrointestinal

disorders

Constipation

Dyspepsia

Nausea

Salivary hypersecretion

Vomiting

Pancreatitis

Dysphagia

Diarrhoea

Abdominal discomfort

Stomach discomfort

Hepatobiliary disorders

Hepatic failure

Hepatitis

Jaundice

Increased Alanine

Aminotransferase (ALT)

Increased Aspartate

Aminotransferase (AST)

Increased Gamma Glutamyl

Transferase (GGT)

Increased alkaline

phosphatase

Skin and subcutaneous

tissue disorders

Rash

Photosensitivity reaction

Alopecia

Hyperhidrosis

Musculoskeletal and

connective tissue

disorders

Rhabdomyolysis

Myalgia

Stiffness

Renal and urinary

disorders

Urinary incontinence

Urinary retention

Pregnancy, puerperium

and perinatal conditions

Drug withdrawal syndrome

neonatal (see section 4.6)

Reproductive system

Priapism

and breast disorders

General disorders and

administration site

conditions

Fatigue

Temperature regulation

disorder (e.g. hypothermia,

pyrexia)

Chest pain

Peripheral oedema

Investigations

Blood glucose increased

Glycosylated haemoglobin

increased

Blood glucose fluctuation

Increased creatine

phosphokinase

Description of selected adverse reactions

Extrapyramidal symptoms (EPS)

Schizophrenia: in a long term 52-week controlled trial, aripiprazole-treated patients had an overall lower

incidence (25.8 %) of EPS including parkinsonism, akathisia, dystonia and dyskinesia compared with

those treated with haloperidol (57.3 %). In a long term 26-week placebo-controlled trial, the incidence of

EPS was 19 % for aripiprazole-treated patients and 13.1 % for placebo-treated patients. In another long-

term 26-week controlled trial, the incidence of EPS was 14.8 % for aripiprazole-treated patients and 15.1

% for olanzapine-treated patients.

Manic episodes in Bipolar I Disorder - in a 12-week controlled trial, the incidence of EPS was 23.5 % for

aripiprazole-treated patients and 53.3 % for haloperidol-treated patients. In another 12-week trial, the

incidence of EPS was 26.6 % for patients treated with aripiprazole and 17.6 % for those treated with

lithium. In the long term 26-week maintenance phase of a placebo-controlled trial, the incidence of EPS

was 18.2 % for aripiprazole-treated patients and 15.7 % for placebo-treated patients.

Akathisia

In placebo-controlled trials, the incidence of akathisia in bipolar patients was 12.1 % with aripiprazole

and 3.2 % with placebo. In schizophrenia patients the incidence of akathisia was 6.2 % with aripiprazole

and 3.0 % with placebo.

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 medicinal products. An elevated risk of acute dystonia is observed in males and younger

age groups.

Prolactin

In clinical trials for the approved indications and post-marketing, both increase and decrease in serum

prolactin as compared to baseline was observed with aripiprazole (section 5.1).

Laboratory parameters

Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentially

clinically significant changes in routine laboratory and lipid parameters (see section 5.1) revealed no

medically important differences. Elevations of CPK (Creatine Phosphokinase), generally transient and

asymptomatic, were observed in 3.5 % of aripiprazole treated patients as compared to 2.0 % of patients

who received placebo.

Paediatric population

Schizophrenia in adolescents aged 15 years and older

In a short-term placebo-controlled clinical trial involving 302 adolescents (13 to 17 years) with

schizophrenia, the frequency and type of undesirable effects were similar to those in adults except for the

following reactions that were reported more frequently in adolescents receiving aripiprazole than in adults

receiving aripiprazole (and more frequently than placebo): somnolence/sedation and extrapyramidal

disorder were reported very commonly (≥ 1/10), and dry mouth, increased appetite, and orthostatic

hypotension were reported commonly (≥ 1/100 to < 1/10). The safety profile in a 26-week open-label

extension trial was similar to that observed in the short-term, placebo-controlled trial.

The safety profile of a long-term, double-blind placebo controlled trial was also similar except for the

following reactions that were reported more frequently than paediatric patients taking placebo: weight

decreased, blood insulin increased, arrhythmia, and leukopenia were reported commonly (≥ 1/100, <

1/10).

