Data Sheet
ABILIFY™
aripiprazole
Tablets: 5mg, 10mg, 15mg, 20mg & 30mg
NAME OF THE DRUG
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 C23H27Cl2N3O2 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 (Po/w) of aripiprazole range from 3.4 at pH 2.0 to > 1000 at pH 6.0.
ABILIFY™ is available as 5mg (blue, unscored), 10mg (pink, unscored), 15mg (yellow, unscored), 20mg (white, unscored), and 30mg (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: 5mg tablets - indigo carmine CI73015 aluminium lake; 10mg tablets - red iron oxide CI77491; 15mg tablets - yellow iron oxide CI77492; 20mg tablets - nil; 30mg tablets - red iron oxide CI77491.
PHARMACOLOGY
Pharmacodynamics
The mechanism of action of ABILIFY™, as well as other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that the efficacy of ABILIFY™ is mediated through a combination of partial agonist activity at dopamine D2 and serotonin 5HT1A receptors and antagonist activity at serotonin 5HT2A receptors.
ABILIFY™ activity is primarily due to the parent drug, aripiprazole
Aripiprazole exhibited higher affinity binding in vitro for dopamine D2 and D3, serotonin 5HT1A and 5HT2A receptors (Ki values of 0.3, 0.8, 1.7, and 3.4nM, respectively), than for dopamine D4, serotonin 5HT2C and 5HT7, alpha1-adrenergic and histamine H1 receptors (Ki values of 44, 15, 39, 57, and 61nM, respectively) and the serotonin reuptake site (Ki value of 98nM). Aripiprazole exhibited no appreciable affinity for muscarinic receptors (IC50 >1000nM).
The predominant metabolite in human plasma, dehydro-aripiprazole has been shown to have a similar affinity for dopamine D2 and D3 receptors (Ki values 0.4 and 0.5nM, 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 for aripiprazole and 12 hours for the active metabolite. Aripiprazole accumulation is predictable from single dose pharmacokinetics. At steady state, the pharmacokinetics of aripiprazole are dose-proportional. There is no diurnal variation in the disposition of aripiprazole and its active metabolite, dehydro-aripiprazole.
Distribution
Aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 L/kg. At therapeutic concentrations, aripiprazole is highly bound (88 -97% to > 99%, as determined by polydimethylsiloxane-glass bead and equilibrium dialysis assays, respectively) to serum proteins, primarily albumin, in vitro. Aripiprazole did not alter the pharmacokinetics and pharmacodynamics of highly protein-bound warfarin, suggesting that protein displacement of warfarin did not occur.
Metabolism
Aripiprazole undergoes minimal pre-systemic metabolism. Aripiprazole is extensively metabolized by the liver primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are primarily responsible for dehydrogenation and hydroxylation of aripiprazole, while N-dealkylation is primarily catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in systemic circulation. At steady state, dehydro-aripiprazole, the active metabolite, represented about 39% of aripiprazole AUC in plasma. Approximately 8% of Caucasians lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are extensive metabolizers (EM). PMs have about an 80% increase in aripiprazole exposure and about a 30% decrease in exposure to the active metabolite compared to EMs, resulting in about a 60% higher exposure to the total active moieties from a given dose of aripiprazole compared to EMs. Subjects were entered into clinical studies without knowledge of their metabolizer status and, therefore, the safety profile reflects experience in both EMs and PMs.
Excretion
Following a single, oral dose of [14C]-labeled aripiprazole, approximately 27% and 60% of the administered radioactivity was recovered in the urine and faeces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the faeces. The total body clearance of aripiprazole is 0.7mL/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 in schizophrenic patients. In formal single-dose pharmacokinetic studies (with aripiprazole given in a single dose of 15 mg), aripiprazole clearance was 20% lower in elderly (≥ 65 years) subjects compared to younger adult subjects (18-64 years). There was no detectable age effect, however, in the population pharmacokinetic analysis in schizophrenia patients. Also, the pharmacokinetics of aripiprazole after multiple doses in elderly patients appeared similar to that observed in young healthy subjects. No dosage adjustment is recommended for elderly patients. (See PRECAUTIONS: Increased Mortality in Elderly Patients with Dementia- Related Psychosis and 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 nonsmokers. No dosage adjustment is recommended based on smoking status.
