Last Updated on eMC 21-11-2016 View medicine  | Otsuka Pharmaceuticals (UK) Ltd Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties

Date of revision of text on the SPC:15-09-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.8 - paragraphs below have been added:

The safety profile of a long-term, double-blind placebo controlled trial was also similar except for the following reactions that were reported more frequently than paediatric patients taking placebo: weight decreased, blood insulin increased, arrhythmia, and leukopenia were reported commonly (≥ 1/100, < 1/10).


In two long term trials with adolescent (13-17 years) schizophrenia and bipolar patients treated with aripiprazole, incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 37.0 % and 59.4 %, respectively.


Section 5.1 - paragraph below has been added under paediatric population:

In a 60- to 89-week, randomised, double-blind, placebo-controlled trial in adolescent subjects (n = 146; ages 13-17 years) with schizophrenia, there was a statistically significant difference in the rate of relapse of psychotic symptoms between the aripiprazole (19.39%) and placebo (37.50%) groups. The point estimate of the hazard ratio (HR) was 0.461 (95% confidence interval, 0.242-0.879) in the full population. In subgroup analyses the point estimate of the HR was 0.495 for subjects 13 to 14 years of age compared to 0.454 for subjects 15 to 17 years of age. However, the estimation of the HR for the younger (13-14 years) group was not precise, reflecting the smaller number of subjects in that group (aripiprazole, n = 29; placebo, n = 12), and the confidence interval for this estimation (ranging from 0.151 to 1.628) did not allow conclusions to be drawn on the presence of a treatment effect. In contrast the 95% confidence interval for the HR in the older subgroup (aripiprazole, n = 69; placebo, n = 36) was 0.242 to 0.879 and hence a treatment effect could be concluded in the older patients.

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects

Date of revision of text on the SPC:26-04-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.8 - Hiccups added

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

Date of revision of text on the SPC:01-09-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Added to Section 4.8 undesirable effects: hyperprolactinaemia and aggression.

Section 5.1 pharmacodynamic properties updated with details of hyperprolactinaemia.

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects

Date of revision of text on the SPC:30-04-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



In section 4.8 (undesirable effects), hypersexuality has been added (uncommon)

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects

Date of revision of text on the SPC:30-10-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



The change is as follows:

  • Section 4.8 Undesirable effects
    Add
    diplopia as an uncommon adverse reaction under eye disorders for oral formulations.

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:27-03-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Minor changes are made throughout in line with the EU SmPC template

Reasons for adding or updating:

  • Change to section 1 - Name of the medicinal product
  • Change to section 4.8 - Undesirable effects
  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:21-11-2013

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



·         Section 1 Name Of The Medicinal Product

o        remove the black triangle as Abilify is not included on the EU list for additional monitoring of side-effects

·         Section 4.8 Undesirable effects

o        additional statement added under Undesirable effects under paediatric population Schizophrenia in adolescents aged 15 years and older:
In the adolescent (13-17 years) schizophrenia population with aripiprazole exposure of 5 to 30 mg up to 72 months, incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 25.6% and 45.0%, respectively.

o        Details of how to report suspected adverse reactions in the UK added

·         Section 7 Marketing Authorisation Holder

o        Update the address for the MAH

·         Section 10 Date of revision updated

Reasons for adding or updating:

  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.8 - Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Date of revision of text on the SPC:31-07-2013

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



This submission incorporates variations approved on 18th June and 31st July 2013

Section 4.4
(Special warnings and precautions for use)

·         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 accompany antipsychotic therapy. Results of an epidemiological study suggested that there was no increased risk of suicidality with aripiprazole compared to other antipsychotics among adult patients with schizophrenia or bipolar disorder. There are insufficient paediatric data to evaluate this risk in younger patients (below 18 years of age), but there is evidence that the risk of suicide persists beyond the first 4 weeks of treatment for atypical antipsychotics, including aripiprazole.

·         Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V

 

Section 4.5 (Interaction with other medicinal products and other forms of interaction)

Serotonin syndrome: cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and symptoms for this condition can occur especially in cases of concomitant use with other serotonergic drugs, such as SSRI/SNRI, or with drugs that are known to increase aripiprazole concentrations (see section 4.8).