In the pooled adolescent schizophrenia population (13 to 17 years) with exposure up to 2 years, incidence

of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) was 29.5 % and 48.3 %,

respectively. In the adolescent (13 to 17 years) schizophrenia population with aripiprazole exposure of 5

to 30 mg up to 72 months, incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2

ng/ml) was 25.6 % and 45.0 %, respectively.

In two long term trials with adolescent (13-17 years) schizophrenia and bipolar patients treated with

aripiprazole, incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) was

37.0 % and 59.4 %, respectively.

Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older

The frequency and type of undesirable effects in adolescents with Bipolar I Disorder were similar to those

in adults except for the following reactions: very commonly (≥ 1/10) somnolence (23.0 %),

extrapyramidal disorder (18.4 %), akathisia (16.0 %), and fatigue (11.8 %); and commonly (≥ 1/100 to <

1/10) abdominal pain upper, heart rate increased, weight increased, increased appetite, muscle twitching,

and dyskinesia.

The following undesirable effects had a possible dose response relationship; extrapyramidal disorder

(incidences were 10 mg, 9.1 %, 30 mg, 28.8 %, placebo, 1.7 %,); and akathisia (incidences were 10 mg,

12.1 %, 30 mg, 20.3 %, placebo, 1.7 %).

Mean changes in body weight in adolescents with Bipolar I Disorder at 12 and 30 weeks for aripiprazole

were 2.4 kg and 5.8 kg, and for placebo 0.2 kg and 2.3 kg, respectively.

In the paediatric population somnolence and fatigue were observed more frequently in patients with

bipolar disorder compared to patients with schizophrenia.

In the paediatric bipolar population (10 to 17 years) with exposure up to 30 weeks, incidence of low

serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) was 28.0 % and 53.3 %, respectively.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard.

4.9 Overdose

Signs and symptoms

In clinical trials and post-marketing experience, accidental or intentional acute overdose of aripiprazole

alone was identified in adult patients with reported estimated doses up to 1,260 mg with no fatalities. The

potentially medically important signs and symptoms observed included lethargy, increased blood

pressure, somnolence, tachycardia, nausea, vomiting and diarrhoea. In addition, reports of accidental

overdose with aripiprazole alone (up to 195 mg) in children have been received with no fatalities. The

potentially medically serious signs and symptoms reported included somnolence, transient loss of

consciousness and extrapyramidal symptoms.

Management of overdose

Management of overdose should concentrate on supportive therapy, maintaining an adequate airway,

oxygenation and ventilation, and management of symptoms. The possibility of multiple medicinal

product involvement should be considered. Therefore cardiovascular monitoring should be started

immediately and should include continuous electrocardiographic monitoring to detect possible

arrhythmias. Following any confirmed or suspected overdose with aripiprazole, close medical supervision

and monitoring should continue until the patient recovers.

Activated charcoal (50 g), administered one hour after aripiprazole, decreased aripiprazole C

by about

41 % and AUC by about 51 %, suggesting that charcoal may be effective in the treatment of overdose.

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 highly bound to

plasma proteins.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12

Mechanism of action

It has been proposed that aripiprazole's efficacy in schizophrenia and Bipolar I Disorder is mediated

through a combination of partial agonism at dopamine D2 and serotonin 5HT1a receptors and antagonism

of serotonin 5HT2a receptors. Aripiprazole exhibited antagonist properties in animal models of

dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypoactivity.

Aripiprazole exhibited high binding affinity in vitro for dopamine D2 and D3, serotonin 5HT1a and

5HT2a receptors and moderate affinity for dopamine D4, serotonin 5HT2c and 5HT7, alpha-1 adrenergic

and histamine H1 receptors. Aripiprazole also exhibited moderate binding affinity for the serotonin

reuptake site and no appreciable affinity for muscarinic receptors. Interaction with receptors other than

dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.

Aripiprazole doses ranging from 0.5 to 30 mg administered once a day to healthy subjects for 2 weeks

produced a dose-dependent reduction in the binding of

C-raclopride, a D2/D3 receptor ligand, to the

caudate and putamen detected by positron emission tomography.

Clinical efficacy and safety

Schizophrenia

In three short-term (4 to 6 weeks) placebo-controlled trials involving 1,228 schizophrenic adult patients,

presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly

greater improvements in psychotic symptoms compared to placebo.