Renal Impairment
The pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were found to be similar in patients with severe renal disease compared to young healthy subjects. In patients with severe renal impairment (creatinine clearance <30 mL/min), Cmax of aripiprazole (given in a single dose of 15 mg) and dehydro-aripiprazole increased by 36% and 53%, respectively, but AUC was 15% lower for aripiprazole and 7% higher for dehydro-aripiprazole. Renal excretion of both unchanged aripiprazole and dehydro-aripiprazole is less than 1% of the dose. No dosage adjustment is required in subjects with renal impairment.
Hepatic Impairment
A study in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydro-aripiprazole. In a single-dose study (15 mg of aripiprazole) in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C), the AUC of aripiprazole, compared to healthy subjects, increased 31% in mild HI, increased 8% in moderate HI, and decreased 20% in severe HI. None of these differences would require dose adjustment.
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™ to 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 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 10mg 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.
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 | 4.3 | |
| 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 | 4.0 | |
| 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 | 0.1 | -1.4 | -0.2 | 4.0 | |
| 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 | 3.6 | |
| Ari 2 mg | -8.2 | -2.4 | -2.0 | -2.3 | -0.3 | 3.6 | |
| Ari 5 mg | -10.6 | -3.4 | -2.9* | -3.2 | -0.6* | 3.2 | |
| Ari 10 mg | -11.3* | -4.2* | -2.7 | -3.4 | -0.6* | 3.2 | |
| Trial 5 | |||||||
| Placebo | -1.5 | -0.1 | -0.9 | -2.4 | 0.0 | 4.0 | |
| 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 | 3.9 | |
| Ari 2 mg | -8.0 | -1.96 | -2.05 | -1.95 | -0.30 | 3.7 | |
| Ari 10 mg | -8.6 | -2.10 | -2.48 | -1.79 | -0.30 | 3.5 | |
| 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 |
|||||||
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™ 30mg/day and haloperidol
10mg/day, with a one time option to decrease ABILIFY™ to 20mg/day and
haloperidol to 7mg/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 randomized 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™ 15mg or placebo and followed for 26 weeks. Patients were observed for "impending psychotic relapse", defined as CGI-improvement score ≥5 (minimally worse) or scores ≥5 (moderately severe) on the hostility or uncooperativeness items of the PANSS on two consecutive days or ≥20% increase in the PANSS Total Score. Patients in the placebo group experienced a higher relapse rate and/or relapsed sooner than those in the 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.
INDICATIONS
ABILIFY™ is indicated for the treatment of schizophrenia including maintenance of clinical improvement during continuation therapy.
CONTRAINDICATIONS
ABILIFY™ is contraindicated in patients who are hypersensitive to aripiprazole or any of the excipients (see DESCRIPTION).
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.
Suicide
The possibility of a suicide attempt is inherent in psychotic illnesses, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for 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.
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
Seizures occurred in 0.2% (2/1079) of patients treated with ABILIFY™ in acute therapy (up to 6 weeks) in six placebo-controlled trials in schizophrenia. 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 is not approved for the treatment of patients with dementia-related psychosis. (See also PRECAUTIONS: Increased Mortality in Elderly Patients with Dementia-Related Psychosis and 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 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 α1-adrenergic receptor antagonism, ABILIFY™ may be associated with orthostatic hypotension. The incidence of orthostatic hypotension associated adverse events reported during acute therapy (up to 6 weeks) in placebo-controlled trials in schizophrenia included: orthostatic hypotension (placebo, 0.7%; ABILIFY™, 1.8%); dizziness postural (placebo, 0. 5%, ABILIFY™, 0. 6%); and syncope (placebo, 0.5%; ABILIFY™, 0.6%).
