Generic Name: ARIPIPRAZOLE
Brand Name: Aripiprazole
- Substance Name(s):
- ARIPIPRAZOLE
DRUG INTERACTIONS
7 Dosage adjustment due to drug interactions ( 7.1 ): Factors Dosage Adjustments for Aripiprazole Known CYP2D6 Poor Metabolizers Administer half of usual dose Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks 7.1 Drugs Having Clinically Important Interactions with Aripiprazole Table 25: Clinically Important Drug Interactions with Aripiprazole: Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see Clinical Pharmacology (12.3) ] .
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see Dosage and Administration (2.7) ] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see Clinical Pharmacology (12.3) ] .
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see Dosage and Administration (2.7) ] .
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [see Warnings and Precautions (5.8) ] .
Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone.
The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see Warnings and Precautions (5.8) ].
Monitor sedation and blood pressure.
Adjust dose accordingly.
7.2 Drugs Having No Clinically Important Interactions with Aripiprazole Based on pharmacokinetic studies, no dosage adjustment of aripiprazole is required when administered concomitantly with famotidine, valproate, lithium, lorazepam.
In addition, no dosage adjustment is necessary for substrates of CYP2D6 (e.g., dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e.g., warfarin), CYP2C19 (e.g., omeprazole, warfarin, escitalopram), or CYP3A4 (e.g., dextromethorphan) when co-administered with aripiprazole.
Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when co-administered with aripiprazole [see Clinical Pharmacology (12.3) ] .
OVERDOSAGE
10 MedDRA terminology has been used to classify the adverse reactions.
10.1 Human Experience In clinical trials and in post-marketing experience, adverse reactions of deliberate or accidental overdosage with oral aripiprazole have been reported worldwide.
These include overdoses with oral aripiprazole alone and in combination with other substances.
No fatality was reported with aripiprazole alone.
The largest known dose with a known outcome involved acute ingestion of 1260 mg of oral aripiprazole (42 times the maximum recommended daily dose) by a patient who fully recovered.
Deliberate or accidental overdosage was also reported in children (age 12 years and younger) involving oral aripiprazole ingestions up to 195 mg with no fatalities.
Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor.
Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.
10.2 Management of Overdosage No specific information is available on the treatment of overdose with aripiprazole.
An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted.
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 aripiprazole, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole.
Administration of 50 g of activated charcoal, one hour after a single 15 mg oral dose of aripiprazole, decreased the mean AUC and C max of aripiprazole by 50%.
Hemodialysis: Although there is no information on the effect of hemodialysis in treating an overdose with aripiprazole, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.
DESCRIPTION
11 Aripiprazole, USP is an atypical antipsychotic drug that is available as aripiprazole tablets, USP.
Aripiprazole, USP is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril.
The molecular formula is C 23 H 27 Cl 2 N 3 O 2 and its molecular weight is 448.38.
The chemical structure is: Aripiprazole tablets, USP are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg strengths.
Inactive ingredients include croscarmellose sodium, magnesium stearate, microcrystalline cellulose and tartaric acid.
The 2 mg and 5 mg tablets contain FD&C Blue No.
2 indigo carmine aluminum lake (30% to 36%).
The 2 mg and 15 mg tablets contain ferric oxide yellow.
The 10 mg and 30 mg tablets contain FD&C Red No.
40 allura red AC aluminum lake (15% to 17%).
1
CLINICAL STUDIES
14 Efficacy of the oral formulations of aripiprazole was established in the following adequate and well-controlled trials: Four short-term trials and one maintenance trial in adult patients and one short-term trial in adolescents (ages 13 to 17 years) with schizophrenia [see Clinical Studies (14.1) ] One maintenance monotherapy trial and in one maintenance adjunctive trial in adult patients with bipolar I disorder [see Clinical Studies (14.2) ] Two short-term trials in pediatric patients (ages 6 to 17 years) for the treatment of irritability associated with autistic disorder [see Clinical Studies (14.4) ] Two short-term trials in pediatric patients (ages 6 to 18 years) with Tourette’s disorder [see Clinical Studies (14.5) ] 14.1 Schizophrenia Adults The efficacy of aripiprazole in the treatment of schizophrenia was evaluated in five short-term (4-week and 6-week), placebo-controlled trials of acutely relapsed inpatients who predominantly met DSM-III/IV criteria for schizophrenia.
Four of the five trials were able to distinguish aripiprazole from placebo, but one study, the smallest, did not.
Three of these studies also included an active control group consisting of either risperidone (one trial) or haloperidol (two trials), but they were not designed to allow for a comparison of aripiprazole and the active comparators.
In the four positive trials for aripiprazole, four primary measures were used for assessing psychiatric signs and symptoms.
Efficacy was evaluated using the total score on the Positive and Negative Syndrome Scale (PANSS).
The PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210.
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.
In a 4-week trial (n=414) comparing two fixed doses of aripiprazole (15 or 30 mg/day) to placebo, both doses of aripiprazole were superior to placebo in the PANSS total score (Study 1 in Table 26), PANSS positive subscale, and CGI-severity score.
In addition, the 15 mg dose was superior to placebo in the PANSS negative subscale.
In a 4-week trial (n=404) comparing two fixed doses of aripiprazole (20 or 30 mg/day) to placebo, both doses of aripiprazole were superior to placebo in the PANSS total score (Study 2 in Table 26), PANSS positive subscale, PANSS negative subscale, and CGI-severity score.