Aripiprazole is effective in maintaining the clinical improvement during continuation therapy in adult

patients who have shown an initial treatment response. In a haloperidol-controlled trial, the proportion of

responder patients maintaining response to medicinal product at 52-weeks was similar in both groups

(aripiprazole 77 % and haloperidol 73 %). The overall completion rate was significantly higher for

patients on aripiprazole (43 %) than for haloperidol (30 %). Actual scores in rating scales used as

secondary endpoints, including PANSS and the Montgomery-Asberg Depression Rating Scale showed a

significant improvement over haloperidol.

In a 26-week, placebo-controlled trial in adult stabilised patients with chronic schizophrenia, aripiprazole

had significantly greater reduction in relapse rate, 34 % in aripiprazole group and 57 % in placebo.

Weight gain: In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain. In

a 26-week, olanzapine-controlled, double-blind, multi-national study of schizophrenia which included

314 adult patients and where the primary end-point was weight gain, significantly less patients had at

least 7 % weight gain over baseline (i.e. a gain of at least 5.6 kg for a mean baseline weight of ~80.5 kg)

on aripiprazole (n = 18, or 13 % of evaluable patients), compared to olanzapine (n = 45, or 33 % of

evaluable patients).

Lipid parameters: In a pooled analysis on lipid parameters from placebo controlled clinical trials in

adults, aripiprazole has not been shown to induce clinically relevant alterations in levels of total

cholesterol, triglycerides, HDL and LDL.

-Total cholesterol: incidence of changes in levels from normal (< 5.18 mmol/l) to high (≥ 6.22 mmol/l)

was 2.5 % for aripiprazole and 2.8 % for placebo and mean change from baseline was -0.15 mmol/l (95 %

CI: -0.182, -0.115) for aripiprazole and -0.11 mmol/l (95 % CI: -0.148, -0.066) for placebo.

-Fasting triglycerides: incidence of changes in levels from normal (< 1.69 mmol/l) to high (≥ 2.26

mmol/l) was 7.4 % for aripiprazole and 7.0 % for placebo and mean change from baseline was 0.11

mmol/l (95 % CI: -0.182, -0.046) for aripiprazole and -0.07 mmol/l (95 % CI: -0.148, 0.007) for placebo.

-HDL: incidence of changes in levels from normal (≥ 1.04 mmol/l) to low (< 1.04 mmol/l) was 11.4 % for

aripiprazole and 12.5 % for placebo and mean change from baseline was -0.03 mmol/l (95 % CI: -0.046,

-0.017) for aripiprazole and -0.04 mmol/l (95 % CI: -0.056, -0.022) for placebo.

-Fasting LDL: incidence of changes in levels from normal (< 2.59 mmol/l) to high (≥ 4.14 mmol/l) was

0.6 % for aripiprazole and 0.7 % for placebo and mean change from baseline was -0.09 mmol/l (95 % CI:

-0.139, -0.047) for aripiprazole and -0.06 mmol/l (95 % CI: -0.116, -0.012) for placebo.

Prolactin: Prolactin levels were evaluated in all trials of all doses of aripiprazole (n = 28,242). The

incidence of hyperprolactinaemia or increased serum prolactin in patients treated with aripiprazole (0.3

%) was similar to that of placebo (0.2 %). For patients receiving aripiprazole, the median time to onset

was 42 days and median duration was 34 days.

The incidence of hypoprolactinaemia or decreased serum prolactin in patients treated with aripiprazole

was 0.4 %, compared with 0.02 % for patients treated with placebo. For patients receiving aripiprazole,

the median time to onset was 30 days and median duration was 194 days

Manic episodes in Bipolar I Disorder

In two 3-week, flexible-dose, placebo-controlled monotherapy trials involving patients with a manic or

mixed episode of Bipolar I Disorder, aripiprazole demonstrated superior efficacy to placebo in reduction

of manic symptoms over 3 weeks. These trials included patients with or without psychotic features and

with or without a rapid-cycling course.

In one 3-week, fixed-dose, placebo-controlled monotherapy trial involving patients with a manic or mixed

episode of Bipolar I Disorder, aripiprazole failed to demonstrate superior efficacy to placebo.