Orthostatic hypotension occurred in 1.1% (92/8456) of ABILIFY™ -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 or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolaemia, and treatment with antihypertensive medications).
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.
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).
Use in Patients with Concomitant Illness
Clinical experience with ABILIFY™ in patients with certain concomitant systemic illnesses is limited. (See PHARMACOLOGY: Renal Impairment and 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:
In three, 10-week, placebo-controlled studies of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease (n=938; mean age: 82.4 years; range: 56-99 years), the treatment-emergent adverse events that were reported at an incidence of ≥5% and aripiprazole incidence at least twice that for placebo were lethargy [placebo 2%, aripiprazole 5%], somnolence (including sedation) [placebo 3%, aripiprazole 8%] and incontinence ( primarily, urinary incontinence) [ placebo 1%, aripiprazole 5%].
The safety and efficacy of 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 and Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis.)
Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. (See PRECAUTIONS: Interactions)
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 and 0.3 to 3 times the maximum recommended human dose [MRHD] based on mg/m2, respectively). SD rats were dosed orally by gavage for 2 years at 10, 20, 40, and 60 mg/kg/day (3 to 18 times the MRHD based on mg/m2). There was no evidence of tumorigenesis in male mice or rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.1 to 0.9 times MRHD based on AUC and 0.5 to 5 times the MRHD based on mg/m2). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (< 0.1 times MRHD based on AUC and 3 times the MRHD based on mg/m2); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral gavage dose of 60 mg/kg/day (10 times the MRHD based on AUC and 18 times MRHD based on mg/m2). In male rats, the incidence of benign and combined benign/malignant phaeochromocytomas were also increased at an oral gavage dose of 60 mg/kg/day (10 times the MRHD based on AUC and 18 times the MRHD based on mg/m2).
Proliferative changes in the pituitary and mammary gland of rodents have been observed following chronic administration of other antipsychotic agents and are considered prolactin-mediated. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. 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 to chronic drug-related adrenocortical cytotoxicity. The no-effect-dose (40 mg/kg/day) was 7 - 12 times the MRHD based on AUC and mg/m2.
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.
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/m2) for 2 weeks prior to mating through gestation day 7. Drug-related effects (persistent dioestrus and increased mating time pre-implantation losses, and corpora lutea) observed at all doses were considered the result of perturbed oestrous cyclicity secondary to drug-mediated hyperprolactinaemia.
Aripiprazole had no effect on fertility in male rats treated with PO doses of 20, 40, and 60 mg/kg/day (6, 12, and 18 times the MRHD based on mg/m2) for 9 weeks prior to mating through mating. Disturbances of spermatogenesis were seen at 60 mg/kg/day and prostatic atrophy was seen at 40 and 60 mg/kg/day.
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/m2 basis) of aripiprazole during the period of organogenesis. At 30 mg/kg, treatment was associated with slightly prolonged gestation, and a slight delay in foetal development as evidenced by decreased foetal weight, undescended testes, and delayed skeletal ossification. There were no adverse effects on embryofoetal or pup survival. Delivered offspring had increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia at 30 mg/kg (the other doses were not examined for these findings). (A low incidence of diaphragmatic hernia was also seen in the foetuses exposed to 30 mg/kg). Postnatally, decreased pup weight (persisting into adulthood) was seen at 30 mg/kg, delayed vaginal opening was seen at 10 and 30 mg/kg, and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, and live foetuses, and increased post-implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg. Maternal toxicity was seen at 30 mg/kg, which was similar to doses eliciting embryotoxicity.
