Abilify

Main information

  • Trade name:
  • Abilify 2 mg Tablet
  • Dosage:
  • 2 mg
  • Pharmaceutical form:
  • Tablet
  • Units in package:
  • Blister pack, AL/AL - 5 tablets, 5 tablets
  • Class:
  • Prescription
  • Prescription type:
  • Prescription
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug
  • Manufactured by:
  • Otsuka Pharmaceutical Co Ltd

Documents

Localization

  • Available in:
  • Abilify 2 mg Tablet
    New Zealand
  • Language:
  • English

Therapeutic information

  • Therapeutic indications:
  • ABILIFY is indicated of the treatment of schizophrenia including maintenance of clinical improvement during continuation therapy.

Other information

Status

  • Source:
  • Medsafe - Medicines Safety Authority - New Zealand
  • Authorization number:
  • 12898
  • Authorization date:
  • 18-08-2006
  • Last update:
  • 27-09-2017

Summary of Product characteristics: dosage,interactions,side effects

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Data Sheet

ABILIFY

TM

aripiprazole

Tablets: 5 mg 10 mg, 15 mg, 20 mg & 30 mg

NAME OF THE MEDICINE

Aripiprazole.

Aripiprazole is 7-[4-[4-(2, 3-dichlorophenyl)-1-piperazinyl] butoxy]-3, 4- dihydrocarbostyril.

DESCRIPTION

ABILIFY

is a novel antipsychotic agent with unique pharmacologic properties and a chemical

structure that differs from current antipsychotic

agents.

The empirical formula is C

and its molecular weight is 448.39. The chemical

structure is:

The CAS registry number for aripiprazole is 129722-12-9.

Since aripiprazole is insoluble in water with its equilibrium solubility being about 0.00001% w/v,

its pKa was established in 20% aqueous ethanol pKa = 7.6 (20% ethanol, at 25

C). The partition

coefficients (P

) of aripiprazole range from 3.4 at pH 2.0 to > 1000 at pH 6.0.

ABILIFY

is available as 5 mg (blue, unscored), 10 mg (pink, unscored), 15 mg (yellow,

unscored), 20 mg

(white, unscored), and 30 mg (pink, unscored) tablets for oral administration.

The inactive ingredients in the tablets are: lactose, maize starch, microcrystalline cellulose,

hydroxypropylcellulose, and magnesium stearate. The following colorants are also contained in

the tablets: 5 mg tablets - indigo carmine CI73015 aluminium lake; 10 mg tablets - red iron oxide

CI77491; 15 mg tablets – yellow iron oxide CI77492; 20 mg tablets – nil; 30 mg tablets – red iron

oxide CI77491.

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PHARMACOLOGY

Pharmacodynamics

The mechanism of action of ABILIFY

, as well as other drugs having efficacy in schizophrenia

and bipolar disorder, is unknown. However, it has been proposed that the efficacy of ABILIFY

is mediated through a combination of partial agonist activity at dopamine D

and serotonin 5HT

receptors and antagonist activity at serotonin 5HT

receptors.

ABILIFY

activity is primarily due to the parent drug, aripiprazole

Aripiprazole exhibited higher affinity binding

in vitro

for dopamine D

and D

, serotonin 5HT

and 5HT

receptors (K

values of 0.3, 0.8, 1.7, and 3.4nM, respectively), than for dopamine D

serotonin 5HT

and 5HT

, alpha

-adrenergic and histamine H

receptors (K

values of 44, 15, 39,

57, and 61nM, respectively) and the serotonin reuptake site (K

value of 98nM). Aripiprazole

exhibited no appreciable affinity for muscarinic receptors (IC

>1000nM).

The predominant metabolite in human plasma, dehydro-aripiprazole has been shown to have a

similar affinity for dopamine D

and D

receptors (K

values 0.4 and 0.5nM, respectively) as the

parent compound and a much lower affinity for the other receptor subtypes.

Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and

agonist properties in animal models of dopaminergic hypoactivity.

Interaction with receptors other than dopamine and serotonin subtypes may explain some of the

other clinical effects of ABILIFY

Pharmacokinetics

Absorption

Aripiprazole is well absorbed after oral

administration of ABILIFY

, with peak plasma

concentrations occurring within 3-5 hours after dosing. The absolute oral bioavailability of the

tablet formulation of ABILIFY

is 87%. ABILIFY

can be administered without regard to

meals. Following administration of a 15 mg ABILIFY

tablet with a standard high-fat meal, the

Cmax of aripiprazole and its active metabolite, dehydro-aripiprazole, increased by 11%. The AUC

of aripiprazole was increased by 18% and that of the active metabolite by 14%. Food delayed

Tmax by 3 hours

aripiprazole and 12 hours for the

active metabolite. Aripiprazole

accumulation

predictable

from

single

dose

pharmacokinetics.

steady

state,

pharmacokinetics of aripiprazole are dose-proportional. There is no diurnal variation in the

disposition of aripiprazole and its active metabolite, dehydro-aripiprazole.

Distribution

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

4.9 L/kg. At therapeutic concentrations, aripiprazole is highly bound (88 –97% to > 99%, as

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determined by polydimethylsiloxane-glass bead and equilibrium dialysis assays, respectively) to

serum proteins, primarily albumin

, in vitro

. Aripiprazole did not alter the pharmacokinetics and

pharmacodynamics of highly protein-bound warfarin, suggesting that protein displacement of

warfarin did not occur.

Metabolism

Aripiprazole

undergoes

minimal

pre-systemic

metabolism.

Aripiprazole

extensively

metabolized by the liver primarily by

three

biotransformation pathways: dehydrogenation,

hydroxylation, and N-dealkylation. Based on

in vitro

studies, CYP3A4 and CYP2D6 enzymes are

primarily responsible for dehydrogenation and hydroxylation of aripiprazole, while N-dealkylation

is primarily catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in systemic

circulation. At steady state, dehydro-aripiprazole, the active metabolite, represented about 39% of

aripiprazole AUC in plasma. Approximately 8% of Caucasians lack the capacity to metabolize

CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are extensive

metabolizers (EM). PMs have about an 80% increase in aripiprazole exposure and about a 30%

decrease in exposure to the active metabolite compared to EMs, resulting in about a 60% higher

exposure to the total active moieties from a given dose of aripiprazole compared to EMs. Subjects

were entered into clinical studies without knowledge of their metabolizer status and, therefore, the

safety profile reflects experience in both EMs and PMs.

Excretion

Following a single, oral dose of [

C]-labelled aripiprazole, approximately 27% and 60% of the

administered radioactivity was recovered in the urine and faeces, respectively. Less than 1% of

unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was

recovered unchanged in the faeces. The total body clearance of aripiprazole is 0.7mL/min/kg,

which is primarily hepatic.

In a bioavailability study comparing fasted and fed subjects at a dose of 15 mg, the elimination

half-life of aripiprazole from human plasma was found to be 75 hours mean, range 32–146 hours,

n=58, in fasted subjects and 84 hours mean, range 32-157 hours, n=57 in subjects taking a high-

fat meal immediately before drug administration. Steady-state concentrations are attained within

14 days of dosing. The plasma elimination half-life of the chief metabolite, dehydro-aripiprazole,

from human plasma was found to be approx. 100 hours.

Elderly

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

younger adult subjects nor was there any detectable effect of age in a population pharmacokinetic

analysis

schizophrenic

patients.

formal

single-dose

pharmacokinetic

studies

(with

aripiprazole given in a single dose of 15 mg), aripiprazole clearance was 20% lower in elderly (

65 years) subjects compared to younger adult subjects (18-64 years). There was no detectable age

effect, however, in the population pharmacokinetic analysis in schizophrenia patients. Also, the

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pharmacokinetics of aripiprazole after multiple doses in elderly patients appeared similar to that

observed in young healthy subjects. No dosage adjustment is recommended for elderly patients.

(See

PRECAUTIONS

: Increased Mortality in Elderly Patients with Dementia- Related

Psychosis

Use in the Elderly

Gender

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

female subjects nor was there any detectable effect of gender in a population pharmacokinetic

analysis in schizophrenic patients.

Cmax and AUC of aripiprazole and its active metabolite,

dehydro-aripiprazole, are 30 to 40% higher in women than in men, and correspondingly, the

apparent oral clearance of aripiprazole is lower in women. These differences, however, are largely

explained by differences in body weight (25%) between men and women. No dosage adjustment

is recommended based on gender.

Race

Population pharmacokinetic evaluation has revealed no evidence of clinically significant race-

related differences in the pharmacokinetics of aripiprazole.

Smoking

Population pharmacokinetic evaluation has revealed no evidence of clinically significant effects

of smoking on the pharmacokinetics of aripiprazole. Based on studies utilizing human liver

enzymes

in vitro

, aripiprazole is not a substrate for CYP1A2 and also does not undergo direct

glucuronidation. Smoking should, therefore, not have an effect on the pharmacokinetics of

aripiprazole. Consistent with these

in vitro

results, population pharmacokinetic evaluation did not

reveal any significant pharmacokinetic differences between smokers and non-smokers. No dosage

adjustment is recommended based on smoking status.

Renal Impairment

The pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were found to be

similar in patients with severe renal disease compared to young healthy subjects. In patients with

severe renal impairment (creatinine clearance <30 mL/min), Cmax of aripiprazole (given in a

single dose of 15 mg) and dehydro-aripiprazole increased by 36% and 53%, respectively, but AUC

was 15% lower for aripiprazole and 7% higher for dehydro-aripiprazole. Renal excretion of both

unchanged aripiprazole and dehydro-aripiprazole is less than 1% of the dose. No dosage

adjustment is required in subjects with renal impairment.

Hepatic Impairment

A study in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C) did

not reveal a significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and

dehydro-aripiprazole.

In a single-dose study (15 mg of aripiprazole) in subjects with varying

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degrees of liver cirrhosis (Child-Pugh Classes A, B, and C), the AUC of aripiprazole, compared to

healthy subjects, increased 31% in mild HI, increased 8% in moderate HI, and decreased 20% in

severe HI. None of these differences would require dose adjustment.

Clinical Trials

Schizophrenia

The efficacy of ABILIFY

in the treatment of schizophrenia was evaluated in six short-term (4-

and 6-week), placebo-controlled trials of inpatients, four of which also included an active control

group consisting of either risperidone (one trial) or haloperidol (three trials). Studies were not

powered to allow for a comparison of ABILIFY

and the active comparators. Efficacy was also

documented in two long-term trials, one of 52 weeks duration, which compared ABILIFY

haloperidol and one of 26 weeks duration, which compared ABILIFY

to placebo. Patients in

these trials met DSM-III/IV criteria for schizophrenia or schizo-affective disorder.