In two 12-week, placebo- and active-controlled monotherapy trials in patients with a manic or mixed

episode of Bipolar I Disorder, with or without psychotic features, aripiprazole demonstrated superior

efficacy to placebo at week 3 and a maintenance of effect comparable to lithium or haloperidol at week

12. Aripiprazole also demonstrated a comparable proportion of patients in symptomatic remission from

mania as lithium or haloperidol at week 12.

In a 6-week, placebo-controlled trial involving patients with a manic or mixed episode of Bipolar I

Disorder, with or without psychotic features, who were partially non-responsive to lithium or valproate

monotherapy for 2 weeks at therapeutic serum levels, the addition of aripiprazole as adjunctive therapy

resulted in superior efficacy in reduction of manic symptoms than lithium or valproate monotherapy.

In a 26-week, placebo-controlled trial, followed by a 74-week extension, in manic patients who achieved

remission on aripiprazole during a stabilisation phase prior to randomisation, aripiprazole demonstrated

superiority over placebo in preventing bipolar recurrence, primarily in preventing recurrence into mania

but failed to demonstrate superiority over placebo in preventing recurrence into depression.

In a 52-week, placebo-controlled trial, in patients with a current manic or mixed episode of Bipolar I

Disorder who achieved sustained remission (Y-MRS and MADRS total scores ≤ 12) on aripiprazole (10

mg/day to 30 mg/day) adjunctive to lithium or valproate for 12 consecutive weeks, adjunctive

aripiprazole demonstrated superiority over placebo with a 46 % decreased risk (hazard ratio of 0.54) in

preventing bipolar recurrence and a 65 % decreased risk (hazard ratio of 0.35) in preventing recurrence

into mania over adjunctive placebo but failed to demonstrate superiority over placebo in preventing

recurrence into depression. Adjunctive aripiprazole demonstrated superiority over placebo on the

secondary outcome measure, CGI-BP Severity of Illness score (mania).

In this trial, patients were assigned by investigators with either open-label lithium or valproate

monotherapy to determine partial non-response. Patients were stabilised for at least 12 consecutive weeks

with the combination of aripiprazole and the same mood stabiliser.

Stabilised patients were then randomised to continue the same mood stabiliser with double-blind

aripiprazole or placebo. Four mood stabiliser subgroups were assessed in the randomised phase:

aripiprazole + lithium; aripiprazole + valproate; placebo + lithium; placebo + valproate.

The Kaplan-Meier rates for recurrence to any mood episode for the adjunctive treatment arm were 16 %

in aripiprazole + lithium and 18 % in aripiprazole + valproate compared to 45 % in placebo + lithium and

19 % in placebo + valproate.

Paediatric population

Schizophrenia in adolescents

In a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients (13-17 years),

presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly

greater improvements in psychotic symptoms compared to placebo.

In a sub-analysis of the adolescent patients between the ages of 15 to 17 years, representing 74 % of the

total enrolled population, maintenance of effect was observed over the 26-week open-label extension trial.

In a 60- to 89-week, randomised, double-blind, placebo-controlled trial in adolescent subjects (n = 146;

ages 13-17 years) with schizophrenia, there was a statistically significant difference in the rate of relapse

of psychotic symptoms between the aripiprazole (19.39 %) and placebo (37.50 %) groups. The point

estimate of the hazard ratio (HR) was 0.461 (95% confidence interval, 0.242-0.879) in the full population.

In subgroup analyses the point estimate of the HR was 0.495 for subjects 13 to 14 years of age compared

to 0.454 for subjects 15 to 17 years of age. However, the estimation of the HR for the younger (13-14

years) group was not precise, reflecting the smaller number of subjects in that group (aripiprazole, n = 29;

placebo, n = 12), and the confidence interval for this estimation (ranging from 0.151 to 1.628) did not

allow conclusions to be drawn on the presence of a treatment effect. In contrast the 95 % confidence

interval for the HR in the older subgroup (aripiprazole, n = 69; placebo, n = 36) was 0.242 to 0.879 and

hence a treatment effect could be concluded in the older patients.

Manic episodes in Bipolar I Disorder in children and adolescents

Aripiprazole was studied in a 30-week placebo-controlled trial involving 296 children and adolescents

(10-17 years), who met DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes with or

without psychotic features and had a Y-MRS score ≥ 20 at baseline. Among the patients included in the

primary efficacy analysis, 139 patients had a current co-morbid diagnosis of ADHD.

