ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
ABILIFY 5 mg tablets
2.
Each tablet contains 5 mg of aripiprazole.
Excipient: 67 mg lactose per tablet
For a full list of excipients, see section 6.1.
3.
Tablet
Rectangular and blue, engraved with "A-007" and "5" on one side.
4.
ABILIFY is indicated for the treatment of schizophrenia in adults and in adolescents 15 years and
older.
ABILIFY 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 patients who experienced predominantly manic
episodes and whose manic episodes responded to aripiprazole treatment (see section 5.1).
Posology
Adults:
Schizophrenia:
the recommended starting dose for ABILIFY is 10 or 15 mg/day with a maintenance
dose of 15 mg/day administered on a once-a-day schedule without regard to meals.
ABILIFY is effective in a dose range of 10 to 30 mg/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:
the recommended starting dose for ABILIFY is 15 mg 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.
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.
Paediatric population:
Schizophrenia in adolescents 15 years and older
: the recommended dose for ABILIFY is 10 mg/day
administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg
(using ABILIFY 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
2
administered in 5 mg increments without exceeding the maximum daily dose of 30 mg (see section
5.1).
ABILIFY 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 in adolescents although individual patients may benefit
from a higher dose.
ABILIFY is not recommended for use in patients below 15 years of age due to insufficient data on
safety and efficacy (see sections 4.8 and 5.1).
Irritability associated with autistic disorder:
the safety and efficacy of ABILIFY in children and
adolescents below 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.
Patients with 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).
Patients with renal impairment
: no dosage adjustment is required in patients with renal impairment.
Elderly
: the effectiveness of ABILIFY in the treatment of schizophrenia and Bipolar I Disorder in
patients 65 years of age or 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 ABILIFY 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
ABILIFY tablets are for oral use.
Hypersensitivity to the active substance or to any of the excipients.
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.
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 therapy, including
treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should
3
accompany antipsychotic therapy.
Results of an epidemiological study suggested that there was no
increased risk of suicidality with aripiprazole compared to other antipsychotics among patients with
schizophrenia or bipolar disorder.
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 drugs. Since patients
treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors
for VTE should be identified before and during treatment with ABILIFY and preventive measures
undertaken.
Conduction abnormalities:
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.
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 ABILIFY, dose reduction or discontinuation should be considered.
These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.
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 medicinal products, including ABILIFY,
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.
Elderly patients with dementia-related psychosis
:
Increased mortality:
in three placebo-controlled trials (n= 938; mean age: 82.4 years; range:
56-99 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.
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:
78-88 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.
ABILIFY 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 agents, including ABILIFY. Risk factors that may predispose patients to severe
4
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 ABILIFY and with
other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with
any antipsychotic agents, including ABILIFY, 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.
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
ABILIFY. 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 (see section 5.1).
Dysphagia
: oesophageal dysmotility and aspiration have been associated with antipsychotic treatment,
including ABILIFY. Aripiprazole and other antipsychotic active substances should be used cautiously
in patients at risk for aspiration pneumonia.
Lactose
: ABILIFY tablets contain lactose. Patients with rare hereditary problems of galactose
intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.
Due to its α
1
-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 ABILIFY
:
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.
In a clinical trial in healthy subjects, a potent inhibitor of CYP2D6 (quinidine) increased aripiprazole
AUC by 107%, while C
max
was unchanged. The AUC and C
max
of dehydro-aripiprazole, the active
metabolite, decreased by 32% and 47%. ABILIFY dose should be reduced to approximately one-half
of its prescribed dose when concomitant administration of ABILIFY 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.
In a clinical trial in healthy subjects, a potent inhibitor of CYP3A4 (ketoconazole) increased
aripiprazole AUC and C
max
by 63% and 37%, respectively. The AUC and C
max
of dehydro-aripiprazole
5
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 ABILIFY, potential benefits should outweigh the potential risks
to the patient. When concomitant administration of ketoconozole with ABILIFY occurs, ABILIFY
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 3A4 inhibitor, the dosage of ABILIFY 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 ABILIFY, modest increases in aripiprazole concentrations might be expected.
Following concomitant administration of carbamazepine, a potent inducer of CYP3A4, the geometric
means of C
max
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 C
max
and AUC after carbamazepine co-administration were 69% and 71% lower, respectively, than
those following treatment with aripiprazole alone.
ABILIFY dose should be doubled when concomitant administration of ABILIFY 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 ABILIFY should be reduced to the recommended dose.