Several instruments were used for assessing psychiatric signs and symptoms. The Positive and

Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) are both multi-

item inventories of general psychopathology used to evaluate the effects of drug treatment in

schizophrenia. The BPRS Psychosis Cluster (Core Score), a subset of the BPRS that can also be

derived from the PANSS, is used to assess actively psychotic patients. The Clinical Global

Impression (CGI) assessment reflects the impression of a skilled observer, fully familiar with the

manifestations of schizophrenia, about the overall clinical state of the patient.

Four short-term, fixed-dose trials were well controlled and powered to statistically demonstrate

the efficacy of ABILIFY

over placebo. The results of these trials are described below.

Trial 1) In a 4-week, placebo-controlled trial (n=414) involving administration of 2 fixed doses of

ABILIFY

(15 or 30 mg/day) and haloperidol (10 mg/day) in acutely relapsed patients with a

DSM-IV diagnosis of schizophrenia or schizo-affective disorder, ABILIFY

15 mg/day was

superior to placebo with clinically meaningful changes in PANSS total, PANSS positive and

negative subscales, CGI-severity, CGI-improvement, and PANSS-derived BPRS-core scores. The

30-mg dose was superior to placebo for all parameters except PANSS negative subscale.

Trial 2) In a 4-week, placebo controlled trial (n=404) involving administration of 2 fixed doses of

ABILIFY

(20 or 30 mg/day) and risperidone (6 mg/day) in acutely relapsed patients with a

DSM-IV diagnosis of schizophrenia or schizo-affective disorder, both doses of ABILIFY

were

superior to placebo with clinically meaningful changes in the PANSS total, PANSS positive and

negative subscales, CGI-severity, CGI-improvement and PANSS-derived BPRS-core scores.

Trial 3) In a 6-week, placebo-controlled trial (n=420) involving administration of 3 fixed doses of

ABILIFY

(10, 15, or 20 mg/day) in acutely relapsed patients with a DSM-IV diagnosis of

schizophrenia, all ABILIFY

dose groups were superior to placebo with clinically meaningful

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changes in the PANSS total score, the PANSS positive and negative subscales, the CGI severity

and improvement scales, and the PANSS-derived BPRS core score.

Trial 4) In a 6-week trial (n=367) comparing three fixed doses of ABILIFY

(2, 5 or 10mg/day)

to placebo, in acutely relapsed patients with a DSM-IV diagnosis of schizophrenia, the 10 mg dose

of ABILIFY

was superior to placebo in the PANSS total score, the primary outcome measure

of the study. In addition, the 10 mg dose was also superior to placebo in the PANSS positive

subscale and the CGI severity score. Although the 5 mg dose of ABILIFY

did not reach

significance in the PANSS total score or the PANSS positive subscale, it was superior to placebo

in the PANSS

negative subscale and the CGI severity scale. The 2 mg dose did not reach

significance in any of these outcome measures.

Two initial placebo-controlled trials were conducted to explore the efficacy of ABILIFY

. The

first one (Trial 5) was a placebo-controlled, 4-week ascending dose trial of ABILIFY

(5 to 30

mg/day) in 103 patients diagnosed with schizophrenia according to the DSM-III-R criteria with

acute schizophrenic relapse and a history of response to antipsychotic drugs. In this trial,

ABILIFY

differentiated from placebo in the PANSS total score, the PANSS positive subscale,

and the CGI severity scale. The second one (Trial 6) was a placebo-controlled, 4-week, fixed-dose

trial of ABILIFY

(2, 10, or 30 mg/day) in 272 patients diagnosed with schizophrenia according

to the DSM-IV criteria with acute schizophrenic relapse and a history of response to antipsychotic

drugs. Statistical significance was reached only for the 30 mg dose on the PANSS total score, the

PANSS positive subscale, and the CGI severity and improvement scales.

Thus, the efficacy of 10 mg, 15 mg, 20 mg and 30 mg was established in two studies for each dose.

Among these doses there was no evidence that the higher dose groups offered any advantage over

the lowest dose group. Broad efficacy was established across a variety of endpoints with an onset

of action as early as Week 1 for positive symptoms at doses of 15 mg and higher.

Table 1 summarizes the results across all six trials

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Table 1:

Key Efficacy Results in Short-Term, Placebo-Controlled Trials

PANSS

Total

Score

PANSS

Positive

Subscale

Score

PANSS

Negative

Subscale

Score

PANSS-

Derived

BPRS

Core Score

CGI-

Severity

Score

CGI

Improve-

ment Score

Trial/

Treatment

Mean

Change

Mean

Change

Mean

Change

Mean

Change

Mean

Change

Mean

Change

Trial 1

Placebo

-2.9

-0.6

-1.2

-1.1

-0.1

Ari 15 mg

-15.5**

-4.2**

-3.6**

-3.1**

-0.6**

3.5**

Ari 30 mg

-11.4**

-3.8**

-2.3

-3.0**

-0.4**

3.8*

Trial 2

Placebo

-5.0

-1.8

-0.8

-1.7

-0.2

Ari 20 mg

-14.5**

-4.9**

-3.4**

-3.5**

-0.5*

3.4**

Ari 30 mg

-13.9**

-3.9*

-3.4**

-3.3*

-0.6**

3.3**

Trial 3

Placebo

-2.3

-1.1

-1.4

-0.2

Ari 10 mg

-15.0**

-5.0**

-3.5**

-3.9**

-0.7**

3.3**

Ari 15 mg

-11.7**

-3.8**

-2.6**

-2.9*

-0.5*

3.4**

Ari 20 mg

-14.4**

-4.5**

-3.3**

-3.6**

-0.6**

3.3**

Trial 4

Placebo

-5.3

-2.3

-1.3

-2.3

-0.3

Ari 2 mg

-8.2

-2.4

-2.0

-2.3

-0.3

Ari 5 mg

-10.6

-3.4

-2.9*

-3.2

-0.6*

Ari 10 mg

-11.3*

-4.2*

-2.7

-3.4

-0.6*

Trial 5

Placebo

-1.5

-0.1

-0.9

-2.4

Ari 5-30 mg

-13.5**

-3.0*

-3.6

-8.6*

-0.6**

3.5*

Trial 6

Placebo

-3.0

-0.97

-1.31

-1.48

-2.8

Ari 2 mg

-8.0

-1.96

-2.05

-1.95

-0.30

Ari 10 mg

-8.6

-2.10

-2.48

-1.79

-0.30

Ari 30 mg

-13.7**

-3.89*

-3.11

-2.97

-0.60*

3.1**

** (P

0.01), *(0.01<P

0.05) significantly different from placebo.

NOTE: Results in boxes indicate the protocol-specified primary efficacy measures.

Ari = aripiprazole

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A 52-week, haloperidol-controlled, long-term, maintenance trial (n=1294) was conducted in

patients with acute relapse of chronic schizophrenia. In this trial involving the administration of

ABILIFY

30 mg/day and haloperidol 10 mg

day, with a one time option to decrease

ABILIFY

to 20 mg/day and haloperidol to 7 mg/day, ABILIFY

was at least comparable to haloperidol in

time-to-failure to maintain response in responders. Based on patients who responded at any time

during the 52-week study (610/853, 72% in the ABILIFY

group and 298/430, 69% in the

haloperidol group), there was a 12% lower risk of subsequent failure with ABILIFY

relative to

haloperidol (relative risk: 0.881, 95% CI: 0.645 - 1.204). ABILIFY

was comparable to

haloperidol in time-to-failure to maintain response in all randomised patients. Patients in the

ABILIFY

group had a 14% lower risk of failure compared with the haloperidol group (relative

risk: 0.858, 95% CI: 0.721, 1.021). ABILIFY

was statistically superior to haloperidol in the

analysis of the proportion of patients on treatment and in response at Weeks 8, 26, and 52

(prespecified key time points). At Week 52, 40% of ABILIFY

patients were still on-study and

in response compared to 27% of haloperidol patients (p

0.001). ABILIFY

-treated patients had

a statistically significant lower risk (31%) of discontinuations due to lack of efficacy or adverse

event relative to haloperidol treated patients (relative risk 0.692; 95% CI: 0.573 - 0.837). There

were no significant differences between ABILIFY

and haloperidol groups in terms of change

from baseline PANSS total scores, PANSS positive subscores, CGI-severity or improvement

scores. ABILIFY

did result in a significantly greater improvement

in the PANSS negative

subscores at weeks 26 & 52 and the MADRS total score at Weeks 8, 26, and 52. [Mean change

PANSS negative subscale score (week 26: p=0.029; 95% CI: -1.52, -0.08) (week 52: p=0.011;

95% CI: -1.73, -0.23). Mean change MADRS total score (week 8: p=0.027; 95% CI: -1.74, -0.11)

(week 26: p=0.22; 95% CI:-1.95, -0.15) (week 52: p= 0.031; 95% CI: -1.97, -0.09).]

To further demonstrate the maintenance effects of ABILIFY

, a double-blind study was

conducted in chronic, symptomatically stable schizophrenic patients (n=310) randomised to

ABILIFY

15 mg or placebo and followed for 26 weeks. Patients were observed for “impending

psychotic relapse”, defined as CGI-improvement score

5 (minimally worse) or scores

(moderately severe) on the hostility or uncooperativeness items of the PANSS on two consecutive

days or

20% increase in the PANSS Total Score. Patients in the placebo group experienced a

higher relapse rate and/or relapsed sooner than those in the ABILIFY

group. From 4 weeks

onwards there were noticeably more relapses in the placebo group than the ABILIFY

group.

Kaplan Meier estimates showed that the estimated probability of not experiencing relapse prior to

week 26 was 39% in the placebo group versus 63% in the ABILIFY

group [relative risk

ABILIFY

: placebo = 0.50 (95% CI=0.35, 0.71, p

0.01)]. The number of relapses was

significantly lower in the ABILIFY

group compared to placebo (34% vs 57%, RR=0.59, 95%

CI: 0.45, 0.75, p

0.01).

No trials have been conducted in patients with first episode schizophrenia or treatment-resistant

schizophrenia. Thus, efficacy in these groups of patients has not been established.