Aripiprazole was superior to placebo in change from baseline at week 4 and at week 12 on the Y-MRS

total score. In a post-hoc analysis, the improvement over placebo was more pronounced in the patients

with associated co-morbidity of ADHD compared to the group without ADHD, where there was no

difference from placebo. Recurrence prevention was not established.

Table 1: Mean improvement from baseline YMRS score by psychiatric comorbidity

Psychiatric

comorbidities

Week 4

Week 12

ADHD

Week 4

Week 12

Aripiprazole 10 mg

(n = 48)

14.9

15.1

Aripiprazole 10 mg

(n = 44)

15.2

15.6

Aripiprazole 30 mg

(n = 51)

16.7

16.9

Aripiprazole 30 mg

(n = 48)

15.9

16.7

Placebo (n = 52)

Placebo (n = 47)

No psychiatric

comorbidities

Week 4

Week 12

No ADHD

Week 4

Week 12

Aripiprazole 10 mg

(n = 27)

12.8

15.9

Aripiprazole 10 mg

(n = 37)

12.7

15.7

(n = 25)

15.3

14.7

Aripiprazole 30 mg

14.6

13.4

(n = 30)

Placebo (n = 18)

Placebo (n = 25)

10.0

n = 51 at Week 4

n = 46 at Week 4

The most common treatment-emergent adverse events among patients receiving 30 mg were

extrapyramidal disorder (28.3 %), somnolence (27.3 %), headache (23.2 %), and nausea (14.1 %). Mean

weight gain in the 30 weeks treatment-interval was 2.9 kg as compared to 0.98 kg in patients treated with

placebo.

Irritability associated with autistic disorder in paediatric patients (see section 4.2)

Aripiprazole was studied in patients aged 6 to 17 years in two 8-week, placebo-controlled trials [one

flexible-dose (2-15 mg/day) and one fixed-dose (5, 10, or 15 mg/day)] and in one 52-week open-label

trial. Dosing in these trials was initiated at 2 mg/day, increased to 5 mg/day after one week, and increased

by 5 mg/day in weekly increments to the target dose. Over 75 % of patients were less than 13 years of

age. Aripiprazole demonstrated statistically superior efficacy compared to placebo on the Aberrant

Behaviour Checklist Irritability subscale. However, the clinical relevance of this finding has not been

established. The safety profile included weight gain and changes in prolactin levels. The duration of the

long-term safety study was limited to 52 weeks. In the pooled trials, the incidence of low serum prolactin

levels in females (< 3 ng/ml) and males (< 2 ng/ml) in aripiprazole-treated patients was 27/46 (58.7 %)

and 258/298 (86.6 %), respectively. In the placebo-controlled trials, the mean weight gain was 0.4 kg for

placebo and 1.6 kg for aripiprazole.

Aripiprazole was also studied in a placebo-controlled, long-term maintenance trial. After a 13-26 week

stabilisation on aripiprazole (2-15 mg/day) patients with a stable response were either maintained on

aripiprazole or substituted to placebo for further 16 weeks. Kaplan-Meier relapse rates at week 16 were

35 % for aripiprazole and 52 % for placebo; the hazard ratio for relapse within 16 weeks

(aripiprazole/placebo) was 0.57 (non-statistically significant difference). The mean weight gain over the

stabilisation phase (up to 26 weeks) on aripiprazole was 3.2 kg, and a further mean increase of 2.2 kg for

aripiprazole as compared to 0.6 kg for placebo was observed in the second phase (16 weeks) of the trial.

Extrapyramidal symptoms were mainly reported during the stabilisation phase in 17 % of patients, with

tremor accounting for 6.5 %.

Tics associated with Tourette's disorder in paediatric patients (see section 4.2)

The efficacy of aripiprazole was studied in paediatric subjects with Tourette's disorder (aripiprazole: n =

99, placebo: n = 44) in a randomised, double-blind, placebo controlled, 8 week study using a fixed dose

weight-based treatment group design over the dose range of 5 mg/day to 20 mg/day and a starting dose of

2 mg. Patients were 7 to 17 years of age and presented an average score of 30 on Total Tic Score on the

Yale Global Tic Severity Scale (TTS-YGTSS) at baseline. Aripiprazole showed an improvement on TTS-

YGTSS change from baseline to Week 8 of 13.35, for the low dose group (5 mg or 10 mg) and 16.94 for

the high dose group (10 mg or 20 mg) as compared with an improvement of 7.09 to in the placebo group.