When either valproate or lithium were administered concomitantly with aripiprazole, there was no
clinically significant change in aripiprazole concentrations.
Potential for ABILIFY to affect other medicinal products:
In clinical studies, 10-30 mg/day doses of aripiprazole had no significant effect on the metabolism of
substrates of CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), 2C9 (warfarin), 2C19
(omeprazole), and 3A4 (dextromethorphan). Additionally, aripiprazole and dehydro-aripiprazole 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.
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.
Aripiprazole was excreted in the milk of treated rats during lactation. It is not known whether
aripiprazole is excreted in human milk. Patients should be advised not to breast feed if they are taking
aripiprazole.
6
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 (see section 4.8).
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.
The following adverse reactions occurred more often
(≥ 1/100)
than placebo, or were identified as
possibly medically relevant adverse reactions (*):
The frequency listed below is defined using the following convention: common (≥ 1/100 to < 1/10)
and uncommon (≥ 1/1,000 to < 1/100).
Psychiatric disorders
Common:
restlessness, insomnia, anxiety
Uncommon:
depression*
Nervous system disorders
Common:
extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache
Eye disorders
Common:
blurred vision
Cardiac disorders
Uncommon:
tachycardia*
Vascular disorders
Uncommon:
orthostatic hypotension*
Gastrointestinal disorders
Common:
dyspepsia, vomiting, nausea, constipation, salivary hypersecretion
General disorders and administration site conditions
Common:
fatigue
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.
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 drugs. An elevated risk of acute dystonia is observed in males and
younger age groups.
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
7
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.
Other findings
:
Adverse reactions known to be associated with antipsychotic therapy and also reported during
treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure,
cerebrovascular adverse reactions and increased mortality in elderly demented patients,
hyperglycaemia and diabetes mellitus (see section 4.4).
Paediatric population:
In a short-term placebo-controlled clinical trial involving 302 adolescents (13-17 years) with
schizophrenia, the frequency and type of undesirable effects were similar to those in adults except for
the following events 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, < 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.
In the pooled adolescent schizophrenia population (13-17 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.
Post-Marketing:
The following adverse reactions have been reported during post-marketing surveillance. The
frequency of these reactions is considered not known (cannot be estimated from the available data).
Blood and the 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:
hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic
hyperosmolar coma
Metabolism and nutrition
disorders:
weight gain, weight decreased, anorexia, hyponatremia
Psychiatric disorders:
agitation, nervousness; suicide attempt, suicidal ideation, and
completed suicide (see section 4.4)
Nervous system disorders:
speech disorder, Neuroleptic Malignant Syndrome (NMS), grand
mal convulsion
Cardiac disorders:
QT prolongation, ventricular arrhythmias, sudden unexplained
death, cardiac arrest, torsades de pointes, bradycardia
Vascular disorders:
syncope, hypertension, venous thromboembolism (including
pulmonary embolism and deep vein thrombosis)
Respiratory, thoracic and
mediastinal disorders:
oropharyngeal spasm, laryngospasm, aspiration pneumonia
Gastrointestinal disorders:
pancreatitis, dysphagia, abdominal discomfort, stomach discomfort,
diarrhoea
8
Hepato-biliary disorders:
jaundice, hepatitis, 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
Reproductive system and
breast disorders:
priapism
General disorders and
administration site conditions:
temperature regulation disorder (e.g. hypothermia, pyrexia), chest
pain, peripheral oedema
Investigations:
increased Creatine Phosphokinase, blood glucose increased, blood
glucose fluctuation, glycosylated haemoglobin increased
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 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
max
by
about 41% and AUC by about 51%, suggesting that charcoal may be effective in the treatment of
overdose.
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12
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
9
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
11
C-raclopride, a D2/D3 receptor ligand, to the
caudate and putamen detected by positron emission tomography.
Further information on clinical trials:
Schizophrenia in adults:
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.
ABILIFY 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 stabilised patients with chronic schizophrenia, aripiprazole
had significantly greater reduction in relapse rate, 34% in aripiprazole group and 57% in placebo.
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.
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.
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 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:
10
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.
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 stabilization phase prior to randomization, 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 stabilizer.
Stabilized patients were then randomised to continue the same mood stabilizer with double-blind
aripiprazole or placebo. Four mood stabilizer subgroups were assessed in the randomised phase:
aripiprazole + lithium; aripiprazole + valproate; placebo + lithium; placebo + valproate.