 

Section 4.6 (Fertility, pregnancy and lactation)

Aripiprazole was excreted in the milk of treated rats during lactation. It is not known whether aripiprazole is excreted in human breast milk. Patients should be advised not to breast feed if they are taking aripiprazole.

 

Section 4.8 (Undesirable effects, Post-Marketing)

·         Nervous system disorders: speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion, serotonin syndrome

·         Hepatobiliary disorders: hepatic failure, jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatise

·         Reporting of suspected adverse reactions

·         Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V

 

 

Section 5.1 Pharmacodynamic properties

·         Aripiprazole was also studied in a placebo-controlled, long-term maintenance trial. After a 13-26 week stabilisation on aripiprazole (2-15 mg/day) patients with a stable response were either maintained on aripiprazole or substituted to placebo for further 16 weeks. Kaplan-Meier relapse rates at week 16 were 35% for aripiprazole and 52% for placebo; the hazard ratio for relapse within 16 weeks (aripiprazole/placebo) was 0.57 (non-statistically significant difference). The mean weight gain over the stabilisation phase (up to 26 weeks) on aripiprazole was 3.2 kg, and a further mean increase of 2.2 kg for aripiprazole as compared to 0.6 kg for placebo was observed in the second phase (16 weeks) of the trial. Extrapyramidal symptoms were mainly reported during the stabilisation phase in 17% of patients, with tremor accounting for 6.5%.



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:01-02-2013

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



4.2     Posology and method of administration

Elderly: the effectiveness of ABILIFY solution for injection in patients who are aged 65 years of age or and older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant (see section 4.4).


Cardiovascular disorders: Aripiprazole 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.


Other extrapyramidal symptoms: in paediatric clinical trials of aripiprazole akathisia and parkinsonism were observed. If signs and symptoms of other EPS appear in a patient taking ABILIFY, dose reduction and close clinical monitoring should be considered.

Weight gain:

(see section 5.1). In clinical trials of adolescent patients with bipolar mania, aripiprazole has been shown to be associated with weight gain after 4 weeks of treatment. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should be considered (see section 4.8).

 

Patients with ADHD comorbidity: despite the high comorbidity frequency of Bipolar I Disorder and ADHD, very limited safety data are available on concomitant use of ABILIFY and stimulants; therefore, extreme caution should be taken when these drugs are co-administered.


4.7     Effects on ability to drive and use machines

 

As with other antipsychotics, patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that aripiprazole does not affect them adversely . Some paediatric patients with Bipolar I Disorder have an increased incidence of somnolence and fatigue (see section 4.8).



4.8     Undesirable effects

 

Adults:

Paediatric population:

 

Schizophrenia in adolescents aged 15 years and older:


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

The frequency and type of undesirable effects in adolescents with Bipolar I Disorder were similar to those in adults except for the following reactions: very commonly (≥ 1/10) somnolence (23.0%), extrapyramidal disorder (18.4%), akathisia (16.0%), and fatigue (11.8%); and commonly (≥ 1/100, < 1/10) abdominal pain upper, heart rate increased, weight increased, increased appetite, muscle twitching, and dyskinesia.

 

The following undesirable effects had a possible dose response relationship; extrapyramidal disorder (incidences were 10 mg, 9.1%, 30 mg, 28.8%, placebo, 1.7%,); and akathisia (incidences were 10 mg, 12.1%, 30 mg, 20.3%, placebo, 1.7%).

 

Mean changes in body weight in adolescents with Bipolar I Disorder at 12 and 30 weeks for aripiprazole were 2.4 kg and 5.8 kg, and for placebo 0.2 kg and 2.3 kg, respectively.

 

In the paediatric population somnolence and fatigue were observed more frequently in patients with bipolar disorder compared to patients with schizophrenia.

 

In the paediatric bipolar population (10-17 years) with exposure up to 30 weeks, incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 28.0% and 53.3%, respectively.


5.1     Pharmacodynamic properties


Further information on clinical trials in adults:


Agitation in schizophrenia and Bipolar I Disorder in adults with aripiprazole solution for injection:

Schizophrenia in adults with oral aripiprazole:

In a 26-week, placebo-controlled trial in adult stabilised patients with chronic schizophrenia, oral aripiprazole had significantly greater reduction in relapse rate, 34% in oral aripiprazole group and 57% in placebo.

 

Paediatric population:

Schizophrenia in adolescents with oral aripiprazole: 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.