The efficacy of aripiprazole in paediatric subjects with Tourette's syndrome (aripiprazole: n = 32,

placebo: n = 29) was also evaluated over a flexible dose range of 2 mg/day to 20 mg/day and a starting

dose of 2 mg, in a 10 week, randomised, double blind, placebo-controlled study conducted in South

Korea. Patients were 6 to 18 years and presented an average score of 29 on TTS-YGTSS at baseline.

Aripiprazole group showed an improvement of 14.97 on TTS-YGTSS change from baseline to Week 10

as compared with an improvement of 9.62 in the placebo group.

In both of these short term trials, the clinical relevance of the efficacy findings has not been established,

considering the magnitude of treatment effect compared to the large placebo effect and the unclear effects

regarding psycho-social functioning. No long term data are available with regard to the efficacy and the

safety of aripiprazole in this fluctuating disorder.

The European Medicines Agency has deferred the obligation to submit the results of studies with

aripiprazole in one or more subsets of the paediatric population in the treatment of schizophrenia and in

the treatment of bipolar affective disorder (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Aripiprazole is well absorbed, with peak plasma concentrations occurring within 3-5 hours after dosing.

Aripiprazole undergoes minimal pre-systemic metabolism. The absolute oral bioavailability of the tablet

formulation is 87 %. There is no effect of a high fat meal on the pharmacokinetics of aripiprazole.

Distribution

Aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9

l/kg, indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and

dehydro-aripiprazole are greater than 99 % bound to serum proteins, binding primarily to albumin.

Biotransformation

Aripiprazole is extensively metabolised by the liver primarily by three biotransformation pathways:

dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6

enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is

catalysed by CYP3A4. Aripiprazole is the predominant medicinal product moiety in systemic circulation.

At steady state, dehydro-aripiprazole, the active metabolite, represents about 40 % of aripiprazole AUC in

plasma.

Elimination

The mean elimination half-lives for aripiprazole are approximately 75 hours in extensive metabolisers of

CYP2D6 and approximately 146 hours in poor metabolisers of CYP2D6.

The total body clearance of aripiprazole is 0.7 ml/min/kg, which is primarily hepatic.

Following a single oral dose of [

C]-labelled aripiprazole, approximately 27 % of the administered

radioactivity was recovered in the urine and approximately 60 % in the faeces. Less than 1 % of

unchanged aripiprazole was excreted in the urine and approximately 18 % was recovered unchanged in

the faeces.

Oral Solution

Aripiprazole is well absorbed when administered orally as the solution. At equivalent doses, the peak

plasma concentrations of aripiprazole (C

) from the solution were somewhat higher but the systemic

exposure (AUC) was equivalent to tablets. In a relative bioavailability study comparing the

pharmacokinetics of 30 mg aripiprazole as the oral solution to 30 mg aripiprazole tablets in healthy

subjects, the solution to the tablet ratio of geometric mean C

values was 122 % (n = 30). The single

dose pharmacokinetics of aripiprazole was linear and dose-proportional.

Pharmacokinetics in special patient groups

Paediatric population

The pharmacokinetics of aripiprazole and dehydro-aripiprazole in paediatric patients 10 to 17 years of age

were similar to those in adults after correcting for the differences in body weights.

Elderly

There are no differences in the pharmacokinetics of aripiprazole between healthy elderly and younger

adult subjects, nor is there any detectable effect of age in a population pharmacokinetic analysis in

schizophrenic patients.

Gender

There are no differences in the pharmacokinetics of aripiprazole between healthy male and female

subjects nor is there any detectable effect of gender in a population pharmacokinetic analysis in

schizophrenic patients.

Smoking

Population pharmacokinetic evaluation has revealed no evidence of clinically significant effects from

smoking on the pharmacokinetics of aripiprazole.

Race

Population pharmacokinetic evaluation showed no evidence of race-related differences on the

pharmacokinetics of aripiprazole.

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.

Hepatic impairment

A single-dose 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, but the study included only 3 patients with Class C liver cirrhosis, which is

insufficient to draw conclusions on their metabolic capacity.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and

development.