In a 6-week trial (n=420) comparing three fixed doses of aripiprazole (10, 15, or 20 mg/day) to placebo, all three doses of aripiprazole were superior to placebo in the PANSS total score (Study 3 in Table 26), PANSS positive subscale, and the PANSS negative subscale.
In a 6-week trial (n=367) comparing three fixed doses of aripiprazole (2, 5, or 10 mg/day) to placebo, the 10 mg dose of aripiprazole was superior to placebo in the PANSS total score (Study 4 in Table 26), the primary outcome measure of the study.
The 2 and 5 mg doses did not demonstrate superiority to placebo on the primary outcome measure.
Thus, the efficacy of 10 mg, 15 mg, 20 mg, and 30 mg daily doses 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 of these studies.
An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender, or race.
A longer-term trial enrolled 310 inpatients or outpatients meeting DSM-IV criteria for schizophrenia who were, by history, symptomatically stable on other antipsychotic medications for periods of 3 months or longer.
These patients were discontinued from their antipsychotic medications and randomized to aripiprazole 15 mg/day or placebo for up to 26 weeks of observation for relapse.
Relapse during the double-blind phase was defined as CGI-Improvement score of ≥5 (minimally worse), scores ≥5 (moderately severe) on the hostility or uncooperativeness items of the PANSS, or ≥20% increase in the PANSS total score.
Patients receiving aripiprazole 15 mg/day experienced a significantly longer time to relapse over the subsequent 26 weeks compared to those receiving placebo (Study 5 in Figure 6).
Pediatric Patients The efficacy of aripiprazole in the treatment of schizophrenia in pediatric patients (13 to 17 years of age) was evaluated in one 6-week, placebo-controlled trial of outpatients who met DSM-IV criteria for schizophrenia and had a PANSS score ≥70 at baseline.
In this trial (n=302) comparing two fixed doses of aripiprazole (10 mg/day or 30 mg/day) to placebo, aripiprazole was titrated starting from 2 mg/day to the target dose in 5 days in the 10 mg/day treatment arm and in 11 days in the 30 mg/day treatment arm.
Both doses of aripiprazole were superior to placebo in the PANSS total score (Study 6 in Table 26), the primary outcome measure of the study.
The 30 mg/day dosage was not shown to be more efficacious than the 10 mg/day dose.
Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.
Table 26: Schizophrenia Studies Study Number Treatment Group Primary Efficacy Measure: PANSS Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference * (95% CI) Study 1 Aripiprazole (15 mg/day) † 98.5 (17.2) -15.5 (2.40) -12.6 (-18.9, -6.2) Aripiprazole (30 mg/day) † 99.0 (19.2) -11.4 (2.39) -8.5 (-14.8, -2.1) Placebo 100.2 (16.5) -2.9 (2.36) — Study 2 Aripiprazole (20 mg/day) † 92.6 (19.5) -14.5 (2.23) -9.6 (-15.4, -3.8) Aripiprazole (30 mg/day) † 94.2 (18.5) -13.9 (2.24) -9.0 (-14.8, -3.1) Placebo 94.3 (18.5) -5.0 (2.17) — Study 3 Aripiprazole (10 mg/day) † 92.7 (19.5) -15.0 (2.38) -12.7 (-19.00, -6.41) Aripiprazole (15 mg/day) † 93.2 (21.6) -11.7 (2.38) -9.4 (-15.71, -3.08) Aripiprazole (20 mg/day) † 92.5 (20.9) -14.4 (2.45) -12.1 (-18.53, -5.68) Placebo 92.3 (21.8) -2.3 (2.35) — Study 4 Aripiprazole (2 mg/day) 90.7 (14.5) -8.2 (1.90) -2.9 (-8.29, 2.47) Aripiprazole (5 mg/day) 92.0 (12.6) -10.6 (1.93) -5.2 (-10.7, 0.19) Aripiprazole (10 mg/day) † 90.0 (11.9) -11.3 (1.88) -5.9 (-11.3, -0.58) Placebo 90.8 (13.3) -5.3 (1.97) — Study 6 (Pediatric, 13 to 17 years) Aripiprazole (10 mg/day) † 93.6 (15.7) -26.7 (1.91) -5.5 (-10.7, -0.21) Aripiprazole (30 mg/day) † 94.0 (16.1) -28.6 (1.92) -7.4 (-12.7, -2.13) Placebo 94.6 (15.6) -21.2 (1.93) — SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.
*Difference (drug minus placebo) in least-squares mean change from baseline.
† Doses statistically significantly superior to placebo.
Figure 6: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Schizophrenia Study 5) 1 14.2 Bipolar Disorder Maintenance Treatment of Bipolar I Disorder Monotherapy Maintenance Therapy A maintenance trial was conducted in adult patients meeting DSM-IV criteria for bipolar I disorder with a recent manic or mixed episode who had been stabilized on open-label aripiprazole and who had maintained a clinical response for at least 6 weeks.
The first phase of this trial was an open-label stabilization period in which inpatients and outpatients were clinically stabilized and then maintained on open-label aripiprazole (15 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 randomized in a double-blind fashion, to either the same dose of aripiprazole they were on at the end of the stabilization and maintenance period or placebo and were then monitored for manic or depressive relapse.