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Bipolar Mania

Monotherapy

Adults

The efficacy of ABILIFY

in the treatment of acute manic episodes was established in four 3-

week, placebo-controlled trials in hospitalised patients who met the DSM-IV criteria for Bipolar I

Disorder with manic or mixed episodes. These studies included patients with or without psychotic

features and two of the studies also included patients with or without a rapid-cycling course.

The primary instrument used for assessing manic symptoms was the Young Mania Rating Scale

(Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic

symptomatology (irritability, disruptive/aggressive behaviour, sleep, elevated mood, speech,

increased activity, sexual interest, language/thought disorder, thought content, appearance, and

insight) in a range from 0 (no manic features) to 60 (maximum score). A key secondary instrument

included the Clinical Global Impression – Bipolar (CGI-BP) Scale.

In the four positive, 3 week, placebo-controlled trials (n=268; n=248; n= 480; n= 485) which

evaluated ABILIFY

in a range of 15 mg to 30 mg, once daily (with a starting dose of 15 mg/day

in two studies and 30 mg/day in two studies). ABILIFY

was superior to placebo in the reduction

of Y-MRS total score and CGI-BP Severity of Illness score (mania). In the two studies with a

starting dose of 15 mg/day, 48% and 44% of patients were on 15 mg/day at endpoint.In the two

studies with a starting dose of 30 mg/day, 86% and 85% of patients were on 30 mg/day at endpoint.

A trial was conducted in patients with DSM-IV criteria for Bipolar I Disorder with a recent manic

or mixed episode who had been stabilized on open-label ABILIFY

and who had maintained a

clinical response for at least 6 weeks. The first phase of this trial was an open-label stabilisation

period in which inpatients and outpatients were clinically stabilized and then maintained on open-

label ABILIFY

(15 mg/day or 30 mg/day, with a starting dose of 30 mg/day) for at least 6

consecutive weeks. One hundred sixty-one outpatients were then randomised in a double-blind

fashion, to either the same dose of ABILIFY

they were on the end of stabilization and

maintenance period or placebo and were then monitored for manic or depressive relapse. During

the randomization phase, ABILIFY

was superior to placebo on time to the number of combined

affective relapses (manic plus depressive), the primary outcome measure for this study. The

majority of these relapses were due to manic rather than depressive symptoms. There is insufficient

data to know whether ABILIFY

is effective in delaying the time to occurrence of depression in

patients with Bipolar I Disorder.

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An examination of population subgroups did not reveal any clear evidence of differential

responsiveness on the basis of age and gender, however, there were insufficient numbers of

patients in each of the ethnic groups to adequately assess inter-group differences.

Adjunctive Therapy

The efficacy of adjunctive ABILIFY

with concomitant lithium or valproate in the treatment of

manic or mixed episodes was established in a 6-week, placebo-controlled study (n=384) with a 2-

week lead-in mood stabilizer monotherapy phase in adult patients who met DSM-IV criteria for

Bipolar I Disorder. This study included patients with manic or mixed episodes and with or without

psychotic features.

Patients were initiated on open-label lithium (0.6 mEq/L to 1.0 mEq/L) or valproate (50 µg/mL to

125 µg/mL) at therapeutic serum levels, and remained on stable doses for 2 weeks. At the end of

2 weeks, patients demonstrating inadequate response (Y-MRS total score

16 and

improvement on the Y-MRS total score) to lithium or valproate were randomised to receive either

aripiprazole (15 mg/day or an increase to 30 mg/day as early as day 7) or placebo as adjunctive

therapy with open-label lithium or valproate. In the 6-week placebo-controlled phase, adjunctive

ABILIFY

starting at 15 mg/day with concomitant lithium or valproate (in a therapeutic range of

0.6 mEq/L to 1.0 mEq/L or 50 µg/mL to 125 µg/mL, respectively) was superior to lithium or

valproate with adjunctive placebo in the reduction of the Y-MRS total score and CGI-BP Severity

of Illness score (mania). Seventy-one percent of the patients co-administered valproate and 62%

of the patients coadministered lithium were on 15 mg/day at the 6-week endpoint.

INDICATIONS

ABILIFY

is indicated for the treatment of schizophrenia including maintenance of clinical

improvement during continuation therapy.

ABILIFY

monotherapy is indicated for acute and maintenance treatment of manic and mixed

episodes with Bipolar I Disorder with or without psychotic features.

ABILIFY

is indicated as an adjunctive therapy to either lithium or valproate for the acute

treatment of manic and mixed episodes associated with Bipolar I Disorder with or without

psychotic features.

CONTRAINDICATIONS

ABILIFY

is contraindicated in patients who are hypersensitive to aripiprazole or any of the

excipients (see

DESCRIPTION

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specific

information

about

contraindications

mood

stabilisers

refer

CONTRAINDICATIONS

section

prescribing

information

these

products

when

adjunctive therapy is indicated.

PRECAUTIONS

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at

an increased risk of death compared to placebo. Analyses of seventeen placebo-controlled trials

(modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients

of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10-

week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate

of about 2.6% in the placebo group. Although the causes of death varied, most of the deaths

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

pneumonia) in nature.

In three placebo-controlled trials of ABILIFY

in elderly patients with psychosis associated with

Alzheimer's disease, cerebrovascular adverse events (e.g. stroke, transient ischaemic attack),

including fatalities, occurred in 1.3% (8/595) of ABILIFY

-treated patients compared with 0.6%

(2/343) of placebo-treated patients during the 10-week double-blind period or within 30 days of

the last dose for those who discontinued the study during the double-blind phase. The all cause

mortality rate in the same trials over the same period was 3.5% (21/595) in ABILIFY

-treated

patients and 1.7% (6/343) in the placebo group.

ABILIFY

is not approved for the treatment of patients with dementia-related psychosis.

General

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

days to some weeks. Patients should be closely monitored during this period.

Suicide

The possibility of a suicide attempt is inherent in psychotic illnesses and Bipolar Disorder, and

close

supervision

high-risk

patients

should

accompany

drug

therapy.

Prescriptions

ABILIFY

should be written for the smallest quantity consistent with good patient management,

in order to reduce the risk of overdose.

Tardive Dyskinesia

The risk of tardive dyskinesia increases with long-term exposure to antipsychotic treatment. If

signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY

, a dose reduction or

drug discontinuation should be considered. These symptoms can temporally deteriorate or even

arise after discontinuation of treatment.

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Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome

(NMS) has been reported in association with administration of antipsychotic drugs including

ABILIFY

. Rare cases of NMS occurred during aripiprazole treatment in the worldwide clinical

database. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status,

and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis,

and cardiac dysrhythmia). Additional signs may include elevated creatine kinase, myoglobinuria

(rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of

NMS, or presents with unexplained high fever without additional clinical manifestations of NMS,

all antipsychotic drugs, including ABILIFY

must be discontinued.

Seizure

In short-term, placebo controlled trials, seizures occurred in 0.1% (3/2,467) of adult patients

treated with aripiprazole.

As with other antipsychotic drugs, ABILIFY

should be used cautiously in patients who have a

history of seizure disorder or have conditions associated with seizures.

Cerebrovascular

Adverse

Events,

Including

Stroke,

in

Elderly

Patients

with

Dementia-Related Psychosis

In placebo-controlled clinical studies (2 flexible dose and 1 fixed dose study) of dementia-related

psychosis, there was an increased incidence of cerebrovascular adverse events (e.g., stroke,

transient ischemic attack), including fatalities, in aripiprazole-treated patients (mean age: 84 years;

range: 78-88 years). In the fixed dose study, there was a statistically significant dose response

relationship for cerebrovascular adverse events in patients treated with aripiprazole. Aripiprazole

approved

treatment

patients

with

dementia-related

psychosis.

(See

also

PRECAUTIONS

:

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Use in Patients with Concomitant Illness: Safety Experience in Elderly Patients with

Psychosis Associated with Alzheimer’s Disease

Hyperglycaemia and Diabetes Mellitus

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

or death, has been reported in patients treated with atypical antipsychotic agents including

ABILIFY

. In clinical trials with ABILIFY

there were no significant differences in the

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

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

related adverse events 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

NZ_DS_Abilify_V2.1_ August2016

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

diabetes mellitus should be monitored regularly for worsening of glucose control.

Cardiovascular Adverse Events

Potentially due to its

-adrenergic receptor antagonism, ABILIFY

may be associated with

orthostatic hypotension.

The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled

trials of adult patients on oral ABILIFY

(n=2,467) included (aripiprazole incidence, placebo

incidence): orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope

(0.5%, 0.4%).

Orthostatic hypotension occurred in 0.8% (112/13,543) of oral aripiprazole-treated patients during

clinical trials.

As with other atypical antipsychotics, ABILIFY

should be used with caution in patients with

known cardiovascular disease (history of myocardial infarction or ischaemic heart disease, heart

failure

conduction

abnormalities),

cerebrovascular

disease

conditions

which

would

predispose

patients

hypotension

(dehydration,

hypovolaemia,

treatment

with

antihypertensive medications).

Venous Thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since

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

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

preventive measures taken.

Weight Gain

Weight gain is commonly seen in schizophrenic and bipolar mania patients due to co-

morbidities, use of antipsychotics known to cause weight gain, poorly managed life-style and

might lead to severe complications. Weight gain has been reported post-marketing among

patients prescribed aripiprazole. When seen, it is usually in those with significant risk factors

such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole

has not been shown to induce clinically relevant weight gain in adults.

Body Temperature Regulation

Disruption of the body’s ability to increase or reduce core body temperature has been attributed to

antipsychotic agents, including ABILIFY

. Appropriate care is advised when prescribing

ABILIFY

for patients who will be experiencing conditions which may contribute to an elevation

in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving

concomitant medication with anticholinergic activity, or being subject to dehydration.

NZ_DS_Abilify_V2.1_ August2016

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Patients should be advised regarding appropriate care in avoiding overheating and dehydration.

Dysphagia

Oesophageal dysmotility and aspiration have been associated with antipsychotic drug use.

ABILIFY

and other antipsychotic drugs should be used cautiously in patients at risk of

aspiration pneumonia (e.g. elderly patients).

Akathisia

Class effect:

The presentation of akathisia may be variable and comprises subjective complaints of

restlessness and an overwhelming urge to move and either distress or motor phenomena such as

pacing, swinging of the legs while seated, rocking from foot to foot, or both. Particular attention

should be paid to the monitoring for such symptoms and signs as, left untreated, akathisia is

associated with poor compliance and an increased risk of relapse.