Pregnant rabbits were treated with oral doses of 10, 30, and 100 mg/kg/day (2, 3, and 11 times human exposure at MRHD based on AUC and 8, 24, and 81 times the MRHD based on mg/m2) of aripiprazole during the period of organogenesis. Decreased maternal food consumption, and increased abortions were seen at 100 mg/kg. Treatment caused increased foetal mortality (100 mg/kg), decreased foetal weight (30 mg and 100 mg/kg), increased incidence of a skeletal abnormality (fused sternebrae at 100 mg/kg) and minor skeletal variations (100 mg/kg).
Rats were treated with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 9 times the MRHD on a mg/m2 basis) of aripiprazole from late gestation through weaning. At 30 mg/kg, maternal toxicity, slightly prolonged gestation, an increase in stillbirths, poor postnatal care/nursing, and decreases in pup weight (persisting into adulthood) and survival were seen.
There are no adequate and well-controlled studies of ABILIFY™ in pregnant women. It is not known whether ABILIFY™ can cause harm when administered to pregnant women or can affect reproductive capacity. ABILIFY™ should be used during pregnancy only if the potential benefit outweighs the potential risk to the foetus.
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. It is not known whether aripiprazole or its metabolites are excreted in human 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/m2) and were attributed to precipitation of sulfate conjugates of hydroxy metabolites, which exceeded their solubility limits in bile. Human biliary concentrations of these sulfate conjugates after repeated daily administration of the MRHD are substantially lower (0.2 - 14% of their in vitro solubility limits).
Bilateral retinal degeneration was observed in albino rats given oral aripiprazole for 6 months 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/m2. 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 did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 8456 patients treated with ABILIFY™ in clinical trials, 1000 (12%) were ≥65 years old and 794 (9%) were ≥75 years old. The majority (87%) of the 1000 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 and Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis and 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
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 or lithium pharmacokinetics when aripiprazole 30 mg once daily was administered concomitantly for 7 days with either divalproex sodium 500 mg every 12 hours or controlled release lithium 450 mg every 12 hours.
Antihypertensive Agents
Due to its α1-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 be 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™ 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 (IC 50 values 2.4 -25 μM). Neither aripiprazole nor dehydro-aripiprazole inhibited CYP1A2 -mediated metabolism in vitro (IC 50 value >50 - 66 μM).
In clinical studies, 10-30 mg/day doses of ABILIFY™ had no significant effect on metabolism of substrates of 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 H2 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 REACTIONS
ABILIFY™ has been evaluated for safety in 8456 patients who participated in multiple-dose premarketing trials in schizophrenia (including schizo-affective disorder), bipolar mania, and dementia of the Alzheimer's type, and who had approximately 5635 patient-years of exposure. A total of 2442 ABILIFY™-treated patients were treated for at least 180 days and 1667 ABILIFY™-treated patients had at least 1 year of exposure.
The conditions and duration of treatment with ABILIFY™ included (in overlapping categories) double-blind and 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 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.
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.
Adverse Events Occurring at an Incidence of at Least 1.0% Among ABILIFY™-Treated Patients in Short-Term Placebo-Controlled Trials
Table 2 enumerates the incidence, of treatment-emergent adverse events that occurred during acute therapy (up to 6 weeks) during placebo-controlled trials of schizophrenia, including only those events that occurred in at least 1.0% of patients treated with ABILIFY™ (doses ≥2 mg/day). All reported events are included.