Weight gain:

In clinical trials oral aripiprazole has not been shown to induce clinically relevant weight gain. In a 26-week, olanzapine-controlled, double-blind, multi-national study of schizophrenia which included 314 adult patients and where the primary end-point was weight gain, significantly less patients had at least 7% weight gain over baseline (i.e. a gain of at least 5.6 kg for a mean baseline weight of ~80.5 kg) on oral aripiprazole (N= 18, or 13% of evaluable patients), compared to oral olanzapine (N= 45, or 33% of evaluable patients).


Paediatric population:

 

Schizophrenia in adolescents with oral aripiprazole:

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.

 

Paediatric population:

 

Schizophrenia in adolescents with oral aripiprazole:

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.

 

Manic episodes in Bipolar I Disorder in children and adolescents:

Aripiprazole was studied in a 30-week placebo-controlled trial involving 296 children and adolescents (10-17 years), who met DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes with or without psychotic features and had a Y-MRS score ³20 at baseline. Among the patients included in the primary efficacy analysis, 139 patients had a current co-morbid diagnosis of ADHD.

 

Aripiprazole was superior to placebo in change from baseline at week 4 and at week 12 on the Y-MRS total score. In a post-hoc analysis, the improvement over placebo was more pronounced in the patients with associated co-morbidity of ADHD compared to the group without ADHD, where there was no difference from placebo. Recurrence prevention was not established.



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

Psychiatric
comorbidities

Week 4

Week 12

ADHD

Week 4

Week 12

Abilify 10 mg (n=48)

14.9

15.1

Abilify 10 mg  (n=44)

15.2

15.6

Abilify 30 mg (n=51)

16.7

16.9

Abilify 30 mg (n=48)

15.9

16.7

Placebo (n=52)a

7.0

8.2

Placebo (n=47)b

6.3

7.0

No psychiatric comorbidities

Week 4

Week 12

No ADHD

Week 4

Week 12

Abilify 10 mg (n=27)

12.8

15.9

Abilify 10 mg (n=37)

12.7

15.7

Abilify 30 mg (n=25)

15.3

14.7

Abilify 30 mg (n=30)

14.6

13.4

Placebo (n=18)

9.4

9.7

Placebo (n=25)

9.9

10.0


a n=51 at Week 4

b n=46 at Week 4

 

The most common treatment-emergent adverse events among patients receiving 30 mg were extrapyramidal disorder (28.3%), somnolence (27.3%), headache (23.2%), and nausea (14.1%). Mean weight gain in the 30 weeks treatment-interval was 2.9 kg as compared to 0.98 kg in patients treated with placebo.

 

The European Medicines Agency has deferred the obligation to submit the results of studies with ABILIFY in one or more subsets of the paediatric population in the treatment of schizophrenia and in the treatment of bipolar affective disorder (see section 4.2 for information on paediatric use).


7.       MARKETING AUTHORISATION HOLDER

 

Otsuka Pharmaceutical Europe Ltd.
Hunton House, Highbridge Business ParkEstate, Oxford Road
Uxbridge - Middlesex UB8 1HU 1LX - United Kingdom


10.     DATE OF REVISION OF THE TEXT

 

01 February 2013



Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:19-11-2012

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

4.4       Special warnings and precautions for use

Pathological gambling: post-marketing reports of pathological gambling have been reported among patients prescribed ABILIFY, regardless of whether these patients had a prior history of gambling. Patients with a prior history of pathological gambling may be at increased risk and should be monitored carefully (see section 4.8).

4.8       Undesirable effects

Psychiatric disorders:

agitation, nervousness, pathological gambling; suicide attempt, suicidal ideation, and completed suicide (see section 4.4)


10.        Change of Revision of text  
November 2012





 

Reasons for adding or updating:

  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:01-09-2011

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

10.       DATE OF REVISION OF THE TEXT

            September 2011

Reasons for adding or updating:

  • Change to section 10 date of revision of the text
  • Addition of Legal Category
  • Improved Electronic Presentation

Date of revision of text on the SPC:30-03-2012

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



Section 10  -  DATE OF REVISION OF THE TEXT

 

March 2012

 

Section 11  -  LEGAL CATEGORY

 

POM

Reasons for adding or updating:

  • Change to section 4.6 - Pregnancy and Lactation
  • Change to section 4.8 - Undesirable Effects
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:21-09-2011

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

4.6  Fertility, pregnancy and lactation

the following has been added :

Neonates exposed to antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.