During the randomization phase, aripiprazole was superior to placebo on time to the number of combined affective relapses (manic plus depressive), the primary outcome measure for this study (Study 7 in Figure 7).
A total of 55 mood events were observed during the double-blind treatment phase.
Nineteen were from the aripiprazole group and 36 were from the placebo group.
The number of observed manic episodes in the aripiprazole group (6) were fewer than that in the placebo group (19), while the number of depressive episodes in the aripiprazole group (9) was similar to that in the placebo group (11).
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.
Figure 7: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Bipolar Study 7) Adjunctive Maintenance Therapy An adjunctive maintenance trial was conducted in adult patients meeting DSM-IV criteria for bipolar I disorder with a recent manic or mixed episode.
Patients were initiated on open-label lithium (0.6 mEq/L to 1.0 mEq/L) or valproate (50 mcg/mL to 125 mcg/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 ≤35% improvement on the Y-MRS total score) to lithium or valproate received aripiprazole with a starting dose of 15 mg/day with the option to increase to 30 mg or reduce to 10 mg as early as day 4, as adjunctive therapy with open-label lithium or valproate.
Prior to randomization, patients on the combination of single-blind aripiprazole and lithium or valproate were required to maintain stability (Y-MRS and MADRS total scores ≤12) for 12 consecutive weeks.
Three hundred thirty-seven patients were then randomized in a double-blind fashion, to either the same dose of aripiprazole they were on at the end of the stabilization period or placebo plus lithium or valproate and were then monitored for manic, mixed, or depressive relapse for a maximum of 52 weeks.
Aripiprazole was superior to placebo on the primary endpoint, time from randomization to relapse to any mood event (Study 8 in Figure 8).
A mood event was defined as hospitalization for a manic, mixed, or depressive episode, study discontinuation due to lack of efficacy accompanied by Y-MRS score >16 and/or a MADRS >16, or an SAE of worsening disease accompanied by Y-MRS score >16 and/or a MADRS >16.
A total of 68 mood events were observed during the double-blind treatment phase.
Twenty-five were from the aripiprazole group and 43 were from the placebo group.
The number of observed manic episodes in the aripiprazole group (7) were fewer than that in the placebo group (19), while the number of depressive episodes in the aripiprazole group (14) was similar to that in the placebo group (18).
The Kaplan-Meier curves of the time from randomization to relapse to any mood event during the 52-week, double-blind treatment phase for aripiprazole and placebo groups are shown in Figure 8.
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.
Figure 8: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse to Any Mood Event (Bipolar Study 8) 1 1 14.4 Irritability Associated with Autistic Disorder Pediatric Patients The efficacy of aripiprazole in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in pediatric patients (6 to 17 years of age) who met the DSM-IV criteria for autistic disorder and demonstrated behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these problems.
Over 75% of these patients were under 13 years of age.
Efficacy was evaluated using two assessment scales: The Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Improvement (CGI-I) scale.
The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I).
The ABC-I subscale measured symptoms of irritability in autistic disorder.
The results of these trials are as follows: In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=98), aged 6 to 17 years, received daily doses of placebo or aripiprazole 2 mg/day to 15 mg/day.
Aripiprazole, starting at 2 mg/day with increases allowed up to 15 mg/day based on clinical response, significantly improved scores on the ABC-I subscale and on the CGI-I scale compared with placebo.
The mean daily dose of aripiprazole at the end of 8-week treatment was 8.6 mg/day (Study 1 in Table 29).
In the other 8-week, placebo-controlled trial in children and adolescents with autistic disorder (n=218), aged 6 to 17 years, three fixed doses of aripiprazole (5 mg/day, 10 mg/day, or 15 mg/day) were compared to placebo.
Aripiprazole dosing started at 2 mg/day and was increased to 5 mg/day after one week.
After a second week, it was increased to 10 mg/day for patients in the 10 and 15 mg dose arms, and after a third week, it was increased to 15 mg/day in the 15 mg/day treatment arm (Study 2 in Table 29).
All three doses of aripiprazole significantly improved scores on the ABC-I subscale compared with placebo.
Table 29: Irritability Associated with Autistic Disorder Studies (Pediatric) Study Number Treatment Group Primary Efficacy Measure: ABC-I Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference * (95% CI) Study 1 Aripiprazole (2 mg/day to 15 mg/day) † 29.6 (6.37) -12.9 (1.44) -7.9 (-11.7, -4.1) Placebo 30.2 (6.52) -5.0 (1.43) — Study 2 Aripiprazole (5 mg/day) † Aripiprazole (10 mg/day) † Aripiprazole (15 mg/day) 28.6 (7.56) 28.2 (7.36) 28.9 (6.41) -12.4 (1.36) -13.2 (1.25) -14.4 (1.31) -4.0 (-7.7, -0.4) -4.8 (-8.4, -1.3) -6.0 (-9.6, -2.3) Placebo 28.0 (6.89) -8.4 (1.39) — SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.
* Difference (drug minus placebo) in least-squares mean change from baseline.
† Doses statistically significantly superior to placebo.