Leucopoenia, Neutropenia and Agranulocytosis

Class Effect: In clinical trial and/or postmarketing experience, events of leucopenia/neutropenia

have

been

reported

temporally

related

antipsychotic

agents,

including

ABILIFY

Agranulocytosis has also been reported.

Possible risk factors for leucopenia/neutropenia include pre-existing low white blood cell count

(WBC) and history of drug-induced leucopoenia/neutropenia. Patients with a history of a clinically

significant low WBC or drug-induced leucopoenia/neutropenia should have their complete blood

cell (CBC) monitored frequently during the first few months of therapy and discontinuation of

ABILIFY

should be considered at the first sign of a clinically significant decline in WBC in the

absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other

symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients

with severe neutropenia (absolute neutrophil count < 1000/mm

) should discontinue ABILIFY

and have their WBC followed until recovery.

Potential for Cognitive and Motor Impairment

ABILIFY

, like other antipsychotics, may have the potential to impair judgment, thinking, or

motor skills.

In short-term, placebo-controlled trials, somnolence (including sedation) was

reported as follows (aripiprazole incidence, placebo incidence): in adult patients (n=2,467) treated

with oral ABILIFY

(11%, 6%). Somnolence (including sedation) led to discontinuation in 0.3%

(8/2,467) of adult patients on oral ABILIFY

in short-term, placebo-controlled trials.

Despite the relatively modest increased incidence of these events compared to placebo, patients

should be cautioned about operating hazardous machinery, including automobiles, until they are

reasonably certain that therapy with ABILIFY

does not affect them adversely.

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Pathological gambling and impulse-control disorders

Patients can experience increased urges, particularly for gambling, and the inability to control these

urges while taking aripiprazole. Other urges, reported include: increased sexual urges, compulsive

spending, binge or compulsive eating, and other impulsive and compulsive behaviours. It is

important for prescribers to ask patients or their caregivers specifically about the development of

new or increased gambling urges, sexual urges, compulsive spending, binge or compulsive eating,

or other urges while being treated with aripiprazole. It should be noted that impulse-control

symptoms can be associated with the underlying disorder; however, in some cases urges were

reported to have stopped when the dose was reduced or the medication was discontinued. Impulse

control disorders may result in harm to the patient and others if not recognized. Consider dose

reduction or stopping the medication if a patient develops such urges while taking aripiprazole.

(See

ADVERSE EFFECTS.

Use in Patients with Concomitant Illness

Clinical experience with ABILIFY

in patients with certain concomitant systemic illnesses is

limited. (See

PHARMACOLOGY

Renal Impairment

Hepatic Impairment

ABILIFY

has not been evaluated or used to any appreciable extent in patients with a recent

history of myocardial infarction or unstable heart disease. Patients with these diagnoses were

excluded from premarketing clinical studies.

Safety Experience in Elderly Patients with Psychosis Associated with Alzheimer’s Disease:

three, 10-week, placebo-controlled studies of aripiprazole in elderly patients with psychosis

associated with Alzheimer’s disease (n=938; mean age: 82.4 years; range: 56-99 years), the

treatment-emergent adverse events that were reported at an incidence of ≥5% and aripiprazole

incidence at least twice that for placebo were lethargy [placebo 2%, aripiprazole 5%], somnolence

(including

sedation)

[placebo

aripiprazole

incontinence

primarily,

urinary

incontinence) [ placebo 1%, aripiprazole 5%].

The safety and efficacy of ABILIFY

in the treatment of patients with psychosis associated with

dementia have not been established. ABILIFY

is not indicated for the treatment of psychosis

associated with Alzheimer’s disease. (See also

PRECAUTIONS

: Increased Mortality in

Elderly Patients with Dementia-Related Psychosis

Cerebrovascular Adverse Events,

Including Stroke, in Elderly Patients with Dementia-Related Psychosis.

Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to take, any

prescription

over-the-counter

drugs,

since

there

potential

interactions.

(See

PRECAUTIONS,

INTERACTIONS

and

DOSAGE

AND

ADMINISTRATION

Concomitant Medications)

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Carcinogenicity and Mutagenicity

Carcinogenicity:

Lifetime carcinogenicity studies were conducted in ICR mice and in Sprague-

Dawley (SD) and Fischer (F344) rats. Aripiprazole was administered for 2 years in the diet at

doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2 to 5

times

maximum

recommended

human

dose

[MRHD]

based

mg/m

respectively). SD rats were dosed orally by gavage for 2 years at 10, 20, 40, and 60 mg/kg/day (3

to 18 times the MRHD based on mg/m

). There was no evidence of tumorigenesis in male mice or

rats.

female

mice,

incidences

pituitary

gland

adenomas

mammary

gland

adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.1

to 0.9 times MRHD based on AUC and 0.5 to 5 times the MRHD based on mg/m

). In female rats,

the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day

(< 0.1 times MRHD based on AUC and 3 times the MRHD based on mg/m

); and the incidences

of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased

at an oral gavage dose of 60 mg/kg/day (10 times the MRHD based on AUC and 18 times MRHD

based on mg/m

). In male rats, the incidence of benign and combined benign/malignant

phaeochromocytomas were also increased at an oral gavage dose of 60 mg/kg/day (10 times the

MRHD based on AUC and 18 times the MRHD based on mg/m

Proliferative changes in the pituitary and mammary gland of rodents have been observed following

chronic administration of other antipsychotic agents and are considered prolactin-mediated.

Serum prolactin was not measured in the aripiprazole carcinogenicity studies. At the doses

associated with mammary gland and pituitary tumours, hyperprolactinaemia was observed in

female mice in a 13-week dietary study but not in female rats in 4- and 13-week dietary studies.

Serum prolactin was increased in female rats, and decreased in male rats, after 5 and 13 weeks of

oral gavage dosing at 60 mg/kg/day. The relationship between tumourigenic findings with

aripiprazole and prolactin is unclear and the relevance for human risk of prolactin-mediated

tumours is unknown. The adrenocortical response in female rats is considered a consequence of

increased

adrenocortical

cell

proliferation

secondary

chronic

drug-related

adrenocortical

cytotoxicity. The no-effect-dose (40 mg/kg/day) was 7 – 12 times the MRHD based on AUC and

mg/m

Mutagenicity:

Aripiprazole was tested in a standard range of assays for gene mutation,

chromosomal damage, and DNA damage and repair. Aripiprazole was non-genotoxic in the

in

vitro

bacterial reverse-mutation assay, the

in vitro

forward gene mutation assay in mouse

lymphoma cells,

in vitro

bacterial DNA repair assay, and the unscheduled DNA synthesis assay in

rat hepatocytes. However, aripiprazole and its minor metabolite 2,3-DCPP were clastogenic in the

in vitro

chromosomal aberration assay in Chinese hamster lung (CHL)

cells in both the presence

and absence of metabolic activation. A positive response for aripiprazole in 1 of 6

in vivo

mouse

micronucleus tests was attributed to drug-induced hypothermia.

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Impairment of Fertility

Aripiprazole had no effect on fertility in female rats treated orally with 2, 6, and 20 mg/kg/day

(0.6, 2, and 6 times the MRHD based on mg/m

) for 2 weeks prior to mating through gestation day

7. Drug-related effects (persistent dioestrus and increased mating time pre-implantation losses,

and corpora lutea) observed at all doses were considered the result of perturbed oestrous cyclicity

secondary to drug-mediated hyperprolactinaemia.

Aripiprazole had no effect on fertility in male rats treated with PO doses of 20, 40, and 60

mg/kg/day (6, 12, and 18 times the MRHD based on mg/m

) for 9 weeks prior to mating through

mating. Disturbances of spermatogenesis were seen at 60 mg/kg/day and prostatic atrophy was

seen at 40 and 60 mg/kg/day.

Use in Pregnancy (

Category B3)

In animal studies aripiprazole demonstrated developmental toxicity, including possible teratogenic

effects, in rats and rabbits.

Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 9 times the MRHD

on a mg/m

basis) of aripiprazole during the period of organogenesis. At 30 mg/kg, treatment was

associated with slightly prolonged gestation, and a slight delay in foetal development as evidenced

by decreased foetal weight, undescended testes, and delayed skeletal ossification. There were no

adverse effects on embryofoetal or pup survival. Delivered offspring had increased incidences of

hepatodiaphragmatic nodules and diaphragmatic hernia at 30 mg/kg (the other doses were not

examined for these findings). (A low incidence of diaphragmatic hernia was also seen in the

foetuses exposed to 30 mg/kg). Postnatally, decreased pup weight (persisting into adulthood) was

seen at 30 mg/kg, delayed vaginal opening was seen at 10 and 30 mg/kg, and impaired reproductive

performance (decreased fertility rate, corpora lutea, implants, and live foetuses, and increased post-

implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg.

Maternal toxicity was seen at 30 mg/kg, which was similar to doses eliciting embryotoxicity.

Pregnant rabbits were treated with oral doses of 10, 30, and 100 mg/kg/day (2, 3, and 11 times

human exposure at MRHD based on AUC and 8, 24, and 81 times the MRHD based on mg/m

of aripiprazole during the period of organogenesis. Decreased maternal food consumption, and

increased abortions were seen at 100 mg/kg. Treatment caused increased foetal mortality (100

mg/kg), decreased foetal weight (30 mg and 100 mg/kg), increased incidence of a skeletal

abnormality (fused sternebrae at 100 mg/kg) and minor skeletal variations (100 mg/kg).

Rats were treated with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 9 times the MRHD on a

mg/m

basis) of aripiprazole from late gestation through weaning. At 30 mg/kg, maternal toxicity,

slightly prolonged gestation, an increase in stillbirths, poor postnatal care/nursing, and decreases

in pup weight (persisting into adulthood) and survival were seen.

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Neonates exposed to antipsychotic drugs (including ABILIFY

)

during the third trimester of

pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal

symptoms following delivery. There have been post-market reports of agitation, hypertonia,

hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These

complications have varied in severity; while in some cases symptoms have been self-limited, in

other cases neonates have required additional medical treatment or monitoring.

ABILIFY

should be used during pregnancy only if the anticipated benefit outweighs the risk and

the administered dose and duration of treatment should be as low and as short as possible.

Patients should be advised to notify their doctors if they become pregnant or intend to become

pregnant.

Use in Lactation

Aripiprazole and/or its metabolites have been found in the milk of lactating rats. Aripiprazole is

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

ABILIFY

Use in Labor and Delivery

The effect of aripiprazole on labor and delivery has not been studied.