4.8     Undesirable effects

The following has been added :

Pregnancy, puerperium and perinatal conditions:

 

drug withdrawal syndrome neonatal (see section 4.6)

Reasons for adding or updating:

  • Change to section 5.1 - Pharmacodynamic Properties

Date of revision of text on the SPC:01-01-2011

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



The following has been added to section 5.1  



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.

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.

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC:01-11-2010

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

In section 4,8 the following text in red has  has been added :

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 oral aripiprazole thatn in adults receiving oral 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.

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.6 - Pregnancy and Lactation
  • Change to section 4.7 - Effects on Ability to Drive and Use Machines
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 5.3 - Preclinical Safety Data
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:29-03-2010

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



4.2     Posology and method of administration

 

Posology

 

The recommended initial dose for aripiprazole solution for injection is 9.75 mg (1.3 ml), administered as a single intramuscular injection. The effective dose range of aripiprazole solution for injection is 5.25‑15 mg as a single injection. A lower dose of 5.25 mg (0.7 ml) may be given, on the basis of individual clinical status, which should also include consideration of medicinal products already administered either for maintenance or acute treatment (see section 4.5). A second injection may be administered 2 hours after the first injection, on the basis of individual clinical status and no more than three injections should be given in any 24-hour period.

 

The maximum daily dose of aripiprazole is 30 mg (including all formulations of aripiprazole).

 

If continued treatment is indicated with oral aripiprazole, see the Summary of Product Characteristics for ABILIFY tablets, ABILIFY orodispersible tablets, or ABILIFY oral solution.

 

ABILIFY solution for injection is for intramuscular use.

 

To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended.

 

ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1).

 

Paedriatic populationChildren and adolescents: there is no experience in children and adolescents under 18 years of age.

 

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 solution for injection in patients who are 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 solution for injection is for intramuscular use.

 

To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended.

 

ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1).

 

 

 

 

4.4     Special warnings and precautions for use

 

 

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 accompany antipsychotic therapy. Results of an epidemiological study suggestedfound that there was no increased risk of suicidality with aripiprazole compared to other antipsychotics among patients with schizophrenia or bipolar disorder.

 

 

 

4.6     PregnancyFertility, pregnancy and lactation

 

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.

 

4.7     Effects on ability to drive and use machines

 

No studies on the effect on the ability to drive and use machines have been performed. However, asAs 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).

 

4.8     Undesirable effects

 

Paediatric patientspopulation:

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 oral aripiprazole thatn in adults receiving oral 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.

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

Paediatric population:

Schizophrenia in adolescents with oral aripiprazole:

In 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.

 

 

 

5.2     Pharmacokinetic properties

 

 

Pharmacokinetics in special patient groups

 

Paediatric patientspopulation:

The pharmacokinetics of oral 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.

 

 

5.3     Preclinical safety data

 

Administration of aripiprazole solution for injection was well tolerated and produced no direct target organ toxicity in rats or monkeys after repeated dosing at systemic exposures (AUC) that were 15 and 5 times, respectively, human exposure at the maximum recommended human dose of 30 mg intramuscular. In intravenous reproductive toxicity studies, no new safety concerns were observed at maternal exposures up to 15 (rat) and 29 (rabbit) times human exposure at 30 mg.

 

Non-clinical safety data revealed no special hazard for humans based on conventional oral aripiprazole studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.

 

Date of latest renewal: 4 June 2009

 

 

10.     DATE OF REVISION OF THE TEXT

 

March 2010November 2009

 

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/

Reasons for adding or updating:

  • Correction of spelling/typing errors

Date of revision of text on the SPC:05-11-2009

Legal Category:POM

Black Triangle (CHM): YES

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.8 - Undesirable Effects
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:01-11-2009

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

Section 4.4: Add the following text:

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.



Section 4.8

Amendment of the introductory statement to:

The most commonly reported adverse reactions in placebo-controlled trials are nausea, dizziness and somnolence each occurring in more than 3% of patients treated with aripiprazole solution for injection..