14.5 Tourette’s Disorder Pediatric Patients The efficacy of aripiprazole in the treatment of Tourette’s disorder was established in one 8-week (7 to 17 years of age) and one 10-week (6 to 18 years of age), placebo-controlled trials in pediatric patients (6 to 18 years of age) who met the DSM-IV criteria for Tourette’s disorder and had a Total Tic score (TTS) ≥ 20 to 22 on the Yale Global Tic Severity Scale (YGTSS).
The YGTSS is a fully validated scale designed to measure current tic severity.
Efficacy was evaluated using two assessment scales: 1) the Total Tic score (TTS) of the YGTSS and 2) the Clinical Global Impressions Scale for Tourette’s Syndrome (CGI-TS), a clinician-determined summary measure that takes into account all available patient information.
Over 65% of these patients were under 13 years of age.
The primary outcome measure in both trials was the change from baseline to endpoint in the TTS of the YGTSS.
Ratings for the TTS are made along 5 different dimensions on a scale of 0 to 5 for motor and vocal tics each.
Summation of these 10 scores provides a TTS (i.e., 0 to 50).
The results of these trials are as follows: In the 8-week, placebo-controlled, fixed-dose trial, children and adolescents with Tourette’s disorder (n=133), aged 7 to 17 years, were randomized 1:1:1 to low dose aripiprazole, high dose aripiprazole, or placebo.
The target doses for the low and high dose aripiprazole groups were based on weight.
Patients <50 kg in the low dose aripiprazole group started at 2 mg per day with a target dose of 5 mg per day after 2 days.
Patients ≥50 kg in the low dose aripiprazole group, started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a target dose of 10 mg per day at day 7.
Patients < 50 kg in the high dose aripiprazole group started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a target dose of 10 mg per day at day 7.
Patients ≥ 50 kg in the high dose aripiprazole group, started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a dose of 10 mg per day at day 7 and were allowed weekly increases of 5 mg per day up to a target dose 20 mg per day at Day 21.
Aripiprazole (both high and low dose groups) demonstrated statistically significantly improved scores on the YGTSS TTS (Study 1 in Table 30) and on the CGI-TS scale compared with placebo.
The estimated improvements on the YGTSS TTS over the course of the study are displayed in Figure 9.
Figure 9: Least Square Means of Change from Baseline in YGTSS TTS by Week (Tourette’s Disorder Study 1) In the 10-week, placebo-controlled, flexible-dose trial in children and adolescents with Tourette’s disorder (n=61), aged 6 to 18 years, patients received daily doses of placebo or aripiprazole, starting at 2 mg/day with increases allowed up to 20 mg/day based on clinical response.
Aripiprazole demonstrated statistically significantly improved scores on the YGTSS TTS scale compared with placebo (Study 2 in Table 30).
The mean daily dose of aripiprazole at the end of 10-week treatment was 6.54 mg/day.
Table 30: Tourette’s Disorder Studies (Pediatric) Study Number Treatment Group Primary Efficacy Measure: YGTSS TTS Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference * (95% CI) Study 1 Aripiprazole (low dose) † 29.2 (5.63) -13.4 (1.59) -6.3 (-10.2, -2.3) Aripiprazole (high dose) † 31.2 (6.40) -16.9 (1.61) -9.9 (-13.8, -5.9) Placebo 30.7 (5.95) -7.1 (1.55) — Study 2 Aripiprazole (2 to 20 mg/day) † 28.3 (5.51) -15.0 (1.51) -5.3 (-9.8, -0.9) Placebo 29.5 (5.60) -9.6 (1.64) — SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.
*Difference (drug minus placebo) in least-squares mean change from baseline.
† Doses statistically significantly superior to placebo.
1
HOW SUPPLIED
16 /STORAGE AND HANDLING 16.1 How Supplied Aripiprazole tablets USP, 2 mg, are supplied as green to light green colored, mosaic appearance, modified rectangle shaped, uncoated tablet with debossing “AN896” and “2” on one side and plain on the other side.
They are available as follows: Bottles of 30: NDC 65162-896-03 Bottles of 90: NDC 65162-896-09 Bottles of 500: NDC 65162-896-50 Bottles of 1000: NDC 65162-896-11 Aripiprazole tablets USP, 5 mg, are supplied as blue to light blue colored, mosaic appearance, modified rectangle shaped, uncoated tablet with debossing “AN897” and “5” on one side and plain on the other side.
They are available as follows: Bottles of 30: NDC 65162-897-03 Bottles of 90: NDC 65162-897-09 Bottles of 500: NDC 65162-897-50 Bottles of 1000: NDC 65162-897-11 Aripiprazole tablets USP, 10 mg, are supplied as pink to light pink colored, mosaic appearance, modified rectangle shaped, uncoated tablet with debossing “AN898” and “10” on one side and plain on the other side.
They are available as follows: Bottles of 30: NDC 65162-898-03 Bottles of 90: NDC 65162-898-09 Bottles of 500: NDC 65162-898-50 Bottles of 1000: NDC 65162-898-11 Aripiprazole tablets USP, 15 mg, are supplied as yellow to light yellow colored, mosaic appearance, round shaped, uncoated tablet with debossing “AN899” and “15” on one side and plain on the other side.
They are available as follows: Bottles of 30: NDC 65162-899-03 Bottles of 90: NDC 65162-899-09 Bottles of 500: NDC 65162-899-50 Bottles of 1000: NDC 65162-899-11 Aripiprazole tablets USP, 20 mg, are supplied as white to off-white, round shaped, uncoated tablet with debossing “AN901” and “20” on one side and plain on the other side.