|
Table 2 Treatment-Emergent Adverse Events in Short-Term, Placebo-Controlled Trials |
||
|---|---|---|
| Percentage of Patients Reporting Eventa | ||
| System Organ Class | ABILIFY™ | Placebo |
| Primary Term | (N=1079) | (N=566) |
| Cardiac Disorders | ||
| Tachycardia | 1.0 | 0.9 |
| Ear and Labyrinth Disorders | ||
| Ear pain | 1.3 | 1.2 |
| Eye Disorders | ||
| Vision Blurred | 2.4 | 1.2 |
| Gastrointestinal Disorders | ||
| Nausea | 12.5 | 7.6 |
| Vomiting | 12.0 | 6.0 |
| Constipation | 9.0 | 6.5 |
| Dyspesia | 8.6 | 8.7 |
| Diarrhoea | 4.6 | 4.8 |
| Toothache | 4.3 | 3.9 |
| Dry Mouth | 3.3 | 2.8 |
| Abdominal Pain Upper | 2.9 | 1.9 |
| Abdominal Discomfort | 2.5 | 1.9 |
| Stomach Discomfort | 1.9 | 1.4 |
| Abdominal Pain | 1.7 | 1.6 |
| Salivary Hypersecretion | 1.3 | 0.5 |
| General Disorders and Administrative Site Conditions | ||
| Fatigue | 4.8 | 3.0 |
| Pain | 2.9 | 2.3 |
| Pyrexia | 1.6 | 0.5 |
| Peripheral Oedema | 1.5 | 0.4 |
| Chest Pain | 1.3 | 1.9 |
| Asthenia | 1.2 | 1.1 |
| Infections and Infestations | ||
| Upper respiratory Tract Infections | 1.9 | 0.9 |
| Nasopharyngitis | 1.8 | 1.6 |
| Tinea Pedis | 1.5 | 0.7 |
| Vaginal Mycosisa | 1.0 | 0.6 |
| Metabolism and Nutrition Disorders | ||
| Decreased Appetite | 1.3 | 1.8 |
| Musculoskeletal and Connective Tissue Disorders | ||
| Arthralgia | 4.4 | 2.7 |
| Back Pain | 3.2 | 4.2 |
| Musculoskeletal Stiffness | 3.2 | 2.8 |
| Pain in Extremity | 3.1 | 1.2 |
| Myalgia | 1.7 | 1.4 |
| Muscle Cramp | 1.3 | 1.1 |
| Neck Pain | 1.3 | 0.7 |
| Nervous System Disorders | ||
| Headache | 28.1 | 20.5 |
| Dizziness | 10.4 | 5.7 |
| Akathisia | 7.4 | 4.4 |
| Extrapyramidal Disorder | 5.4 | 5.1 |
| Sedation | 4.6 | 3.7 |
| Tremor | 4.4 | 2.3 |
| Somnolence | 4.1 | 3.4 |
| Lethargy | 1.9 | 0.7 |
| Psychiatric Disorders | ||
| Insomnia | 26.0 | 22.6 |
| Agitation | 25.9 | 26.1 |
| Anxiety | 23.4 | 22.8 |
| Psychotic disorder | 5.1 | 5.8 |
| Restlessness | 3.6 | 2.8 |
| Depression | 1.2 | 1.8 |
| Schizophrenia | 1.1 | 2.8 |
| Reproductive System and Breast Disorders | ||
| Dysmenorrhoeaa | 4.7 | 3.6 |
| Respiratory, Thoracic and Mediastinal Disorders | ||
| Pharyngolaryngeal Pain | 3.5 | 2.5 |
| Cough | 2.6 | 1.9 |
| Nasal Congestion | 2.6 | 1.9 |
| Skin and Subcutaneous Tissue Disorders | ||
| Rash | 3.0 | 2.5 |
| Pruritus | 1.1 | 1.9 |
| Hyperhydrosis | 1.0 | 0.9 |
| Vascular Disorders | ||
| Orthostatic Hypotension | 1.8 | 0.7 |
| Hypertension | 1.3 | 0.7 |
| Hypotension | 1.0 | 0.9 |
| a Denominator was used for females only (ABILIFY™, N=298; placebo, N=169). | ||
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%; 10mg, 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 vs. 2% (3/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity (8/12 mild and 4/12 moderate), occurred early in therapy (9/12 ≤49 days), and were of limited duration (7/12 ≤10 days). Tremor infrequently led to discontinuation (<1%) of ABILIFY. In addition, in a long-term (52-week), active-controlled study, the incidence of tremor for ABILIFY was 5% (40/859).
Weight Gain
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™ 6% compared to placebo 4% in long-term studies; p = n.s.).