Amendment within table:

Vascular disorders:

syncope, hypertension, venous thromboembolism (including pulmonary embolism and deep vein thrombosis)


Section 10: Update revision of text date to:

November 2009

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 5.3 - Preclinical Safety Data
  • Change to section 9 - Date of first Authorisation/renewal of the Authorisation
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:21-08-2009

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:


Section 4.8 After the paragraph on 'other findings' a paragraph has been added on 'Paediatric patients'

Section 5.1 before the paragraph on 'weight gain' a paragraph has been added on 'Schizophrenia in adolescents' regarding a 6-week trial and a sub-analysi of the trial.

Section 5.2 under 'pharmacokinetics in special patient groups' a paragraph has been added on 'Paediatric patients'.

Section 5.3 before the last paragraph on genotoxicity tests, a paragraph has been added on 'repeat dose studies in juvenile rats and dogs..'

Section 9 A typo has been amended for the date of latest renewal to 4 June 2009.

Section 10 the date of revision of the text has been updated to August 2009.

Reasons for adding or updating:

  • Change to section 4.6 - Pregnancy and Lactation
  • Change to section 4.8 - Undesirable Effects
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:07-07-2009

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

4.6 This statement has been added: Congenital anomalies have been reported; however causal relationship with aripiprazole could not be established.

4.8 The introduction has been added: The most commonly reported adverse reactions in placebo-controlled trials are headache, insomnia and nausea each occurring in more than 10% of patients treated with oral aripiprazole.

Also a class effect on dystonia has been added:

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.



Section 10. The date of revision of text is 07/2009

Reasons for adding or updating:

  • Change to section 1 -Name of the Medicinal product
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.7 - Effects on Ability to Drive and Use Machines
  • Change to section 4.8 - Undesirable Effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:08-06-2009

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



 

 

1.       NAME OF THE MEDICINAL PRODUCT

 

ABILIFY®q 7.5 mg/ml solution for injection

 

 

4.2     Posology and method of administration

 

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).

 

 

4.4     Special warnings and precautions for use

 

Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic treatment, including ABILIFY. Aripiprazole and other antipsychotic drugs active substances should be used cautiously in patients at risk for aspiration pneumonia.

 

4.5     Interaction with other medicinal products and other forms of interaction

 

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).

 

When aripiprazole was administered concomitantly with either valproate or , lithium or lamotrigine, there was no clinically important change in valproate or , lithium or lamotrigine concentrations.

 

 


 

4.7     Effects on ability to drive and use machines

 

No studies on the effect on the ability to drive and use machines have been performed. However, 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).

.

4.8     Undesirable effects

 

The following adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1):

The frequency listed below is defined using the following convention: common (³ 1/100 to < 1/10) and uncommon (³ 1/1,000 to < 1/100).

 

The following undesirable effects adverse events occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1):

 

Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory and lipid parameters (see section 5.1) revealed no medically important differences. Elevations of CPK (Creatine Phosphokinase), generally transient and asymptomatic, were observed in 3.5% of aripiprazole treated patients as compared to 2.0% of patients who received placebo.

 

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, thromboembolic reactionsevents

 

 

Respiratory, thoracic and mediastinal disorders:

oropharyngeal spasm, laryngospasm, aspiration pneumonia

 

 

Gastrointestinal disorders:

pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea

 

 

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

 

4.9     Overdose

 

In clinical trials and post-marketing experience, accidental or intentional acute overdosage 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.

 

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

Further information on clinical trials:

 

Weight gain: in clinical trials oral 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 oral aripiprazole (N= 18, or 13% of evaluable patients), compared to oral olanzapine (N= 45, or 33% of evaluable patients).

 

Lipid parameters: in a pooled analysis on lipid parameters from placebo controlled clinical trials in adults, aripiprazole has not been shown to induce clinically relevant alterations in levels of total cholesterol, triglycerides, HDL and LDL.

-Total cholesterol: incidence of changes in levels from normal (<5.18 mmol/l) to high (≥ 6.22 mmol/l) was 2.5% for aripiprazole and 2.8% for placebo and mean change from baseline was -0.15 mmol/l

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

-Fasting triglycerides: incidence of changes in levels from normal (<1.69 mmol/l) to high (≥ 2.26 mmol/l) was 7.4% for aripiprazole and 7.0% for placebo and mean change from baseline was -0.11 mmol/l

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

-HDL: incidence of changes in levels from normal (≥ 1.04 mmol/l) to low (<1.04 mmol/l) was 11.4% for aripiprazole and 12.5% for placebo and mean change from baseline was -0.03 mmol/l

(95% CI: -0.046, -0.017) for aripiprazole and -0.04 mmol/l (95% CI: -0.056, -0.022) for placebo.