11
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.
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.
Metabolism:
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 [
14
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.
Pharmacokinetics in special patient groups
Paediatric population:
The pharmacokinetics of aripiprazole and dehydro-aripiprazole in paediatric patients 13 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 and Race:
Population pharmacokinetic evaluation has revealed no evidence of clinically significant race-related
differences or effects from smoking upon the pharmacokinetics of aripiprazole.
12
Renal Disease:
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 Disease:
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 safety data revealed no special hazard for humans based on conventional studies of safety
pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and 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
2
). 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 effects 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.
6.1 List of excipients
Lactose monohydrate
Maize starch
Microcrystalline cellulose
Hydroxypropyl cellulose
Magnesium stearate
Indigo carmine aluminium lake (E132)
13
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Aluminium perforated unit dose blisters in cartons of 14 x 1, 28 x 1, 49 x 1, 56 x 1, 98 x 1 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Otsuka Pharmaceutical Europe Ltd.
Hunton House, Highbridge Business Park, Oxford Road
Uxbridge - Middlesex UB8 1HU - United Kingdom
8.
EU/1/04/276/001-005
9.
Date of first authorisation: 4 June 2004
Date of latest renewal: 4 June 2009
{MM/YYYY}
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu/
14
1.
ABILIFY 10 mg tablets
2.
Each tablet contains 10 mg of aripiprazole.
Excipient: 62.18 mg lactose per tablet
For a full list of excipients, see section 6.1.
3.
Tablet
Rectangular and pink, engraved with "A-008" and "10" on one side.
4.
ABILIFY is indicated for the treatment of schizophrenia in adults and in adolescents 15 years and
older.
ABILIFY 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 patients who experienced predominantly manic
episodes and whose manic episodes responded to aripiprazole treatment (see section 5.1).
Posology
Adults:
Schizophrenia:
the recommended starting dose for ABILIFY is 10 or 15 mg/day with a maintenance
dose of 15 mg/day administered on a once-a-day schedule without regard to meals.
ABILIFY is effective in a dose range of 10 to 30 mg/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:
the recommended starting dose for ABILIFY is 15 mg 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.
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.
Paediatric population:
Schizophrenia in adolescents 15 years and older
: the recommended dose for ABILIFY is 10 mg/day
administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg
(using ABILIFY 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
15
administered in 5 mg increments without exceeding the maximum daily dose of 30 mg (see section
5.1).
ABILIFY 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 in adolescents although individual patients may benefit
from a higher dose.
ABILIFY is not recommended for use in patients below 15 years of age due to insufficient data on
safety and efficacy (see sections 4.8 and 5.1).
Irritability associated with autistic disorder:
the safety and efficacy of ABILIFY in children and
adolescents below 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.
Patients with 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).
Patients with renal impairment
: no dosage adjustment is required in patients with renal impairment.
Elderly
: the effectiveness of ABILIFY in the treatment of schizophrenia and Bipolar I Disorder in
patients 65 years of age or 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 ABILIFY 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
ABILIFY tablets are for oral use.
Hypersensitivity to the active substance or to any of the excipients.
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.
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 therapy, including
treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should
16
accompany antipsychotic therapy.
Results of an epidemiological study suggested that there was no
increased risk of suicidality with aripiprazole compared to other antipsychotics among patients with
schizophrenia or bipolar disorder.
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 drugs. Since patients
treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors
for VTE should be identified before and during treatment with ABILIFY and preventive measures
undertaken.
Conduction abnormalities:
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.
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 ABILIFY, dose reduction or discontinuation should be considered.
These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.
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 medicinal products, including ABILIFY,
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.
Elderly patients with dementia-related psychosis
:
Increased mortality:
in three placebo-controlled trials (n= 938; mean age: 82.4 years; range:
56-99 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.
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:
78-88 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.
ABILIFY 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 agents, including ABILIFY. Risk factors that may predispose patients to severe
17
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 ABILIFY and with
other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with
any antipsychotic agents, including ABILIFY, 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.
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
ABILIFY. 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 (see section 5.1).
Dysphagia
: oesophageal dysmotility and aspiration have been associated with antipsychotic treatment,
including ABILIFY. Aripiprazole and other antipsychotic active substances should be used cautiously
in patients at risk for aspiration pneumonia.