They are available as follows: Bottles of 30: NDC 65162-901-03 Bottles of 90: NDC 65162-901-09 Bottles of 500: NDC 65162-901-50 Bottles of 1000: NDC 65162-901-11 Aripiprazole tablets USP, 30 mg, are supplied as pink to light pink colored, mosaic appearance, round shaped, uncoated tablet with debossing “AN902” and “30” on one side and plain on the other side.
They are available as follows: Bottles of 30: NDC 65162-902-03 Bottles of 90: NDC 65162-902-09 Bottles of 500: NDC 65162-902-50 Bottles of 1000: NDC 65162-902-11 16.2 Storage Tablets Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] in tightly closed containers.
GERIATRIC USE
8.5 Geriatric Use No dosage adjustment is recommended for elderly patients [see Boxed Warning , Warnings and Precautions (5.1) , and Clinical Pharmacology (12.3) ] .
Of the 13,543 patients treated with oral aripiprazole in clinical trials, 1,073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old.
Placebo-controlled studies of oral aripiprazole in schizophrenia, or other indications did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
Aripiprazole is not approved for the treatment of patients with psychosis associated with Alzheimer’s disease [see Boxed Warning and Warnings and Precautions (5.1) ] .
MECHANISM OF ACTION
12.1 Mechanism of Action The mechanism of action of aripiprazole in schizophrenia, is unclear.
However, the efficacy of aripiprazole in the listed indications could be mediated through a combination of partial agonist activity at D 2 and 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors.
INDICATIONS AND USAGE
1 Aripiprazole Oral Tablets are indicated for the treatment of: Schizophrenia Irritability Associated with Autistic Disorder Treatment of Tourette’s Disorder Aripiprazole tablets are an atypical antipsychotic.
The oral formulations are indicated for: Schizophrenia.
( 14.1 ) Irritability Associated with Autistic Disorder.
( 14.4 ) Treatment of Tourette’s disorder.
( 14.5 )
PEDIATRIC USE
8.4 Pediatric Use The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight [see Clinical Pharmacology (12.3) ] .
Schizophrenia Safety and effectiveness in pediatric patients with schizophrenia were established in a 6-week, placebo-controlled clinical trial in 202 pediatric patients aged 13 to 17 years [see Dosage and Administration (2.1) , Adverse Reactions (6.1) , and Clinical Studies (14.1) ] .
Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.
Irritability Associated with Autistic Disorder Safety and effectiveness in pediatric patients demonstrating irritability associated with autistic disorder were established in two 8-week, placebo-controlled clinical trials in 212 pediatric patients aged 6 to 17 years [see Indications and Usage (1) , Dosage and Administration (2.4) , Adverse Reactions (6.1) , and Clinical Studies (14.4) ] .
A maintenance trial was conducted in pediatric patients (6 to 17 years of age) with irritability associated with autistic disorder.
The first phase of this trial was an open-label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were stabilized (defined as > 25% improvement on the ABC-I subscale, and a CGI-I rating of “much improved” or “very much improved”) on aripiprazole for 12 consecutive weeks.
Overall, 85 patients were stabilized and entered the second, 16-week, double-blind phase where they were randomized to either continue aripiprazole treatment or switch to placebo.
In this trial, the efficacy of aripiprazole for the maintenance treatment of irritability associated with autistic disorder was not established.
Tourette’s Disorder Safety and effectiveness of aripiprazole in pediatric patients with Tourette’s Disorder were established in one 8-week (aged 7 to 17 years) and one 10-week trial (aged 6 to 18 years) in 194 pediatric patients [see Dosage and Administration (2.5) , Adverse Reactions (6.1) , and Clinical Studies (14.5) ] .
Maintenance efficacy in pediatric patients has not been systematically evaluated.
Juvenile Animal Studies Aripiprazole in juvenile rats caused mortality, CNS clinical signs, impaired memory and learning, and delayed sexual maturation when administered at oral doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old).
At 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other CNS signs were observed in both genders.
In addition, delayed sexual maturation was observed in males.
At all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed.
The changes in female reproductive organs were considered secondary to the increase in prolactin serum levels.
A No Observed Adverse Effect Level (NOAEL) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC 0-24 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day.
All drug-related effects were reversible after a 2-month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies.
Aripiprazole in juvenile dogs (2 months old) caused CNS clinical signs of tremors, hypoactivity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day.
Mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values.
A NOAEL could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC 0-24 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day.
All drug-related effects were reversible after a 2-month recovery period.
BOXED WARNING
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS WITH ANTIDEPRESSANT DRUGS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
Aripiprazole is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1) ] .
Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies.
These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24 years; there was a reduction in risk with antidepressant use in patients aged 65 years and older [see Warnings and Precautions (5.3) ] .
In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors.
Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.3) ] .
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS WITH ANTIDEPRESSANT DRUGS See full prescribing information for complete boxed warning.
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
Aripiprazole is not approved for the treatment of patients with dementia-related psychosis.
( 5.1 ) Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants.
Monitor for worsening and emergence of suicidal thoughts and behaviors.
( 5.3 )
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities).
( 5.2 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring.