-Fasting LDL: incidence of changes in levels from normal (<2.59 mmol/l) to high (≥ 4.14 mmol/l) was 0.6% for aripiprazole and 0.7% for placebo and mean change from baseline was -0.09 mmol/l

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

 

 

10.     DATE OF REVISION OF THE TEXT

 

0406/2009

 

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/



 

 

Reasons for adding or updating:

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 6. 6 - Instructions for use, handling and disposal
  • Change to section 9 - Date of first Authorisation/renewal of the Authorisation
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:21-04-2009

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each ml contains 7.5 mg of aripiprazole.

 

A Each vial contains 9.75 mg aripiprazole.

 

4.2     Posology and method of administration

 

For intramuscular use.

 

To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended.

 

ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1).

 

The recommended initial dose for aripiprazole solution for injection is 9.75 mg (1.3 ml), administered as a single intramuscular injection. The effective dose range of aripiprazole solution for injection is 5.25‑15 mg as a single injection. A lower dose of 5.25 mg (0.7 ml) may be given, on the basis of individual clinical status, which should also include consideration of medicinal products already administered either for maintenance or acute treatment (see section 4.5). A second injection may be administered 2 hours after the first injection, on the basis of individual clinical status and no more than three injections should be given in any 24-hour period.

 

The maximum daily dose of aripiprazole is 30 mg (including all formulations of aripiprazole).

 

If continued treatment is indicated with oral aripiprazole, see the Summary of Product Characteristics for ABILIFY tablets, ABILIFY orodispersible tablets, or ABILIFY oral solution.

 

ABILIFY solution for injection is for intramuscular use.

 

To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended.

 

ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1).

 

............................

 

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).

 

4.4     Special warnings and precautions for use

..............................................

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 medicationsmedicinal products) or hypertension, including accelerated or malignant.

 

.......................

 

Tardive Dyskinesiadyskinesia: 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.

 

....................................................

 

Cerebrovascular adverse eventsreactions: in the same trials, cerebrovascular adverse eventsreactions (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 eventsreactions 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 eventsreactions in patients treated with aripiprazole.

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

 

Hyperglycaemia and Diabetes diabetes Mellitusmellitus: 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 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 eventsreactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse eventsreactions 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 drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

 

Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8).

 

4.5     Interaction with other medicinal products and other forms of interaction

 

Due to its α1‑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 undesirable effects adverse reactions such as sedation (see section 4.8).

 

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

 

 

4.8     Undesirable effects

 

The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1):

The frequency listed below is defined using the following convention: common (³ 1/100 to < 1/10) and uncommon (³ 1/1,000 to < 1/100).

 

Cardiac disorders

Uncommon: tachycardia*

 

Nervous system disorders

Common: somnolence, dizziness, headache, akathisia

 

Cardiac disorders

Uncommon: tachycardia*

 

Vascular disorders

Uncommon: orthostatic hypotension*, increased diastolic blood pressure*

 

Gastrointestinal disorders

Common: nausea, vomiting

Uncommon: dry mouth*

Vascular disorders

Uncommon: orthostatic hypotension*, increased diastolic blood pressure*

 

General disorders and administration site conditions

Uncommon: fatigue*

 

 

The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1):

 

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*

Nervous system disorders

Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache

Eye disorders

Common: blurred vision

Vascular disorders

Uncommon: orthostatic hypotension*

Gastrointestinal disorders

Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion

Vascular disorders

Uncommon: orthostatic hypotension*

General disorders and administration site conditions

Common: fatigue

Psychiatric disorders

Common: restlessness, insomnia, anxiety

Uncommon: depression*

 

.........................

 

Other findings:

Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4).