Animal Toxicology

Choleliths (gallsand and/or gallstones) were observed in the bile of monkeys given aripiprazole

orally for 4 – 52 weeks at doses of 25 –125 mg/kg/day (1 – 3 times the MRHD based on plasma

AUC and 15 –76 times the MRHD based on mg/m

) and were attributed to precipitation of sulfate

conjugates of hydroxy metabolites, which exceeded their solubility limits in bile. Human biliary

concentrations of these sulfate conjugates after repeated daily administration of the MRHD are

substantially lower (0.2 – 14% of their

in vitro

solubility limits).

Bilateral retinal degeneration was observed in albino rats given oral aripiprazole for 6 months at a

dose of 60 mg/kg/day and 2 years at doses of 40 – 60 mg/kg/day. These doses were 7 – 13 times

the MRHD based on AUC and 12 – 18 times the MRHD based on mg/m

. The mechanism and

clinical relevance of this finding is unknown.

Use in Children

Safety and effectiveness in patients under 18 years of age have not been established.

Use in the Elderly

Placebo-controlled studies of ABILIFY

in schizophrenia or Bipolar Mania did not include

sufficient numbers of subjects aged 65 and over to determine whether they respond differently

from younger subjects. Of the 13,543 patients treated with oral ABILIFY

in clinical trials, 1,073

NZ_DS_Abilify_V2.1_ August2016

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(8%) were

65 years old and 799 (6%) were

75 years old. The majority (81%) of the 1,073

patients were diagnosed with Dementia of the Alzheimer’s Type.

Studies of elderly patients with psychosis associated with Alzheimer’s disease have suggested that

there may be a different tolerability profile in this population compared to younger patients with

schizophrenia (see

PRECAUTIONS

: Increased Mortality in Elderly Patients with Dementia-

Related

Psychosis

Cerebrovascular

Adverse

Events,

Including

Stroke,

in

Elderly

Patients with Dementia-Related Psychosis

Use in Patients with Concomitant Illness

). The

safety and efficacy of ABILIFY in the treatment of patients with psychosis associated with

Alzheimer’s disease has not been established. ABILIFY

is not indicated for the treatment of

psychosis associated with Alzheimer’s disease.

There was no effect of age on the pharmacokinetics of a single, 15 mg dose of ABILIFY

Aripiprazole clearance was decreased by 20% in elderly subjects (>65 years) compared to younger

adult subjects (18 to 64 years), but there was no detectable effect of age in the population

pharmacokinetic analysis in schizophrenia patients.

Effects on Ability to Drive and to Use Machines

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

including motor vehicles, until they are reasonably certain that ABILIFY

does not affect them

adversely.

INTERACTIONS WITH OTHER MEDICINES

CNS Drugs (including Alcohol)

Given the primary CNS effects of ABILIFY

, caution should be used when ABILIFY

is taken

in combination with other centrally acting drugs and alcohol.

Patients should be advised to avoid alcohol while taking ABILIFY

Coadministration of

lithium

titrated upwards from a starting dose of 900 mg until serum lithium

concentrations near the upper end of the lithium therapeutic concentration range (1.0 – 1.4

mmol/L) were achieved and maintained for at least 5 days or until dose-limiting adverse events

were observed and

valproate

(divalproex sodium)

titrated upwards from a starting dose of 250 mg

twice daily to achieve serum concentrations within the therapeutic range of 50 – 125 μg/mL for at

least 14 days, with 30 mg ABILIFY

once daily had no clinically significant effects on the

pharmacokinetics of aripiprazole. Nor was there any clinically significant change in

valproic acid

lithium

pharmacokinetics

when aripiprazole 30 mg once daily was administered concomitantly

for 7 days with either divalproex sodium 500 mg every 12 hours or controlled release lithium 450

mg every 12 hours.

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Antihypertensive Agents

Due to its

-adrenergic receptor antagonist activity, ABILIFY

has the potential to enhance the

effect of certain antihypertensive agents.

Inhibitors and Inducers of CYP2D6 & CYP3A4

Aripiprazole is metabolized by multiple pathways primarily involving the CYP2D6 and CYP3A4

enzymes. In clinical studies with healthy subjects, potent inhibitors of CYP2D6 (

quinidine

) and

3A4 (

ketoconazole

) decreased oral clearance of aripiprazole by 52% and 38%, respectively. Other

potent inhibitors of CYP3A4 and CYP2D6 may be expected to have similar effects. When

concomitant administration of quinidine or ketoconazole with aripiprazole occurs, the aripiprazole

dose should be halved. When the inhibitor is withdrawn from the combination therapy, the

aripiprazole

dose

should

then

increased

(See

DOSAGE

&

ADMINISTRATION:

Concomitant Medication

No data are available for use of ABILIFY

with other inhibitors of CYP3A4 or CYP2D6.

Examples of medicines or substances that have the potential to inhibit CYP3A4 or CYP2D6

include, but are not limited to, clarithromycin, erythromycin, itraconazole, fluconazole, ritonavir,

indinavir, nefazodone, cyclosporin, amiodarone, cimetidine, fluoxetine, paroxetine and grapefruit

juice.

In a clinical study in patients with schizophrenia or schizo-affective disorder, co-administration of

carbamazepine

(200 mg twice daily), a potent CYP3A4 inducer, with aripiprazole (30 mg daily)

resulted in an approximate 70% decrease in AUC values of both aripiprazole and its active

metabolite, dehydro-aripiprazole. Other potent inducers of CYP3A4 and CYP2D6 may be

expected to have similar effects. When a potent inducer like carbamazepine is added to aripiprazole

therapy, the aripiprazole dose should be increased. Additional dose increases should be based on

clinical evaluation

When the inducer is withdrawn from the combination therapy, the aripiprazole

dose should then be reduced. (See

DOSAGE & ADMINISTRATION

Dosage adjustment for

patients taking CYP3A4 inducers

Inhibitors and Inducers of CYP1A1, CYP1A2, CYP2C9, and CYP2C19

Aripiprazole is not metabolized by CYP1A1, CYP1A2, CYP2C9, and CYP2C19

in vitro,

suggesting that interactions with medications or other factors (e.g., smoking), which are

inhibitors or inducers of these enzymes, are unlikely.

Effects of ABILIFY

TM

on Substrates for CYP2D6, CYP2C9, CYP2C19, CYP3A4, & CYP1A2

Aripiprazole and dehydro-aripiprazole were weak inhibitors of CYP2C9, CYP2C19, CYP2D6,

and CYP3A4-mediated metabolism

in vitro

values 2.4 –25

M). Neither aripiprazole nor

dehydro-aripiprazole inhibited CYP1A2

mediated metabolism

in vitro

value >50 – 66

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In clinical studies, 10-30 mg/day doses of ABILIFY

had no significant effect on metabolism of

substrates

CYP2D6

dextromethorphan),

CYP2C9

warfarin

CYP2C19

omeprazole,

warfarin

), and CYP3A4 (

dextromethorphan

Thus, ABILIFY

is unlikely to cause clinically

important drug interactions mediated by these enzymes.

Famotidine

There was no significant effect of the H

antagonist famotidine, a potent gastric acid blocker, on

the pharmacokinetics of aripiprazole.

Food

ABILIFY

can be administered without regard to meals. Following administration of a 15 mg

ABILIFY

tablet with a standard high-fat meal, the Cmax of aripiprazole and its active

metabolite, dehydro-aripiprazole, increased by 11%. The AUC of aripiprazole was increased by

18% and that of the active metabolite by 14%. Food delayed Tmax by 3 hours for aripiprazole and

12 hours for the active metabolite.

ADVERSE EFFECTS

ABILIFY

has been evaluated for safety in 13,543 patients who participated in multiple-dose

clinical trials in Schizophrenia (including schizo-affective disorder), Bipolar Disorder, Major

Depressive Disorder, Dementia of the Alzheimer’s type, Parkinson’s disease, and alcoholism, and

who had approximately 7,619 patient-years of exposure to oral aripiprazole. A total of 3,390

patients were treated with oral aripiprazole for at least 180 days and 1,933 patients treated with

oral aripiprazole had at least 1 year of exposure.

The conditions and duration of treatment with ABILIFY

(monotherapy and adjunctive therapy

with or mood stabilizers) included (in overlapping categories) double-blind, comparative and

noncomparative open-label studies, inpatient and outpatient studies, fixed- and flexible-dose

studies, and short- and longer- term exposure.

Adverse events during exposure were obtained by collecting voluntarily reported adverse events,

as well as results of physical examinations, vital signs, weights, laboratory analyses, and ECG.

Adverse experiences were recorded by clinical investigators using terminology of their own

choosing. In the tables and tabulations that follow, MedDRA dictionary terminology has been

used initially to classify reported adverse events into a smaller number of standardized event

categories, in order to provide a meaningful estimate of the proportion of individuals experiencing

adverse events.

The stated frequencies of adverse events represent the proportion of individuals who experienced,

at least once, a treatment-emergent adverse event of the type listed. An event was considered

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treatment-emergent if it occurred for the first time or worsened while receiving therapy following

baseline evaluation.

The prescriber should be aware that the figures in the tables and tabulations cannot be used to

predict the incidence of side effects in the course of usual medical practice where patient

characteristics and other factors differ from those that prevailed in the clinical trials. Similarly,

the cited frequencies cannot be compared with figures obtained from other clinical investigations

involving different treatment uses and investigators. The cited figures, however, do provide the

prescribing physician with some basis for estimating the relative contribution of drug and nondrug

factors to the adverse event incidence in the population studied.

Oral Administration

Adult Patients with Schizophrenia

Adverse Events Associated with Discontinuation of Treatment in Short-Term,

Placebo-Controlled Trials of Patients with Schizophrenia

Based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which

ABILIFY

was administered to acutely relapsed patients with schizophrenia in doses ranging

from 2 to 30 mg/day, there was no difference in the incidence of discontinuation due to adverse

events between ABILIFY

-treated (7%) and placebo-treated (9%) patients. The types of adverse

events that led to discontinuation were similar between the ABILIFY

and placebo-treated

patients.