( 5.4 ) Tardive Dyskinesia: Discontinue if clinically appropriate.
( 5.5 ) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain.
( 5.6 ) Hyperglycemia/Diabetes Mellitus: Monitor glucose regularly in patients with and at risk for diabetes.
( 5.6 ) Dyslipidemia: Undesirable alterations in lipid levels have been observed in patients treated with atypical antipsychotics.
( 5.6 ) Weight Gain: Weight gain has been observed with atypical antipsychotic use.
Monitor weight.
( 5.6 ) Pathological Gambling and Other Compulsive Behaviors: Consider dose reduction or discontinuation.
( 5.7 ) Orthostatic Hypotension: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope.
( 5.8 ) Leukopenia, Neutropenia, and Agranulocytosis: have been reported with antipsychotics including aripiprazole.
Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of aripiprazole should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
( 5.10 ) Seizures/Convulsions: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold.
( 5.11 ) Potential for Cognitive and Motor Impairment: Use caution when operating machinery.
( 5.12 ) Suicide: The possibility of a suicide attempt is inherent in schizophrenia.
Closely supervise high-risk patients.
( 5.14 ) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Increased Mortality Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
Aripiprazole is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning ] .
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 to 99 years), the adverse reactions that were reported at an incidence of ≥3% 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%], excessive salivation [placebo 0%, aripiprazole 4%], and lightheadedness [placebo 1%, aripiprazole 4%].
The safety and efficacy of aripiprazole in the treatment of patients with psychosis associated with dementia have not been established.
If the prescriber elects to treat such patients with aripiprazole, assess for the emergence of difficulty swallowing or excessive somnolence, which could predispose to accidental injury or aspiration [see Boxed Warning ] .
5.2 Cerebrovascular Adverse Events, Including Stroke In placebo-controlled clinical studies (two flexible dose and one 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 to 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 Boxed Warning ] .
5.3 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
Pooled analyses of short-term, placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24 years) with MDD and other psychiatric disorders.
Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24 years; there was a reduction with antidepressants compared to placebo in adults aged 65 years and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.
The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.
There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.
The risk differences (drug vs.
placebo), however, were relatively stable within age strata and across indications.
These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 5.
Table 5: Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials.
There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e.
beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers.
Such monitoring should include daily observation by families and caregivers.
Prescriptions for aripiprazole should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder.
It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.
Whether any of the symptoms described above represent such a conversion is unknown.
However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
It should be noted that aripiprazole is not approved for use in treating depression in the pediatric population.
5.4 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including aripiprazole.
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 phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated.
In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).
Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available.
There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.
The patient should be carefully monitored, since recurrences of NMS have been reported.
5.5 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs.
Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.
Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase.
However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn.
Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, thereby, may possibly mask the underlying process.
The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, aripiprazole should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.
Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.
In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.
The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, drug discontinuation should be considered.
However, some patients may require treatment with aripiprazole despite the presence of the syndrome.
5.6 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain.
While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
Hyperglycemia/Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics.
There have been reports of hyperglycemia in patients treated with aripiprazole [see Adverse Reactions (6.1 , 6.2 )] .
Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population.
Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood.
However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.
Because aripiprazole was not marketed at the time these studies were performed, it is not known if aripiprazole is associated with this increased risk.
Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.
Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment.
Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.
Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing.
In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Adults In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with schizophrenia or another disorder, the mean change in fasting glucose in aripiprazole-treated patients (+4.4 mg/dL; median exposure 25 days; N=1057) was not significantly different than in placebo-treated patients (+2.5 mg/dL; median exposure 22 days; N=799).
Table 6 shows the proportion of aripiprazole-treated patients with normal and borderline fasting glucose at baseline (median exposure 25 days) that had treatment-emergent high fasting glucose measurements compared to placebo-treated patients (median exposure 22 days).
Table 6: Changes in Fasting Glucose from Placebo-Controlled Monotherapy Trials in Adult Patients Category Change (at least once) from Baseline Treatment Arm n/N % Fasting Glucose Normal to High (< 100 mg/dL to ≥ 126 mg/dL) Aripiprazole 31/822 3.8 Placebo 22/605 3.6 Borderline to High (≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL) Aripiprazole 31/176 17.6 Placebo 13/142 9.2 At 24 weeks, the mean change in fasting glucose in aripiprazole-treated patients was not significantly different than in placebo-treated patients [+2.2 mg/dL (n=42) and +9.6 mg/dL (n=28), respectively].
Pediatric Patients and Adolescents In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with another disorder (10 to 17 years), the mean change in fasting glucose in aripiprazole-treated patients (+4.8 mg/dL; with a median exposure of 43 days; N=259) was not significantly different than in placebo-treated patients (+1.7 mg/dL; with a median exposure of 42 days; N=123).
In an analysis of two placebo-controlled trials in pediatric and adolescent patients with irritability associated with autistic disorder (6 to 17 years) with median exposure of 56 days, the mean change in fasting glucose in aripiprazole-treated patients (–0.2 mg/dL; N=83) was not significantly different than in placebo-treated patients (–0.6 mg/dL; N=33).
In an analysis of two placebo-controlled trials in pediatric and adolescent patients with Tourette’s disorder (6 to 18 years) with median exposure of 57 days, the mean change in fasting glucose in aripiprazole-treated patients (0.79 mg/dL; N=90) was not significantly different than in placebo-treated patients (–1.66 mg/dL; N=58).