In long-term, double-blind, active-comparator trials in schizophrenia, ABILIFY™ was associated with a higher incidence of significant weight gain (≥7% above baseline) compared with haloperidol (20% vs 13%,, respectively; p≤0.01; 1.1 kg vs 0.4 kg , respectively; p=n.s.) but a lower incidence of significant weight gain compared to olanzapine (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 3) from long-term, double-blind, controlled trials in schizophrenia showed that patients with high body mass index (BMI) (>27) were less likely to have significant weight gain on ABILIFY™ than those with low BMI (<23).
|
Table 3 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) | 2.6 | 1.4 | -1.2 |
| % Patients with ≥7% increase of body weight relative to baseline | 30% | 19% | 8% | |
| 26-week Olanzapine Controlled | Mean Change from Baseline (kg) | 1.2 | -0.4 | -1.4 |
| % Patients with ≥7% increase of body weight relative to baseline | 21% | 7% | 11% | |
| 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 | 7% | 5% | 6% | |
Extrapyramidal Symptoms
In the short-term, placebo-controlled trials of schizophrenia, 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. 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 a long-term, double-blind, haloperidol-controlled study in schizophrenia, the incidence of haloperidol-treated patients showing at least one EPS-related adverse event 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.).
ECG Changes
Between group comparisons for pooled, acute, placebo-controlled trials in patients with schizophrenia, revealed no significant differences between ABILIFY™ and placebo in the proportion of patients experiencing potentially important changes in ECG parameters. In fact, within the dose range of 10 to 30 mg/day, aripiprazole tended to slightly shorten the QTc interval. ABILIFY™ was associated with a median increase in heart rate of 4 beats per minute compared to a 1 beat per minute 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 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 a long-term (26-week), placebo-controlled trial, there were no statistically significant differences between the aripiprazole and placebo patients in the mean change from baseline in fasting glucose, triglyceride, LDL, and total cholesterol measurements.
Adverse Reactions Observed During the Premarketing Evaluation of ABILIFY™
The following is a list of modified terms that reflect adverse reactions (treatment-emergent, adverse events for which the causal relationship to ABILIFY™ was categorized by the investigator as certain/definite, probable, or possible). Only adverse reactions that occurred in short-term (3- to 10-week) placebo-controlled clinical trials in 2549 aripiprazole-treated patients with schizophrenia (including schizo-affective disorder), bipolar mania, and dementia of the Alzheimer's type, at an incidence greater than placebo have been included. The listing does not show adverse events mentioned in Table 2 or in other sections of this prescribing information. It is important to emphasise that although the events reported occurred with treatment they are not necessarily caused by it. The adverse reactions are classified by system organ class and are according to the following definitions: common adverse reactions are those occurring in at least 1/100 patients; uncommon adverse reactions are those occurring in at least 1/1000, but less than 1/100 patients; rare adverse reactions are those occurring in less than 1/1000 patients.
Blood and Lymphatic System Disorders: rare - eosinophilia, leukopenia, lymphadenopathy.
Cardiac Disorders: uncommon -bradycardia, sinus bradycardia, palpitation; rare - angina pectoris, atrioventricular block first degree, bundle branch block left, supraventricular extrasystoles.
Ear and Labyrinth Disorders: rare - ear canal erythema, hypoacusis, vertigo positional, tinnitus.
Endocrine Disorders: rare - early menarche.
Eye Disorders: uncommon - dry eye; rare - eye redness, photopsia, chromotopsia, conjunctivitis, eye disorder, eye movement disorder, gaze palsy, lacrimation increased, photophobia.
Gastrointestinal Disorders: uncommon - loose stools, gastritis, dysphagia, gastroesophageal reflux disease, hypoaesthesia oral; rare - abdominal distension, abnormal faeces, eructation, faeces discoloured, faeces hard, gastrointestinal disorder, gastrointestinal pain, glossitis, lip dry, oesophagitis, parotid gland enlargement, pruritus ani, reflux oesophagitis, retching, tongue discolouration.