Adult Patients with Bipolar Mania

Monotherapy

The following findings are based on a pool of 3-week, placebo-controlled, Bipolar mania trials in

which oral aripiprazole was administered at doses of 15 mg/day or 30 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

Overall,

patients

with

Bipolar

Mania,

there

little

difference

incidence

discontinuation due to adverse reactions between aripiprazole-treated (11%) and placebo-treated

(10%) patients. The types of adverse reactions that led to discontinuation were similar between

aripiprazole-treated and placebo-treated patients.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of aripiprazole in patients with

Bipolar Mania (incidence of 5% or greater and aripiprazole incidence at least twice that for

placebo) are shown in the following Table:

Table 2: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled

Trials of Adult Patents with Bipolar Mania Treated with Oral ABILIFY

TM

Monotherapy

NZ_DS_Abilify_V2.1_ August2016

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Percentage of Patients Reporting Reaction

Preferred Term

Aripiprazole

(n=917)

Placebo

(n=753)

Akathisia

Sedation

Restlessness

Tremor

Extrapyramidal Disorder

Less Common Adverse Reactions in Adults

Adverse Events Occurring at an Incidence of at Least 2% Among ABILIFY

TM

-

Treated Patients in Short-Term Placebo-Controlled Trials

Table 3 enumerates the pooled incidence, rounded to the nearest percent, of treatment-emergent

adverse events that occurred during acute therapy (up to 6 weeks in Schizophrenia and up to 3

weeks in Bipolar Mania) including only those events that occurred in at least 2% of patients treated

with ABILIFY

(doses

2 mg/day) and for which the incidence in patients treated with

aripiprazole was greater than the incidence in patients treated with placebo in the combined dataset.

Table 3: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients

Treated with Oral ABILIFY

TM

Percentage of patients Reporting Reaction

System Organ Class

Preferred Term

Aripiprazole

(n=1,843)

Placebo

(n=1,166)

Eye Disorders

Blurred Vision

Gastrointestinal Disorders

Nausea

NZ_DS_Abilify_V2.1_ August2016

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Constipation

Vomiting

Dyspepsia

Dry Mouth

Toothache

Abdominal Discomfort

Stomach Discomfort

General Disorders and Administration Site

Conditions

Fatigue

Pain

Musculoskeletal and Connective Tissue

Disorders

Musculoskeletal Stiffness

Pain in Extremity

Myalgia

Muscle Spasm

Nervous System Disorders

Headache

Dizziness

Akathisia

Sedation

Extrapyramidal Disorder

NZ_DS_Abilify_V2.1_ August2016

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Tremor

Somnolence

Psychiatric Disorders

Agitation

Insomnia

Anxiety

Restlessness

Respiratory, Thoracic, and Mediastinal

Disorders

Pharyngolaryngeal Pain

Cough

Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except

adverse reactions which had an incidence equal to or less than placebo.

An examination of population subgroups did not reveal any clear evidence of differential adverse

reaction incidence on the basis of age, gender, or race.

Adult Patients with Adjunctive Therapy with Bipolar Mania

The following findings are based on a placebo-controlled trial of adult patients with Bipolar

Disorder in which aripiprazole was administered at doses of 15 mg/day or 30 mg/day as adjunctive

therapy with lithium or valproate.

Adverse Reactions Associated with Discontinuation of Treatment

In a study of patients who were already tolerating either lithium or valproate as monotherapy,

discontinuation rates due to adverse reactions were 12% for patients treated with adjunctive

aripiprazole compared with 6% for patients treated with adjunctive placebo. The most common

adverse drug reactions associated with discontinuation in the adjunctive aripiprazole-treated

compared to placebo-treated patients were akathisia (5% and 1%, respectively) and tremor (2%

and 1%, respectively).

Commonly Observed Adverse Reactions

NZ_DS_Abilify_V2.1_ August2016

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The commonly observed adverse reactions associated with adjunctive aripiprazole and lithium or

valproate in patients with Bipolar mania (incidence of 5% or greater and incidence at least twice

that for adjunctive placebo) were: akathisia, insomnia, and extrapyramidal disorder.

Less Common Adverse Reactions in Adults with Adjunctive Therapy in Bipolar

Mania

Table 4 enumerates the incidence, rounded to the nearest percent, of adverse reactions that

occurred during acute treatment (up to 6 weeks), including only those reactions that occurred in

2% or more of patients treated with adjunctive aripiprazole (doses of 15 mg/day or 30 mg/day)

and lithium or valproate and for which the incidence in patients treated with this combination was

greater than the incidence in patients treated with placebo plus lithium or valproate.

Table 4: Adverse Reactions in a Short-Term, Placebo-Controlled Trial of Adjunctive

Therapy in Patients with Bipolar Disorder.

Percentage of Patients Reporting Reaction

a

System Organ Class

Aripiprazole + Lithium or

Valproate

Placebo + Lithium or

Valproate

Preferred Term

(n=253)

(n=130)

Gastrointestinal Disorders

Nausea

Vomiting

Salivary Hypersecretion

Dry Mouth

Infections and Infestations

Nasopharyngitis

Investigations

Weight increased

Nervous System Disorders

Akathisia

NZ_DS_Abilify_V2.1_ August2016

- 27 -

Tremor

Extrapyramidal Disorder

Dizziness

Sedation

Psychiatric Disorders

Insomnia

Anxiety

Restlessness

Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except

adverse reactions which had an incidence equal to or less than placebo

Dose-Related Adverse Events in Short-Term, Placebo-Controlled Trials in

Schizophrenia

Dose response relationships for the incidence of treatment-emergent adverse events were evaluated

from four trials comparing fixed doses (2, 10, 15, 20, and 30 mg/day) of ABILIFY

to placebo.

This analysis, stratified by study, indicated that the only adverse event to have a possible dose

response relationship, and then most prominent only with 30 mg, was somnolence (including

sedation) [placebo, 7.1%; 10 mg, 8.5%, 15 mg, 8.7 %; 20 mg, 7.5%; 30 mg, 12.6%].

Adverse Events Occurring in Long-Term Controlled Trials

The adverse events reported in a 26-week, double-blind trial comparing ABILIFY

and placebo

in patients with schizophrenia were generally consistent with those reported in the short-term,

placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for ABILIFY

2% (3/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity

(8/12 mild and 4/12 moderate), occurred early in therapy (9/12

49 days), and were of limited

duration (7/12

10 days). Tremor infrequently led to discontinuation (<1%) of ABILIFY

. In

addition,

long-term

(52-week),

active-controlled

study,

incidence

tremor

ABILIFY

was 5% (40/859). A similar profile was observed in a long-term study in Bipolar

Disorder.

Weight Gain

NZ_DS_Abilify_V2.1_ August2016

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In placebo-controlled trials, there was a slight difference in mean weight change between

ABILIFY

and placebo patients (+0.7 kg vs –0.05 kg, respectively, in short-term studies; p

0.01,

and –1.3 kg vs –0.9 kg, respectively, in 26 week study; p=n.s.) and also a difference in the

proportion of patients meeting the significant weight gain criterion of

7% of body weight

(ABILIFY

8% compared to placebo 3% in short-term studies; p

0.01; and ABILIFY

compared to placebo 4% in long-term studies; p = n.s.).

In 3-week trials in adults with Mania with monotherapy aripiprazole, the mean weight gain for

aripiprazole and placebo patients was 0.1 kg versus 0.0 kg, respectively. The proportion of patients

meeting a weight gain criterion of

7% of body weight was aripiprazole (2%) compared to placebo

(3%). In the 6-week trial in Mania with aripiprazole as adjunctive therapy with either lithium or

valproate, the mean weight gain for aripiprazole and placebo patients was 0.6 kg versus 0.2 kg,

respectively. The proportion of patients meeting a weight gain criterion of

7% of body weight

with adjunctive aripiprazole was 3% compared to adjunctive placebo 4%.

In long-term, double-blind, active-comparator trials in schizophrenia, ABILIFY

was associated

with

higher

incidence

significant

weight

gain

above

baseline)

compared

with

haloperidol (20% vs 13%,, respectively; p

0.01; 1.1 kg vs 0.4 kg , respectively; p=n.s.) but a lower

incidence of significant weight gain compared to olanzapine (ABILIFY

13% vs olanzapine

33%; p<0.001; -0.9 kg vs 3.4 kg; p<0.001 in a double-blind study).

Weight

change

results

(see

Table

from

long-term,

double-blind,

controlled

trials

schizophrenia showed that patients with high body mass index (BMI) (>27) were less likely to

have significant weight gain on ABILIFY

than those with low BMI (<23).

Table 5

Weight Change Results Categorised by BMI at Baseline in Double-Blind, Controlled Trials in

Schizophrenia

Study

BMI <23

BMI 23-27

BMI >27

52-week

Haloperidol

Controlled

Mean Change

from Baseline (kg)

-1.2

% Patients with

7% increase of

body weight

relative to baseline

26-week

Olanzapine

Controlled

Mean Change

from Baseline (kg)

-0.4

-1.4

NZ_DS_Abilify_V2.1_ August2016

- 29 -

Table 5

Weight Change Results Categorised by BMI at Baseline in Double-Blind, Controlled Trials in

Schizophrenia

Study

BMI <23

BMI 23-27

BMI >27

% Patients with

7% increase of

body weight

relative to baseline

26-week

Placebo

Controlled

Mean Change

from Baseline (kg)

-0.5

-1.3

-2.1

% Patients with

7% increase of

body weight

relative to baseline

Extrapyramidal Symptoms

In the short-term, placebo-controlled trials of schizophrenia in adults, the incidence of reported

EPS-related events excluding events related to akathisia for aripiprazole-treated patients was 13%

vs. 12 % for placebo. The incidence of akathisia-related events for aripiprazole-treated patients

was 8% vs 5% for placebo-treated patients.

In the short-term, placebo-controlled trials in Bipolar Mania in adults, the incidence of reported

EPS-related events, excluding events related to akathisia, for monotherapy aripiprazole-treated

patients was 16% versus 8% for placebo and the incidence of akathisia-related events for

monotherapy aripiprazole-treated patients was 13% versus 4% for placebo. In the 6-week, placebo-

controlled trial in Bipolar Mania for adjunctive therapy with lithium or valproate, the incidence of

reported EPS-related events, excluding events related to akathisia for adjunctive aripiprazole-

treated patients was 15% versus 8% for adjunctive placebo and the incidence of akathisia-related

events for adjunctive aripiprazole-treated patients was 19% versus 5% for adjunctive placebo.

Objectively collected data from those trials on the Simpson Angus Rating Scale (for EPS), the

Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for

dyskinesias) did not show a difference between aripiprazole and placebo, with the exception of the

Barnes Akathisia Scale (aripiprazole, 0.08; placebo, -0.05).