Table 8 shows the proportion of patients with changes in fasting glucose levels from the pooled adolescent schizophrenia and other pediatric patients (median exposure of 42 to 43 days), from two placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder (median exposure of 56 days), and from the two placebo-controlled trials in pediatric patients (6 to 18 year) with Tourette’s Disorder (median exposure 57 days).
Table 8: Changes in Fasting Glucose from Placebo-Controlled Trials in Pediatric and Adolescent Patients Category Change (at least once) from Baseline Indication Treatment Arm n/N % Fasting Glucose Normal to High (< 100 mg/dL to ≥ 126 mg/dL) Pooled Schizophrenia and Another Disorder Aripiprazole 2/236 0.8 Placebo 2/110 1.8 Irritability Associated with Autistic Disorder Aripiprazole 0/73 0 Placebo 0/32 0 Tourette’s Disorder Aripiprazole 3/88 3.4 Placebo 1/58 1.7 Fasting Glucose Borderline to High (≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL) Pooled Schizophrenia and Another Disorder Aripiprazole 1/22 4.5 Placebo 0/12 0 Irritability Associated with Autistic Disorder Aripiprazole 0/9 0 Placebo 0/1 0 Tourette’s Disorder Aripiprazole 0/11 0 Placebo 0/4 0 At 12 weeks in the pooled adolescent schizophrenia and other pediatric disorder trials, the mean change in fasting glucose in aripiprazole-treated patients was not significantly different than in placebo-treated patients [+2.4 mg/dL (n=81) and +0.1 mg/dL (n=15), respectively].
Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
There were no significant differences between aripiprazole- and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting LDLs, and fasting/nonfasting HDLs.
Analyses of patients with at least 12 or 24 weeks of exposure were limited by small numbers of patients.
Adults Table 9 shows the proportion of adult patients, primarily from pooled schizophrenia and other monotherapy placebo-controlled trials, with changes in total cholesterol (pooled from 17 trials; median exposure 21 to 25 days), fasting triglycerides (pooled from eight trials; median exposure 42 days), fasting LDL cholesterol (pooled from eight trials; median exposure 39 to 45 days, except for placebo-treated patients with baseline normal fasting LDL measurements, who had median treatment exposure of 24 days) and HDL cholesterol (pooled from nine trials; median exposure 40 to 42 days).
Table 9: Changes in Blood Lipid Parameters from Placebo-Controlled Monotherapy Trials in Adults Treatment Arm n/N % Total Cholesterol Normal to High (< 200 mg/dL to ≥ 240 mg/dL) Aripiprazole 34/1357 2.5 Placebo 27/973 2.8 Fasting Triglycerides Normal to High (< 150 mg/dL to ≥ 200 mg/dL) Aripiprazole 40/539 7.4 Placebo 30/431 7.0 Fasting LDL Cholesterol Normal to High (< 100 mg/dL to ≥ 160 mg/dL) Aripiprazole 2/332 0.6 Placebo 2/268 0.7 HDL Cholesterol Normal to Low (≥ 40 mg/dL to < 40 mg/dL) Aripiprazole 121/1066 11.4 Placebo 99/794 12.5 In monotherapy trials in adults, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 1/71 (1.4%) vs.
3/74 (4.1%); Fasting Triglycerides, 8/62 (12.9%) vs.
5/37 (13.5%); Fasting LDL Cholesterol, 0/34 (0%) vs.
1/25 (4.0%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 1/42 (2.4%) vs.
3/37 (8.1%); Fasting Triglycerides, 5/34 (14.7%) vs.
5/20 (25%); Fasting LDL Cholesterol, 0/22 (0%) vs.
1/18 (5.6%), respectively.
Pediatric Patients and Adolescents Table 11 shows the proportion of adolescents with schizophrenia (13 to 17 years) and pediatric patients with another disorder (10 to 17 years) with changes in total cholesterol and HDL cholesterol (pooled from two placebo-controlled trials; median exposure 42 to 43 days) and fasting triglycerides (pooled from two placebo-controlled trials; median exposure 42 to 44 days).
Table 11: Changes in Blood Lipid Parameters from Placebo-Controlled Monotherapy Trials in Pediatric and Adolescent Patients in Schizophrenia and Another Disorder Treatment Arm n/N % Total Cholesterol Normal to High (< 170 mg/dL to ≥ 200 mg/dL) Aripiprazole 3/220 1.4 Placebo 0/116 0 Fasting Triglycerides Normal to High (< 150 mg/dL to ≥ 200 mg/dL) Aripiprazole 7/187 3.7 Placebo 4/85 4.7 HDL Cholesterol Normal to Low (≥ 40 mg/dL to < 40 mg/dL) Aripiprazole 27/236 11.4 Placebo 22/109 20.2 In monotherapy trials of adolescents with schizophrenia and pediatric patients with another disorder, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 0/57 (0%) vs.
0/15 (0%); Fasting Triglycerides, 2/72 (2.8%) vs.
1/14 (7.1%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 0/36 (0%) vs.
0/12 (0%); Fasting Triglycerides, 1/47 (2.1%) vs.
1/10 (10.0%), respectively.