Lactose
: ABILIFY tablets contain lactose. Patients with rare hereditary problems of galactose
intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.
Due to its α
1
-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 ABILIFY
:
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.
In a clinical trial in healthy subjects, a potent inhibitor of CYP2D6 (quinidine) increased aripiprazole
AUC by 107%, while C
max
was unchanged. The AUC and C
max
of dehydro-aripiprazole, the active
metabolite, decreased by 32% and 47%. ABILIFY dose should be reduced to approximately one-half
of its prescribed dose when concomitant administration of ABILIFY 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.
In a clinical trial in healthy subjects, a potent inhibitor of CYP3A4 (ketoconazole) increased
aripiprazole AUC and C
max
by 63% and 37%, respectively. The AUC and C
max
of dehydro-aripiprazole
18
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 ABILIFY, potential benefits should outweigh the potential risks
to the patient. When concomitant administration of ketoconozole with ABILIFY occurs, ABILIFY
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 3A4 inhibitor, the dosage of ABILIFY 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 ABILIFY, modest increases in aripiprazole concentrations might be expected.
Following concomitant administration of carbamazepine, a potent inducer of CYP3A4, the geometric
means of C
max
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 C
max
and AUC after carbamazepine co-administration were 69% and 71% lower, respectively, than
those following treatment with aripiprazole alone.
ABILIFY dose should be doubled when concomitant administration of ABILIFY 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 ABILIFY should be reduced to the recommended dose.
When either valproate or lithium were administered concomitantly with aripiprazole, there was no
clinically significant change in aripiprazole concentrations.
Potential for ABILIFY to affect other medicinal products:
In clinical studies, 10-30 mg/day doses of aripiprazole had no significant effect on the metabolism of
substrates of CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), 2C9 (warfarin), 2C19
(omeprazole), and 3A4 (dextromethorphan). Additionally, aripiprazole and dehydro-aripiprazole 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.
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.
Aripiprazole was excreted in the milk of treated rats during lactation. It is not known whether
aripiprazole is excreted in human milk. Patients should be advised not to breast feed if they are taking
aripiprazole.
19
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 (see section 4.8).
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.
The following adverse reactions occurred more often
(≥ 1/100)
than placebo, or were identified as
possibly medically relevant adverse reactions (*):
The frequency listed below is defined using the following convention: common (≥ 1/100 to < 1/10)
and uncommon (≥ 1/1,000 to < 1/100).
Psychiatric disorders
Common:
restlessness, insomnia, anxiety
Uncommon:
depression*
Nervous system disorders
Common:
extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache
Eye disorders
Common:
blurred vision
Cardiac disorders
Uncommon:
tachycardia*
Vascular disorders
Uncommon:
orthostatic hypotension*
Gastrointestinal disorders
Common:
dyspepsia, vomiting, nausea, constipation, salivary hypersecretion
General disorders and administration site conditions
Common:
fatigue
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.
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 drugs. An elevated risk of acute dystonia is observed in males and
younger age groups.
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
20
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.
Other findings
:
Adverse reactions known to be associated with antipsychotic therapy and also reported during
treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure,
cerebrovascular adverse reactions and increased mortality in elderly demented patients,
hyperglycaemia and diabetes mellitus (see section 4.4).
Paediatric population:
In a short-term placebo-controlled clinical trial involving 302 adolescents (13-17 years) with
schizophrenia, the frequency and type of undesirable effects were similar to those in adults except for
the following events 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, < 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.
In the pooled adolescent schizophrenia population (13-17 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.
Post-Marketing:
The following adverse reactions have been reported during post-marketing surveillance. The
frequency of these reactions is considered not known (cannot be estimated from the available data).
Blood and the 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:
hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic
hyperosmolar coma
Metabolism and nutrition
disorders:
weight gain, weight decreased, anorexia, hyponatremia
Psychiatric disorders:
agitation, nervousness; suicide attempt, suicidal ideation, and
completed suicide (see section 4.4)
Nervous system disorders:
speech disorder, Neuroleptic Malignant Syndrome (NMS), grand
mal convulsion
Cardiac disorders:
QT prolongation, ventricular arrhythmias, sudden unexplained
death, cardiac arrest, torsades de pointes, bradycardia
Vascular disorders:
syncope, hypertension, venous thromboembolism (including
pulmonary embolism and deep vein thrombosis)
Respiratory, thoracic and
mediastinal disorders:
oropharyngeal spasm, laryngospasm, aspiration pneumonia
Gastrointestinal disorders:
pancreatitis, dysphagia, abdominal discomfort, stomach discomfort,
diarrhoea
21
Hepato-biliary disorders:
jaundice, hepatitis, 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
Reproductive system and
breast disorders:
priapism
General disorders and
administration site conditions:
temperature regulation disorder (e.g. hypothermia, pyrexia), chest
pain, peripheral oedema
Investigations:
increased Creatine Phosphokinase, blood glucose increased, blood
glucose fluctuation, glycosylated haemoglobin increased
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 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
max
by
about 41% and AUC by about 51%, suggesting that charcoal may be effective in the treatment of
overdose.