In the adult Bipolar Mania trials with monotherapy aripiprazole, The Simpson Angus Rating Scale

and the Barnes Akathisia Scale showed a significant difference between aripiprazole and placebo

(aripiprazole, 0.50; placebo,

-0.01 and aripiprazole, 0.21; placebo,

-0.05). Changes in the

Assessment of Involuntary Movement Scales were similar for the aripiprazole and placebo groups.

In the Bipolar Mania trials with aripiprazole as adjunctive therapy with either lithium or valproate,

The Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference

between adjunctive aripiprazole and adjunctive placebo (aripiprazole, 0.73; placebo, 0.07 and

NZ_DS_Abilify_V2.1_ August2016

- 30 -

aripiprazole, 0.30; placebo, 0.11). Changes in the Assessment of Involuntary Movement Scales

were similar for adjunctive aripiprazole and adjunctive placebo.

In a long-term, double-blind, haloperidol-controlled study in schizophrenia, the incidence of

haloperidol-treated patients showing at least one EPS-related adverse event, including dystonia,

was significantly greater than that of the ABILIFY

group (57% vs 26%; p<0.001). In a long-

term, double-blind, olanzapine-controlled study, the incidence of olanzapine-treated patients

showing at least one EPS-related adverse event was comparable to ABILIFY

-treated patients

(15% vs 15%, respectively; p= n.s.).

Dystonia

Class Effect:

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may

occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include:

spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty,

difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses,

they occur more frequently and with greater severity with high potency and at higher doses of first

generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and

younger age groups.

ECG Changes

Between

group

comparisons

pooled,

acute,

placebo-controlled

trials

patients

with

schizophrenia or Bipolar Mania, revealed no significant differences between oral ABILIFY

placebo

proportion

patients

experiencing

potentially

important

changes

parameters. In fact, within the dose range of 10 to 30 mg/day, aripiprazole tended to slightly

shorten the QTc interval. ABILIFY

was associated with a median increase in heart rate of two

beats per minute compared to no increase among placebo patients.

In a 26-week, placebo-controlled trial in schizophrenia, there were no significant differences

between ABILIFY

and placebo in the proportion of patients experiencing potentially important

changes in ECG parameters.

Laboratory Test Abnormalities

A between group comparison for acute, 3 to 6-week, placebo-controlled trials in adults revealed

no medically important differences between the ABILIFY

and placebo groups in the proportions

of patients experiencing potentially clinically significant changes in routine serum chemistry,

haematology, or urinalysis parameters. Similarly, there were no ABILIFY

/placebo differences

in the incidence of discontinuations for changes in serum chemistry, haematology, or urinalysis in

adult patients.

long-term

(26-week),

placebo-controlled

trial,

there

were

statistically

significant

differences between the aripiprazole and placebo patients in the mean change from baseline in

fasting glucose, triglyceride, LDL, and total cholesterol measurements.

NZ_DS_Abilify_V2.1_ August2016

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Adverse Reactions Observed During the Premarketing Evaluation of oral

ABILIFY

TM

The following is a list of MedRA terms that reflect adverse reactions reported by adult patients

treated with oral aripiprazole at multiple doses ≥ 2 mg/day during any phase of a trial within a

database of 13,543 adult patients. The listing does not show adverse events mentioned in Table 2,

3 and 4 or in other sections of this prescribing information. It is important to emphasise that

although the events reported occurred with treatment they are not necessarily caused by it.

adverse reactions are classified by system organ class and are according to the following

definitions: common adverse reactions are those occurring in at least 1/100 patients; uncommon

adverse reactions are those occurring in at least 1/1000, but less than 1/100 patients; rare adverse

reactions are those occurring in less than 1/1000 patients.

Blood

and

Lymphatic

System

Disorders:

uncommon

leucopoenia,

neutropenia,

thrombocytopenia;

rare

eosinophilia, lymphadenopathy

Cardiac Disorders: uncommon

bradycardia, palpitations, cardiopulmonary failure, myocardial

infarction, cardio-respiratory arrest, atrioventricular block, extrasystoles, sinus tachycardia, atrial

fibrillation,

angina

pectoris,

myocardial

ischaemia;

rare

atrial

flutter,

supraventricular

tachycardia, ventricular tachycardia.

Ear and Labyrinth Disorders: rare –

ear canal erythema, hypoacusis, vertigo positional, tinnitus.

Endocrine Disorders: rare

early menarche.

Eye Disorders: uncommon

dry eye, photophobia, diplopia, eyelid oedema, photopsia;

rare –

eye redness, chromotopsia, conjunctivitis, eye disorder, eye movement disorder, gaze palsy,

lacrimation increased

Gastrointestinal Disorders: uncommon –

diarrhoea, gastritis, dysphagia, gastroesophageal reflux

disease, swollen tongue, oesophagitis, hypoaesthesia oral;

rare –

abdominal distension, abnormal

faeces, eructation, faeces discoloured, constipation, gastrointestinal disorder, gastrointestinal pain,

glossitis, lip dry, parotid gland enlargement, pruritus ani, tongue discolouration, pancreatitis.

General Disorders and Administration Site Conditions: common

– asthenia, peripheral oedema,

irritability, chest pain;

uncommon

face oedema, angiodema, gait disturbance,

adverse event,

chills, discomfort, feeling abnormal, mobility decreased;

rare –

difficulty in walking, facial pain,

, swelling, malaise, thirst, chest discomfort, cyst, energy increased, feeling cold, generalised

oedema, local swelling, oedema, tenderness, xerosis, hypothermia.

Hepatobiliary Disorders: rare –

hepatitis, jaundice.

Immune System Disorders: rare –

decreased immune responsiveness, hypersensitivity.

NZ_DS_Abilify_V2.1_ August2016

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Infections and Infestations: rare –

sinusitis, urinary tract infection, body tinea, gastroenteritis

viral, herpes simplex, localized infection, lower respiratory tract infection, oral candidiasis,

parotitis, gastroenteritis.

Injury, Poisoning, and Procedural Complications:

common

fall;

uncommon

– self mutilation;

rare –

heat stroke,

injury, muscle strain, clavicle fracture, femoral neck fracture, hip fracture,

humerus fracture, mouth injury, open wound.

Investigations: common

– weight decreased, creatinine phosphokinase increased;

uncommon

weight increased, blood creatinine increased, heart rate increased, blood glucose increased,

pyrexia, blood prolactin increased, blood urea increased, electrocardiogram QT prolonged, blood

bilirubin increased, hepatic enzyme increased;

rare

- electrocardiogram abnormal, urine output

increased, blood creatine phosphokinase abnormal, orthostatic hypotension, blood urine present,

electrocardiogram

prolongation,

electrocardiogram

wave

inversion,

eosinophil

count

increased, head lag abnormal, heart rate irregular, physical examination, urine ketone body present,

white

blood

cell

count

increased,

blood

lactate

dehydrogenase

increased,

glycosylated

haemoglobin increased, gamma-glutamyl transferase increased.

Metabolism and Nutrition Disorders: uncommon

hyperlipidaemia, anorexia, diabetes mellitus

(including blood insulin increased, carbohydrate tolerance decreased, diabetes mellitus non-

insulin-dependent, glucose tolerance impaired, glycosuria, glucose urine, glucose urine present),

hyperglycaemia,

hypokalaemia,

hypoglycaemia,

polydipsia,

increased

appetite,

dehydration,

hyponatraemia;

rare –

diabetic ketoacidosis, hyperuricaemia.

Musculoskeletal

and

Connective

Tissue

Disorders:

uncommon

muscle

rigidity,

musculoskeletal

rigidity,

muscle

tightness,

muscle

spasms,

muscular

weakness,

mobility

decreased;

rare -

bone pain, nuchal rigidity, sensation of heaviness, flank pain, jaw disorder,

kyphosis, osteoarthritis, rhabdomyolysis.

Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps): rare

oral

neoplasm, skin papilloma.

Nervous System Disorders: common

– coordination abnormal;

uncommon -

memory impairment,

cerebrovascular accident, hypokinesia, hypotonia, myoclonus, hypertonia, akinesia, bradykinesia,

drooling, cogwheel rigidity, dystonia, disturbance in attention, dizziness postural, dysarthria,

paraesthesia, parkinsonism, psychomotor hyperactivity, hypoaesthesia, speech disorder, tardive

dyskinesia;

rare –

burning sensation, convulsion, depressed level of consciousness, dysgeusia,

akinaesthesia, ataxia, bradykinesia, coma, dysphasia, facial palsy, judgement impaired, loss of

consciousness, migraine, neuroleptic malignant syndrome, paraesthesia circumoral, sleep phase

rhythm disturbance, Grand Mal convulsion, choreoathetosis, unresponsive to verbal stimuli.

NZ_DS_Abilify_V2.1_ August2016

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Psychiatric Disorders: common

– suicidal ideation;

uncommon –

aggression, loss of libido,

suicide attempt, hostility, libido increased, anger, anorgasmia, delirium, intentional self injury,

completed suicide, tic, homicidal ideation, depression,

confusional state, nightmare, mania,

abnormal dreams, hallucination auditory, nervousness, hallucination, apathy, thinking abnormal,

bruxism,

rare –

catatonia, sleep walking, bradyphrenia, delirium, depressed mood, disorientation,

euphoric mood, logorrhea, mental status changes, mood altered, panic attack, sleep disorder,

blunted affect, cognitive deterioration, delusional perception, insomnia, eating disorder, emotional

distress, impulsive behaviour, asthenia, mood swings, psychomotor retardation, somatoform

disorder.

Renal and Urinary Disorders: uncommon –

nocturia, polyuria,

pollakiuria, incontinence, urinary

retention;

rare -

proteinuria, bladder discomfort, chromaturia, enuresis, micturition urgency,

oliguria, urethral discharge, urinary hesitation.

Reproductive System and Breast Disorders: uncommon –

erectile dysfunction, amenorrhea

breast pain, menstruation irregular

rare –

genital pruritus female

, vulvovaginal discomfort

pelvic pain, breast discharge, sexual dysfunction, gynaecomastia, priapism.

Respiratory,

Thoracic

and

Mediastinal

Disorders:

common

nasal

congestion,

dyspnea,

pneumonia aspiration;

uncommon –

hiccups, epistaxis;

rare –

dry throat, rhinorrhoea, sinus

congestion, hoarseness, nasal dryness, painful respiration, paranasal sinus hypersecretion.