Toxicologically significant effects were observed only at doses or exposures that were sufficiently in

excess of the maximum human dose or exposure, indicating that these effects were limited or of no

relevance to clinical use. These included: dose-dependent adrenocortical toxicity (lipofuscin pigment

accumulation and/or parenchymal cell loss) in rats after 104 weeks at 20 to 60 mg/kg/day (3 to 10 times

the mean steady-state AUC at the maximum recommended human dose) and increased adrenocortical

carcinomas and combined adrenocortical adenomas/carcinomas in female rats at 60 mg/kg/day (10 times

the mean steady-state AUC at the maximum recommended human dose). The highest nontumorigenic

exposure in female rats was 7 times the human exposure at the recommended dose.

An additional finding was cholelithiasis as a consequence of precipitation of sulphate conjugates of

hydroxy metabolites of aripiprazole in the bile of monkeys after repeated oral dosing at 25 to 125

mg/kg/day (1 to 3 times the mean steady-state AUC at the maximum recommended clinical dose or 16 to

81 times the maximum recommended human dose based on mg/m

). However, the concentrations of the

sulphate conjugates of hydroxy aripiprazole in human bile at the highest dose proposed, 30 mg per day,

were no more than 6 % of the bile concentrations found in the monkeys in the 39-week study and are well

below (6 %) their limits of in vitro solubility.

In repeat-dose studies in juvenile rats and dogs, the toxicity profile of aripiprazole was comparable to that

observed in adult animals, and there was no evidence of neurotoxicity or adverse reactions on

development.

Based on results of a full range of standard genotoxicity tests, aripiprazole was considered non-genotoxic.

Aripiprazole did not impair fertility in reproductive toxicity studies. Developmental toxicity, including

dose-dependent delayed foetal ossification and possible teratogenic effects, were observed in rats at doses

resulting in subtherapeutic exposures (based on AUC) and in rabbits at doses resulting in exposures 3 and

11 times the mean steady-state AUC at the maximum recommended clinical dose. Maternal toxicity

occurred at doses similar to those eliciting developmental toxicity.

6. Pharmaceutical particulars

6.1 List of excipients

Disodium edetate

Erythritol (E 968)

Hypromellose

Macrogol 4000

Phosphoric acid, concentrated (for pH adjustment)

Propylene glycol (E 1520)

Sodium benzoate (E 211)

Sucralose (E 955)

Water, purified

Grape flavour

6.2 Incompatibilities

The oral solution should not be diluted with other liquids or mixed with any food prior to administration.

6.3 Shelf life

2 years

After first opening: Use within 6 months

6.4 Special precautions for storage

Do not refrigerate or freeze.

Store in the original package in order to protect from light.

6.5 Nature and contents of container

Amber glass bottle with a PE/PP child-resistant screw cap closure containing 150 ml of oral solution,

placed in an outer cardboard carton. The cardboard carton also contains a 5 ml graduated oral PP syringe

(graduated at every 0.5 ml) and HDPE plunger, and a PP 30 ml graduated measuring cup (graduated at

every 5 ml).

Amber PET bottle with a PE/PP child-resistant screw cap closure containing 150 ml of oral solution,

placed in an outer cardboard carton. The cardboard carton also contains a 5 ml graduated oral PP syringe

(graduated at every 0.5 ml) and HDPE plunger, and a PP 30 ml graduated measuring cup (graduated at

every 5 ml).

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Generics [UK] Limited t/a Mylan

Station Close,

Potters Bar,

Hertfordshire, EN6 1TL

United Kingdom

8. Marketing authorisation number(s)

PL 04569/1667

9. Date of first authorisation/renewal of the authorisation

12 July 2016

10. Date of revision of the text

08/2017

Company Contact Details

Generics UK T/A Mylan

Address

Building 4, Trident Place, Mosquito Way, Hatfield, Hertfordshire, AL10 9UL

Telephone

+44 (0)1707 853 000

Medical Information Direct Line

+44 (0)1707 853 000

Customer Care direct line

+44 (0)1707 853 000 select option 2

Stock Availability

+44 (0)1707 853 000 select option 2

http://www.mylan.com

+44 (0)1707 261 803

Medical Information e-mail

[email

protected]

Medical Information Fax

+44 (0)1707 261 803

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