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12
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
22
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
11
C-raclopride, a D2/D3 receptor ligand, to the
caudate and putamen detected by positron emission tomography.
Further information on clinical trials:
Schizophrenia in adults:
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.
ABILIFY 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 stabilised patients with chronic schizophrenia, aripiprazole
had significantly greater reduction in relapse rate, 34% in aripiprazole group and 57% in placebo.
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.
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.
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 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:
23
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.
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 stabilization phase prior to randomization, 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 stabilizer.
Stabilized patients were then randomised to continue the same mood stabilizer with double-blind
aripiprazole or placebo. Four mood stabilizer subgroups were assessed in the randomised phase:
aripiprazole + lithium; aripiprazole + valproate; placebo + lithium; placebo + valproate.
24
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.
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.
Metabolism:
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 [
14
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.
Pharmacokinetics in special patient groups
Paediatric population:
The pharmacokinetics of aripiprazole and dehydro-aripiprazole in paediatric patients 13 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 and Race:
Population pharmacokinetic evaluation has revealed no evidence of clinically significant race-related
differences or effects from smoking upon the pharmacokinetics of aripiprazole.
25
Renal Disease:
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 Disease:
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 safety data revealed no special hazard for humans based on conventional studies of safety
pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and 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
2
). 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 effects 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.
6.1 List of excipients
Lactose monohydrate
Maize starch
Microcrystalline cellulose
Hydroxypropyl cellulose
Magnesium stearate
Red iron oxide (E172)
26
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Aluminium perforated unit dose blisters in cartons of 14 x 1, 28 x 1, 49 x 1, 56 x 1, 98 x 1 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Otsuka Pharmaceutical Europe Ltd.
Hunton House, Highbridge Business Park, Oxford Road
Uxbridge - Middlesex UB8 1HU - United Kingdom
8.
EU/1/04/276/006-010
9.
Date of first authorisation: 4 June 2004
Date of latest renewal: 4 June 2009
{MM/YYYY}
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu/
27
1.
ABILIFY 15 mg tablets
2.
Each tablet contains 15 mg of aripiprazole.
Excipient: 57 mg lactose per tablet
For a full list of excipients, see section 6.1.
3.
Tablet
Round and yellow, engraved with "A-009" and "15" on one side.
4.
ABILIFY is indicated for the treatment of schizophrenia in adults and in adolescents 15 years and
older.
ABILIFY 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 patients who experienced predominantly manic
episodes and whose manic episodes responded to aripiprazole treatment (see section 5.1).
Posology
Adults:
Schizophrenia:
the recommended starting dose for ABILIFY is 10 or 15 mg/day with a maintenance
dose of 15 mg/day administered on a once-a-day schedule without regard to meals.
ABILIFY is effective in a dose range of 10 to 30 mg/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:
the recommended starting dose for ABILIFY is 15 mg 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.
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.
Paediatric population:
Schizophrenia in adolescents 15 years and older
: the recommended dose for ABILIFY is 10 mg/day
administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg
(using ABILIFY 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
28
administered in 5 mg increments without exceeding the maximum daily dose of 30 mg (see section
5.1).
ABILIFY 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 in adolescents although individual patients may benefit
from a higher dose.
ABILIFY is not recommended for use in patients below 15 years of age due to insufficient data on
safety and efficacy (see sections 4.8 and 5.1).
Irritability associated with autistic disorder:
the safety and efficacy of ABILIFY in children and
adolescents below 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.
Patients with 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).
Patients with renal impairment
: no dosage adjustment is required in patients with renal impairment.
Elderly
: the effectiveness of ABILIFY in the treatment of schizophrenia and Bipolar I Disorder in
patients 65 years of age or 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 ABILIFY 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
ABILIFY tablets are for oral use.