General Disorders and Administration Site Conditions: uncommon - gait disturbance, adverse event, chills, discomfort, feeling abnormal, mobility decreased; rare - difficulty in walking, facial pain, sluggishness, swelling, malaise, thirst, chest discomfort, cyst, energy increased, feeling cold, generalised oedema, local swelling, oedema, tenderness, xerosis.
Hepatobiliary Disorders: rare - hepatitis.
Immune System Disorders: rare - decreased immune responsiveness.
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; rare - injury, muscle strain, clavicle fracture, femoral neck fracture, hip fracture, humerus fracture, mouth injury, open wound.
Investigations: uncommon - weight increased, blood creatine phosphokinase increased, heart rate increased, blood glucose increased, alanine aminotransferase increased, body temperature increased; rare - blood cholesterol increased, electrocardiogram abnormal, electrocardiogram QT corrected interval prolonged, hepatic enzyme increased, urine output increased, blood creatine phosphokinase abnormal, blood pressure orthostatic decreased, blood urine present, electrocardiogram PR prolongation, electrocardiogram T wave inversion, eosinophil count increased, head lag abnormal, heart rate irregular, physical examination, urine ketone body present, white blood cell count increased.
Metabolism and Nutrition Disorders: uncommon - increased appetite, dehydration, hyponatraemia; rare - diabetes mellitus, hyperglycaemia, hyperuricaemia.
Musculoskeletal and Connective Tissue Disorders: uncommon - muscle rigidity, joint stiffness, muscle twitching, muscle tightness, muscle spasms, muscular weakness; rare - bone pain, nuchal rigidity, sensation of heaviness, flank pain, jaw disorder, kyphosis, osteoarthritis.
Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps): rare - oral neoplasm, skin papilloma.
Nervous System Disorders: uncommon - drooling, cogwheel rigidity, dystonia, disturbance in attention, dizziness postural, dysarthria, paraesthesia, balance disorder, parkinsonism, psychomotor hyperactivity, hypoaesthesia, speech disorder, tardive dyskinesia; rare - akinesia, burning sensation, convulsion, depressed level of consciousness, dysgeusia, akinaesthesia, ataxia, bradykinesia, cerebrovascular accident, coma, dysphasia, facial palsy, judgement impaired, loss of consciousness, migraine, neuroleptic malignant syndrome, paraesthesia circumoral, paraesthesia oral. Parkinson's disease, sleep phase rhythm disturbance, unresponsive to verbal stimuli, memory impairment.
Psychiatric Disorders: uncommon - depression, confusional state, nightmare, mania, abnormal dreams, hallucination auditory, nervousness, anger, hallucination, hostility, apathy, thinking abnormal, bruxism, suicidal ideation; rare - bradyphrenia, delirium, depressed mood, disorientation, euphoric mood, libido increased, logorrhea, mental status changes, mood altered, panic attack, sleep disorder, blunted affect, cognitive deterioration, delusional perception, depression suicidal, early morning awakening, eating disorder, emotional distress, impulsive behaviour, libido decreased, listless, mood swings, psychomotor retardation, self injurious behaviour, somatoform disorder.
Renal and Urinary Disorders: uncommon - pollakiuria, incontinence, urinary retention; rare - proteinuria, bladder discomfort, chromaturia, enuresis, micturition urgency, oliguria, urethral discharge, urinary hesitation.
Reproductive System and Breast Disorders: uncommon - menorrhagiaf; rare - amenorrhoeaf, genital pruritus femalef, menstruation irregularf, vulvovaginal discomfortf, pelvic pain, breast discharge, breast pain, sexual dysfunction.
Respiratory, Thoracic and Mediastinal Disorders: uncommon - hiccups, dyspnoea, epistaxis; rare - dry throat, rhinorrhoea, sinus congestion, hoarseness, nasal dryness, painful respiration, paranasal sinus hypersecretion.