 

Post-Marketing:

The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions 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, thromboembolic reactions

 

 

Respiratory, thoracic and mediastinal disorders:

oropharyngeal spasm, laryngospasm, aspiration pneumonia

 

 

Gastrointestinal disorders:

pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea

 

 

Hepatobiliary 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

 

 

Cardiac disorders:

QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia

 

 

Blood and the lymphatic system disorders:

leukopenia, neutropenia, thrombocytopenia

 

 

Nervous system disorders:

speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion

 

 

Respiratory, thoracic and mediastinal disorders:

oropharyngeal spasm, laryngospasm, aspiration pneumonia

 

 

Gastrointestinal disorders:

pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea

 

 

Renal and urinary disorders:

urinary incontinence, urinary retention

 

 

Skin and subcutaneous tissue disorders:

rash, photosensitivity reaction, alopecia, hyperhidrosis

 

 

Musculoskeletal and connective tissue disorders:

rhabdomyolysis, myalgia, stiffness

 

 

 

Endocrine disorders:

hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma

 

 

Metabolism and nutrition disorders:

weight gain, weight decreased, anorexia, hyponatremia

 

 

Vascular disorders:

syncope, hypertension, thromboembolic events

 

 

General disorders and administration site conditions:

temperature regulation disorder (e.g. hypothermia, pyrexia),

chest pain, peripheral oedema

 

 

 

Immune system disorders:

allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria)

 

 

Hepatobiliary disorders:

jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase

 

 

Reproductive system and breast disorders:

priapism

 

 

 

Psychiatric disorders:

agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4)

 

 

5.1     Pharmacodynamic properties

 

Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12

 

..................................

 

6.3     Shelf life

 

18 months

After opening: uUse product immediately after opening and discard any unused amount.

 

 

6.6     Special precautions for disposal and other handling

 

Any unused product or waste material should be disposed of in accordance with local requirements.

 

 

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 4 June 2004

Date of latest renewal: 21 April 2009

 

 

10.     DATE OF REVISION OF THE TEXT

 

August 2008 04/2009

 

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:31-08-2008

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



4.4       Special warnings and precautions for use

 

Addition of: 'Results of an epidemiological study found that there was no increased risk of suicidality with aripiprazole compared to other antipsychotics among patients with bipolar disorder.'

10.       DATE OF REVISION OF THE TEXT

 

Changed from March 2008 to August 2008

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 5.3 - Preclinical Safety Data
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:01-06-2008

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



4.1     Therapeutic indications

 

ABILIFY solution for injection is indicated for the rapid control of agitation and disturbed behaviours in patients with schizophrenia or in patients with manic episodes in Bipolar I Disorder, when oral therapy is not appropriate.

Treatment with aripiprazole solution for injection should be discontinued as soon as clinically appropriate and the use of oral aripiprazole should be initiated.

 

4.4     Special warnings and precautions for use

 

The efficacy of aripiprazole solution for injection in patients with agitation and disturbed behaviours has not been established related to conditions other than schizophrenia and manic episodes in Bipolar I Disorder.

4.8     Undesirable effects

 

The following undesirable effects occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1):

The frequency listed below is defined using the following convention: common (³ 1/100, < 1/10) and uncommon (³ 1/1,000, < 1/100).

 

 

 

Cardiac disorders

Uncommon: tachycardia*

 

Nervous system disorders

Common: somnolence, dizziness, headache, akathisia

 

Gastrointestinal disorders

Common: nausea, vomiting

Uncommon: dry mouth*

Vascular disorders

Uncommon: orthostatic hypotension*, increased diastolic blood pressure*

 

General disorders and administration site conditions

Uncommon: fatigue*

 

 

The following undesirable effects occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1):

 

Cardiac disorders

Uncommon: tachycardia*

Nervous system disorders

Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache

Eye disorders

Common: blurred vision

Gastrointestinal disorders

Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion

Vascular disorders

Uncommon: orthostatic hypotension*

General disorders and administration site conditions

Common: fatigue[K1] 

Psychiatric disorders

Common: restlessness, insomnia, anxiety

Uncommon: depression*

 

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.

 

Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory parameters revealed no medically important differences. Elevations of CPK (Creatine Phosphokinase), generally transient and asymptomatic, were observed in 3.5% of aripiprazole treated patients as compared to 2.0% of patients who received placebo.

 

Other findings:

Undesirable effects known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse events and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4).

 

Post-Marketing:

The following adverse events have been reported during post-marketing surveillance. The frequency of these events is considered not known (cannot be estimated from the available data).