Hypersensitivity to the active substance or to any of the excipients.
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.
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 therapy, including
treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should
29
accompany antipsychotic therapy.
Results of an epidemiological study suggested that there was no
increased risk of suicidality with aripiprazole compared to other antipsychotics among patients with
schizophrenia or bipolar disorder.
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 drugs. Since patients
treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors
for VTE should be identified before and during treatment with ABILIFY and preventive measures
undertaken.
Conduction abnormalities:
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.
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 ABILIFY, dose reduction or discontinuation should be considered.
These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.
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 medicinal products, including ABILIFY,
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.
Elderly patients with dementia-related psychosis
:
Increased mortality:
in three placebo-controlled trials (n= 938; mean age: 82.4 years; range:
56-99 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.
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:
78-88 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.
ABILIFY 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 agents, including ABILIFY. Risk factors that may predispose patients to severe
30
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 ABILIFY and with
other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with
any antipsychotic agents, including ABILIFY, 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.
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
ABILIFY. 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 (see section 5.1).
Dysphagia
: oesophageal dysmotility and aspiration have been associated with antipsychotic treatment,
including ABILIFY. Aripiprazole and other antipsychotic active substances should be used cautiously
in patients at risk for aspiration pneumonia.
Lactose
: ABILIFY tablets contain lactose. Patients with rare hereditary problems of galactose
intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.
Due to its α
1
-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 ABILIFY
:
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.
In a clinical trial in healthy subjects, a potent inhibitor of CYP2D6 (quinidine) increased aripiprazole
AUC by 107%, while C
max
was unchanged. The AUC and C
max
of dehydro-aripiprazole, the active
metabolite, decreased by 32% and 47%. ABILIFY dose should be reduced to approximately one-half
of its prescribed dose when concomitant administration of ABILIFY 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.
In a clinical trial in healthy subjects, a potent inhibitor of CYP3A4 (ketoconazole) increased
aripiprazole AUC and C
max
by 63% and 37%, respectively. The AUC and C
max
of dehydro-aripiprazole
31
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 ABILIFY, potential benefits should outweigh the potential risks
to the patient. When concomitant administration of ketoconozole with ABILIFY occurs, ABILIFY
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 3A4 inhibitor, the dosage of ABILIFY 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 ABILIFY, modest increases in aripiprazole concentrations might be expected.
Following concomitant administration of carbamazepine, a potent inducer of CYP3A4, the geometric
means of C
max
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 C
max
and AUC after carbamazepine co-administration were 69% and 71% lower, respectively, than
those following treatment with aripiprazole alone.
ABILIFY dose should be doubled when concomitant administration of ABILIFY 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 ABILIFY should be reduced to the recommended dose.
When either valproate or lithium were administered concomitantly with aripiprazole, there was no
clinically significant change in aripiprazole concentrations.
Potential for ABILIFY to affect other medicinal products:
In clinical studies, 10-30 mg/day doses of aripiprazole had no significant effect on the metabolism of
substrates of CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), 2C9 (warfarin), 2C19
(omeprazole), and 3A4 (dextromethorphan). Additionally, aripiprazole and dehydro-aripiprazole 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.
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.
Aripiprazole was excreted in the milk of treated rats during lactation. It is not known whether
aripiprazole is excreted in human milk. Patients should be advised not to breast feed if they are taking
aripiprazole.
32
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 (see section 4.8).
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.
The following adverse reactions occurred more often
(≥ 1/100)
than placebo, or were identified as
possibly medically relevant adverse reactions (*):
The frequency listed below is defined using the following convention: common (≥ 1/100 to < 1/10)
and uncommon (≥ 1/1,000 to < 1/100).
Psychiatric disorders
Common:
restlessness, insomnia, anxiety
Uncommon:
depression*
Nervous system disorders
Common:
extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache
Eye disorders
Common:
blurred vision
Cardiac disorders
Uncommon:
tachycardia*
Vascular disorders
Uncommon:
orthostatic hypotension*
Gastrointestinal disorders
Common:
dyspepsia, vomiting, nausea, constipation, salivary hypersecretion
General disorders and administration site conditions
Common:
fatigue
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.
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 drugs. An elevated risk of acute dystonia is observed in males and
younger age groups.
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
33
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.
Other findings
:
Adverse reactions known to be associated with antipsychotic therapy and also reported during
treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure,
cerebrovascular adverse reactions and increased mortality in elderly demented patients,
hyperglycaemia and diabetes mellitus (see section 4.4).