Skin and Subcutaneous Tissue Disorders: rare - dermatitis, night sweats, decubitus ulcer, dermatitis contact, face oedema, pemphigus, psoriasis, rash generalised, swelling face, dry skin.
Social Circumstances: rare - smoker.
Vascular Disorders: uncommon -hot flush, rare - flushing, diastolic hypertension, hyperaemia.
f (female) indicates incidence based on gender total
Post-Introduction Safety Experience
The following list of treatment-emergent adverse drug reactions was derived from review of data from post-introduction clinical trials as well as from spontaneous reports.
Blood and Lymphatic System Disorders: very rare (occurring in ≤ 1 in 10,000 patients)- leucopaenia, neutropaenia, thrombocytopaenia
Endocrine Disorder: very rare - hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma
Gastrointestinal Disorders: very rare - pancreatitis, dysphagia.
General Disorders & Administration Site Disorders: very rare - temperature regulation disorder (eg. hypothermia, pyrexia), chest pain.
Hepatobiliary Disorders: very rare - hepatitis, jaundice.
Investigations: very rare - increased creatine phosphokinase, increased ALT, increased AST, increased GGT, hyperglycaemia, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased, weight increased, weight decreased.
Metabolism and Nutrition Disorders: very rare - hyponatraemia, anorexia.
Musculoskeletal, Connective Tissue and Bone Disorders: very rare - rhabdomyolysis, myalgia, musculoskeletal stiffness.
Nervous System Disorders: very rare - neuroleptic malignant syndrome, speech disorder, grand mal convulsion.
Psychiatric Disorders: very rare - agitation.
Reproductive System and Breast Disorders: very rare - priapism.
Renal and Urinary Disorders: very rare - urinary retention, urinary incontinence.
Respiratory, Thoracic and Mediastinal Disorders: very rare - aspiration pneumonia.
Skin and Subcutaneous Tissue Disorders: very rare - allergic reaction (eg anaphylactic reaction, angioedema, pruritus, or urticaria, rash, larynospasm.), hyperhidrosis.
Vascular Disorders: very rare - syncope, hypertension.
Other Findings
Although a causal relationship has not been established, cases of suicide attempt, suicidal ideation and completed suicide, have been reported post marketing.
Drug Abuse And Dependence
ABILIFY™ has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. In self-administration studies in rats and 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
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 10-15mg .
The maintenance dose for ABILIFY™ is 15 mg/day.
Renal Impairment
No dosage adjustment is required in adult patients with renal impairment. (See also DOSAGE & ADMINISTRATION Paediatric).
Hepatic Impairment
No dosage adjustment is required for adult patients with hepatic impairment (Child-Pugh Class A, B or C). (See also DOSAGE & ADMINISTRATION Paediatric).
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. (See also DOSAGE & ADMINISTRATION Paediatric).
Concomitant Medications
Dosage adjustment for patients taking ABILIFY™ 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™ concomitantly with potential CYP2D6 inhibitors: When concomitant administration of potential CYP2D6 inhibitors such as quinidine, 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™ concomitantly with multiple medications that inhibit CYP3A4 and CYP2D6: Although no clinical studies have been conducted in which ABILIFY™ was taken together with multiple drugs that inhibit CYP3A4 and CYP2D6, consideration should be given to reducing the daily dose of ABILIFY™ in individual circumstances.
Dosage adjustment for patients taking ABILIFY™ 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.
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
Tablets
Store below 30°C.
Medicine Classification
Prescription Medicine
NAME AND ADDRESS OF SPONSOR
In New Zealand:
Bristol-Myers Squibb (NZ) Limited.
Simpson Grierson
88 Shortland Street
Auckland
New Zealand
Tel: Toll free 0800 80 40 80
Date of Preparation
11 May 2007
Product under license from Otsuka Pharmaceutical Co., Ltd., Tokyo 101-8535 Japan