 

Investigations:

increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased

 

 

Cardiac disorders:

QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia

 

 

Blood and the lymphatic system disorders:

leucopenia, neutropenia, thrombocytopenia

 

 

Nervous system disorders:

speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion

 

 

Respiratory, thoracic and mediastinal disorders:

oropharyngeal spasm, laryngospasm, aspiration pneumonia

 

 

Gastrointestinal disorders:

pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea[K2] 

 

 

Renal and urinary disorders:

urinary incontinence, urinary retention

 

 

Skin and subcutaneous tissue disorders:

rash, photosensitivity reaction, alopecia, hyperhidrosis

 

 

Musculoskeletal and connective tissue disorders:

rhabdomyolysis, myalgia, stiffness

 

 

 

Endocrine disorders:

hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma

 

 

Metabolism and nutrition disorders:

weight gain, weight decreased, anorexia, hyponatremia

 

 

Vascular disorders:

syncope, hypertension, thromboembolic events

 

 

General disorders and administration site conditions:

temperature regulation disorder (e.g. hypothermia, pyrexia),

chest pain, peripheral oedema

 

 

 

Immune system disorders:

allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria)

 

 

Hepatobiliary disorders:

jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase

 

 

Reproductive system and breast disorders:

priapism

 

 

 

Psychiatric disorders:

agitation, nervousness; suicide attempt, suicidal ideation, and completed suicide (see section 4.4[K3] )


 [K1]Asthenia deleted

 [K2]Inc salivation removed

 [K3] Suicide section enters table

Anxiety here for oral, not IM

5.1     Pharmacodynamic properties

 

Pharmacotherapeutic group: 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 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 11C‑raclopride, a D2/D3 receptor ligand, to the caudate and putamen detected by positron emission tomography.

 

Further information on clinical trials:

 

Agitation in schizophrenia and Bipolar I Disorder with aripiprazole solution for injection:

In two short- term (24-hour) placebo-controlled trials involving 554 schizophrenic patients presenting with agitation and disturbed behaviours, aripiprazole solution for injection was associated with statistically significant greater improvements in agitation/behavioural symptoms compared to placebo and was similar to haloperidol. In one short-term (24-hour) placebo-controlled trial involving 291 patients with bipolar disorder presenting with agitation and disturbed behaviours, aripiprazole solution for injection was associated with statistically significant greater improvements in agitation/behavioural symptoms compared to placebo and was similar to the reference arm lorazepam. The observed mean improvement from baseline on the PANSS Excitement Component score at the primary 2-hour endpoint was 5.8 for placebo, 9.6 for lorazepam, and 8.7 for aripiprazole. In subpopulation analyses on patients with mixed episodes or on patients with severe agitation, a similar pattern of efficacy to the overall population was observed but statistical significance could not be established due to a reduced sample size.

 

Schizophrenia with oral aripiprazole:

In three short-term (4 to 6 weeks) placebo-controlled trials involving 1,228 schizophrenic patients, presenting with positive or negative symptoms, oral 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 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 (oral aripiprazole 77% and haloperidol 73%). The overall completion rate was significantly higher for patients on oral aripiprazole (43%) than for oral 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, oral aripiprazole had significantly greater reduction in relapse rate, 34% in oral aripiprazole group and 57% in placebo.

 

Weight gain: in clinical trials oral 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 oral aripiprazole (N= 18, or 13% of evaluable patients), compared to oral olanzapine (N= 45, or 33% of evaluable patients).

 

Manic episodes in Bipolar I Disorder with oral aripiprazole:

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.

5.3     Preclinical safety data

 

Administration of aripiprazole solution for injection was well tolerated and produced no direct target organ toxicity in rats or monkeys after repeated dosing at systemic exposures (AUC) that were 15 and 5 times, respectively, human exposure at the maximum recommended human dose of 30 mg intramuscular. In intravenous reproductive toxicity studies, no new safety concerns were observed at maternal exposures up to 15 (rat) and 29 (rabbit) times human exposure at 30 mg.

 

Non-clinical safety data revealed no special hazard for humans based on conventional oral aripiprazole studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.

 

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/m2). 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.

 

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.

10.     DATE OF REVISION OF THE TEXT

 

06/2008

(Was Feb08)

Reasons for adding or updating:

  • New SPC for new product