Skin and Subcutaneous Tissue Disorders: common

– rash (including erythematous, exfoliative,

generalised, macular, maculopapular, popular rash, acneiform, allergic, contact, exfoliative,

seborrheic dermatitis, neurodermatitis, and drug eruption), hyperhydrosis;

uncommon -

pruritus,

photosensitivity reaction, alopecia, urticaria;

rare –

decubitus ulcer, face oedema, pemphigus,

psoriasis, dry skin.

Social Circumstances: rare -

smoker.

Vascular Disorders: common

hypertension;

uncommon –

hypotension,

hot flush,

rare –

flushing, hyperaemia.

(female) indicates incidence based on gender total

POSTMARKETING EXPERIENCE

The following adverse reactions have been identified during post approval use of ABILIFY

Because these reactions are reported voluntarily from a population of uncertain size, it is not

always possible to establish a causal relationship to drug exposure: occurrences of allergic

reaction (anaphylactic reaction, angiodema, laryngospasm, pruritis/urticaria, or oropharyngeal

NZ_DS_Abilify_V2.1_ August2016

- 34 -

spasm), and blood glucose fluctuation. Very rare occurrences of increased AST, increased ALT

and hiccups have been reported.

Psychiatric Disorders

Uncommon: Hypersexuality

Unknown: Pathological gambling, impulse-control disorders, obsessive-compulsive disorders,

eating disorders

DRUG ABUSE AND DEPENDENCE

ABILIFY

has not been systematically studied in humans for its potential for abuse, tolerance,

physical

dependence.

self-administration

studies

rats

monkeys,

ABILIFY

demonstrated marginal to no abuse potential. In physical dependence studies in rats and monkeys,

modest withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical

trials did not reveal any tendency for any drug-seeking behaviour, these observations were not

systematic and it is not possible to predict on the basis of this limited experience the extent to

which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently,

patients should be evaluated carefully for a history of drug abuse and such patients should be

observed closely for signs of ABILIFY

misuse or abuse (e.g., development of tolerance,

increases in dose, drug-seeking behaviour).

DOSAGE AND ADMINISTRATION

Recommended Dosage

Schizophrenia

Adults

The recommended starting dose for ABILIFY

is 10 or 15 mg/day administered on a once-a-day

schedule without regard to meals. Doses in the range of 10 to 30 mg/day have been effective in

clinical trials. Daily dosage may be adjusted on the basis of individual clinical status within the

range of 10-30 mg daily. Dosage increases should not be made before 2 weeks, the time needed to

achieve steady state. There is no evidence that doses higher than 15 mg/day are more effective

than the recommended starting dose of 10-15 mg.

The maintenance dose for ABILIFY

is 15 mg/day.

Bipolar Disorder

NZ_DS_Abilify_V2.1_ August2016

- 35 -

Acute Treatment

Adults

The recommended starting and target dose is 15mg as monotherapy or as adjunctive therapy with

lithium or valproate given once a day, without regard to meals. The dose can be increased to

30 mg/day based on clinical response. The safety of doses above 30 mg/day has not been evaluated

in clinical trials.

Maintenance Therapy

Adults

Maintenance of efficacy in Bipolar I disorder was demonstrated in a trial involving patients who

had been symptomatically stable on ABILIFY

Tablets (15 mg/day or 30 mg/day, as monotherapy)

for at least 6 consecutive weeks. These patients were discontinued from those medications and

randomised to either ABILIFY

, at the same dose they were stabilised on, or placebo, and

observed for relapse

.

Patients should be periodically reassessed to determine the continued need

for maintenance treatment.

Renal Impairment

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

Hepatic Impairment

No dosage adjustment is required for adult patients with hepatic impairment (Child-Pugh Class A,

B or C).

Paediatric

The safety and effectiveness of ABILIFY

in patients under 18 years of age has not been

established.

Elderly

No dosage adjustment is required for patients

65 years of age.

Gender

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

Concomitant Medications

Dosage adjustment for patients taking ABILIFY

TM

concomitantly with potential CYP3A4

inhibitors:

When concomitant administration of a potent CYP3A4 inhibitor with ABILIFY

occurs, the ABILIFY

dose should be decreased. When the CYP3A4 inhibitor is withdrawn from

the combination therapy, the ABILIFY

dose should then be increased.

Dosage adjustment for patients taking ABILIFY

TM

concomitantly with potential CYP2D6

inhibitors:

When concomitant administration of potential CYP2D6 inhibitors such as quinidine,

NZ_DS_Abilify_V2.1_ August2016

- 36 -

fluoxetine, or paroxetine with ABILIFY

occurs, the ABILIFY

dose should be halved. When

the CYP2D6 inhibitor is withdrawn from the combination therapy, the ABILIFY

dose should

then be increased.

Dosage adjustment for patients taking ABILIFY

TM

concomitantly with multiple medications

that inhibit CYP3A4 and CYP2D6:

Although no clinical studies have been conducted in which

ABILIFY

taken

together

with

multiple

drugs

that

inhibit

CYP3A4

CYP2D6,

consideration

should

given

reducing

daily

dose

ABILIFY

individual

circumstances.

Dosage adjustment for patients taking ABILIFY

TM

concomitantly with potential CYP3A4

inducers:

When a potent CYP3A4 inducer such as carbamazepine is added to ABILIFY

therapy, the ABILIFY

dose should be increased. Additional dose increases should be based on

clinical evaluation. When the CYP3A4 inducer is withdrawn from the combination therapy, the

ABILIFY

dose should then be reduced.

Smoking Status

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

Switching from Other Antipsychotics

Data was prospectively and systematically collected to address the safety of switching from other

antipsychotics to ABILIFY

(30mg/day). These data indicate that any of the following methods

can be used safely for switching patients to ABILIFY

from another antipsychotic monotherapy:

immediate discontinuation of the patient’s current antipsychotic regimen and immediate

initiation of ABILIFY

immediate initiation of ABILIFY

while tapering off the current antipsychotic regimen over

a 2-week period;

upward titration of ABILIFY

over a 2-week period and simultaneous tapering off of the

patient’s current antipsychotic regimen over the same 2-week period.

OVERDOSAGE

Human Experience

In clinical studies, and postmarketing experience, accidental or intentional acute overdosage of

aripiprazole alone was identified in adult patients with estimated doses up to 1260 mg with no

fatalities. The potentially medically important signs and symptoms observed in adult patients who

overdosed with aripiprazole alone at doses up to 1260 mg included lethargy, blood pressure

increased, somnolence, tachycardia and vomiting. In addition, reports of accidental overdose with

aripiprazole alone (up to 195 mg) in children have been received. The potentially medically serious

signs and symptoms reported include somnolence, and transient loss of consciousness. In the

patients who were evaluated in hospital settings, there were no reported observations indicating a

clinically significant adverse change in vital signs, laboratory assessments, or ECG.

NZ_DS_Abilify_V2.1_ August2016

- 37 -

Management of Overdosage

No specific information is available on the treatment of overdose with ABILIFY

. The possibility

of multiple drug involvement should be considered. Therefore cardiovascular monitoring should

commence immediately and should include continuous electrocardiographic monitoring to detect

possible arrhythmias. Otherwise, management of overdose should concentrate on supportive

therapy, maintaining an adequate airway, oxygenation and ventilation, and management of

symptoms. Close medical supervision and monitoring should continue until the patient recovers.

Charcoal:

In the event of an overdose of ABILIFY

, an early charcoal administration may be

useful in partially preventing the absorption of aripiprazole. In a single-dose study in which 15 mg

of aripiprazole was administered to fully compliant, fully conscious, healthy, male volunteers and

followed by activated charcoal (50 g), administered one hour after ABILIFY

, aripiprazole AUC

and Cmax was decreased by 51 and 41%, respectively, compared to historic controls, suggesting

that charcoal may be effective for overdose management.

Haemodialysis:

Although there is no information on the effect of haemodialysis in treating an

overdose with ABILIFY

, haemodialysis is unlikely to be useful in overdose management, since

aripiprazole is not eliminated unchanged by the kidneys and is highly bound to plasma proteins.

The Poisons Information Centre, telephone number 131126 in Australia and 0800 764 766 in New

Zealand, should be contacted for advice on management.

PRESENTATION

Tablets

ABILIFY

(aripiprazole) is available as:

5 mg blue, modified rectangular, shallow convex, bevel-edged, tablets, marked on one side with

“A-007” and “5”;

10 mg pink, modified rectangular, shallow convex, bevel-edged, tablets, marked on one side with

“A-008” and “10”;

15 mg yellow, round, shallow convex, bevel-edged, tablets, marked on one side with “A-009” and

“15”;

20 mg white to pale yellowish white, round, shallow convex, bevel-edged, tablets, marked on one

side with “A-010” and “20”;

30 mg pink, round, shallow convex, bevel-edged, tablets, marked on one side with “A-011” and

“30”.

ABILIFY

tablets are packed in aluminium blisters in cartons.

STORAGE CONDITIONS

Store below 30

NZ_DS_Abilify_V2.1_ August2016

- 38 -

NAME AND ADDRESS OF SPONSOR

Pharmacy Retailing (NZ) Ltd trading as Healthcare Logistics

58 Richard Pearse Drive

Airport Oaks

Mangere

Auckland 2022

Tel: Toll free 0800 602 200

DATE OF PREPARATION

28 September 2016

ABILIFY is a trademark of Otsuka Pharmaceutical Co., Ltd.

18-10-2018

ABILIFY MAINTENA (Otsuka Pharmaceutical Netherlands B.V.)

ABILIFY MAINTENA (Otsuka Pharmaceutical Netherlands B.V.)

ABILIFY MAINTENA (Active substance: Aripiprazole) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)6925 of Thu, 18 Oct 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/002755/T/0026

Europe -DG Health and Food Safety

29-8-2018

ABILIFY MAINTENA (Otsuka Pharmaceutical Europe Ltd)

ABILIFY MAINTENA (Otsuka Pharmaceutical Europe Ltd)

ABILIFY MAINTENA (Active substance: Aripiprazole) - Centralised - Renewal - Commission Decision (2018)5780 of Wed, 29 Aug 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/2755/R/25

Europe -DG Health and Food Safety

28-8-2018

Abilify (Otsuka Pharmaceutical Netherlands B.V.)

Abilify (Otsuka Pharmaceutical Netherlands B.V.)

Abilify (Active substance: aripiprazole) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)5681 of Tue, 28 Aug 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/471/T/131

Europe -DG Health and Food Safety