Paediatric population:
In a short-term placebo-controlled clinical trial involving 302 adolescents (13-17 years) with
schizophrenia, the frequency and type of undesirable effects were similar to those in adults except for
the following events 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, < 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.
In the pooled adolescent schizophrenia population (13-17 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.
Post-Marketing:
The following adverse reactions have been reported during post-marketing surveillance. The
frequency of these reactions is considered not known (cannot be estimated from the available data).
Blood and the 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:
hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic
hyperosmolar coma
Metabolism and nutrition
disorders:
weight gain, weight decreased, anorexia, hyponatremia
Psychiatric disorders:
agitation, nervousness; suicide attempt, suicidal ideation, and
completed suicide (see section 4.4)
Nervous system disorders:
speech disorder, Neuroleptic Malignant Syndrome (NMS), grand
mal convulsion
Cardiac disorders:
QT prolongation, ventricular arrhythmias, sudden unexplained
death, cardiac arrest, torsades de pointes, bradycardia
Vascular disorders:
syncope, hypertension, venous thromboembolism (including
pulmonary embolism and deep vein thrombosis)
Respiratory, thoracic and
mediastinal disorders:
oropharyngeal spasm, laryngospasm, aspiration pneumonia
Gastrointestinal disorders:
pancreatitis, dysphagia, abdominal discomfort, stomach discomfort,
diarrhoea
34
Hepato-biliary disorders:
jaundice, hepatitis, 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
Reproductive system and
breast disorders:
priapism
General disorders and
administration site conditions:
temperature regulation disorder (e.g. hypothermia, pyrexia), chest
pain, peripheral oedema
Investigations:
increased Creatine Phosphokinase, blood glucose increased, blood
glucose fluctuation, glycosylated haemoglobin increased
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 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
max
by
about 41% and AUC by about 51%, suggesting that charcoal may be effective in the treatment of
overdose.
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12
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
35
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
11
C-raclopride, a D2/D3 receptor ligand, to the
caudate and putamen detected by positron emission tomography.
Further information on clinical trials:
Schizophrenia in adults:
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.
ABILIFY 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 stabilised patients with chronic schizophrenia, aripiprazole
had significantly greater reduction in relapse rate, 34% in aripiprazole group and 57% in placebo.
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.
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.
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 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:
36
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.
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 stabilization phase prior to randomization, 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 stabilizer.
Stabilized patients were then randomised to continue the same mood stabilizer with double-blind
aripiprazole or placebo. Four mood stabilizer subgroups were assessed in the randomised phase:
aripiprazole + lithium; aripiprazole + valproate; placebo + lithium; placebo + valproate.
37
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.
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.
Metabolism:
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 [
14
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.
Pharmacokinetics in special patient groups
Paediatric population:
The pharmacokinetics of aripiprazole and dehydro-aripiprazole in paediatric patients 13 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 and Race:
Population pharmacokinetic evaluation has revealed no evidence of clinically significant race-related
differences or effects from smoking upon the pharmacokinetics of aripiprazole.
38
Renal Disease:
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 Disease:
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 safety data revealed no special hazard for humans based on conventional studies of safety
pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and 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
2
). 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 effects 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.
6.1 List of excipients
Lactose monohydrate
Maize starch
Microcrystalline cellulose
Hydroxypropyl cellulose
Magnesium stearate
Yellow iron oxide (E172)
39
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Aluminium perforated unit dose blisters in cartons of 14 x 1, 28 x 1, 49 x 1, 56 x 1, 98 x 1 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Otsuka Pharmaceutical Europe Ltd.
Hunton House, Highbridge Business Park, Oxford Road
Uxbridge - Middlesex UB8 1HU - United Kingdom
8.
EU/1/04/276/011-015
9.
Date of first authorisation: 4 June 2004
Date of latest renewal: 4 June 2009
{MM/YYYY}
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu/
40
1.
Marketing Authorisation Holder
Otsuka Pharmaceutical Europe Ltd.
Hunton House, Highbridge Business Park, Oxford Road
Uxbridge - Middlesex UB8 1HU - United Kingdom
Manufacturer
Bristol-Myers Squibb S.r.l.
Contrada Fontana del Ceraso
I-03012 Anagni-Frosinone - Italy
206
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This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/
208
Source: European Medicines Agency
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