Table 12 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting) and fasting triglycerides (median exposure 56 days) and HDL cholesterol (median exposure 55 to 56 days) from two placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder.
Table 12: Changes in Blood Lipid Parameters from Placebo-Controlled Trials in Pediatric Patients with Autistic Disorder Treatment Arm n/N % Total Cholesterol Normal to High (< 170 mg/dL to ≥ 200 mg/dL) Aripiprazole 1/95 1.1 Placebo 0/34 0 Fasting Triglycerides Normal to High (< 150 mg/dL to ≥ 200 mg/dL) Aripiprazole 0/75 0 Placebo 0/30 0 HDL Cholesterol Normal to Low (≥ 40 mg/dL to < 40 mg/dL) Aripiprazole 9/107 8.4 Placebo 5/49 10.2 Table 13 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting) and fasting triglycerides (median exposure 57 days) and HDL cholesterol (median exposure 57 days) from two placebo-controlled trials in pediatric patients (6 to 18 years) with Tourette’s Disorder.
Table 13: Changes in Blood Lipid Parameters from Placebo-Controlled Trials in Pediatric Patients with Tourette’s Disorder Treatment Arm n/N % Total Cholesterol Normal to High (<170 mg/dL to ≥200 mg/dL) Aripiprazole 1/85 1.2 Placebo 0/46 0 Fasting Triglycerides Normal to High (<150 mg/dL to ≥200 mg/dL) Aripiprazole 5/94 5.3 Placebo 2/55 3.6 HDL Cholesterol Normal to Low (≥40 mg/dL to <40 mg/dL) Aripiprazole 4/108 3.7 Placebo 2/67 3.0 Weight Gain Weight gain has been observed with atypical antipsychotic use.
Clinical monitoring of weight is recommended.
Adults In an analysis of 13 placebo-controlled monotherapy trials, primarily from pooled schizophrenia and patients with another disorder, with a median exposure of 21 to 25 days, the mean change in body weight in aripiprazole-treated patients was +0.3 kg (N=1673) compared to –0.1 kg (N=1100) in placebo-controlled patients.
At 24 weeks, the mean change from baseline in body weight in aripiprazole-treated patients was –1.5 kg (n=73) compared to –0.2 kg (n=46) in placebo-treated patients.
In the trials adding aripiprazole to antidepressants, patients first received 8 weeks of antidepressant treatment followed by 6 weeks of adjunctive aripiprazole or placebo in addition to their ongoing antidepressant treatment.
The mean change in body weight in patients receiving adjunctive aripiprazole was +1.7 kg (N=347) compared to +0.4 kg (N=330) in patients receiving adjunctive placebo.
Table 14 shows the percentage of adult patients with weight gain ≥7% of body weight by indication.
Table 14: Percentage of Patients from Placebo-Controlled Trials in Adult Patients with Weight Gain ≥ 7% of Body Weight Indication Treatment Arm N Patients n (%) Weight gain ≥ 7% of body weight Schizophrenia * Aripiprazole 852 69 (8.1) Placebo 379 12 (3.2) Another Disorder † Aripiprazole 719 16 (2.2) Placebo 598 16 (2.7) Another Disorder ‡ Aripiprazole 347 18 (5.2) Placebo 330 2 (0.6) * 4 to 6 weeks duration.
† 3 weeks duration.
‡ 6 weeks duration.
Pediatric Patients and Adolescents In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with another disorder (10 to 17 years) with median exposure of 42 to 43 days, the mean change in body weight in aripiprazole-treated patients was +1.6 kg (N=381) compared to +0.3 kg (N=187) in placebo-treated patients.
At 24 weeks, the mean change from baseline in body weight in aripiprazole-treated patients was +5.8 kg (n=62) compared to +1.4 kg (n=13) in placebo-treated patients.
In two short-term, placebo-controlled trials in patients (6 to 17 years) with irritability associated with autistic disorder with median exposure of 56 days, the mean change in body weight in aripiprazole-treated patients was +1.6 kg (n=209) compared to +0.4 kg (n=98) in placebo-treated patients.
In two short-term, placebo-controlled trials in patients (6 to 18 years) with Tourette’s Disorder with median exposure of 57 days, the mean change in body weight in aripiprazole-treated patients was +1.5 kg (n=105) compared to +0.4 kg (n=66) in placebo-treated patients.
Table 15 shows the percentage of pediatric and adolescent patients with weight gain ≥ 7% of body weight by indication.
Table 15: Percentage of Patients from Placebo-Controlled Monotherapy Trials in Pediatric and Adolescent Patients with Weight Gain ≥ 7% of Body Weight Indication Treatment Arm N Patients n (%) Weight gain ≥7% of body weight Pooled Schizophrenia and Another Disorder * Aripiprazole 381 20 (5.2) Placebo 187 3 (1.6) Irritability Associated with Autistic Disorder † Aripiprazole 209 55 (26.3) Placebo 98 7 (7.1) Tourette’s Disorder ‡ Aripiprazole 105 21 (20.0) Placebo 66 5 (7.6) * 4 to 6 weeks duration.
† 8 weeks duration.
‡ 8 to 10 weeks duration.
In an open-label trial that enrolled patients from the two placebo-controlled trials of adolescents with schizophrenia (13 to 17 years) and pediatric patients with another disorder (10 to 17 years), 73.2% of patients (238/325) completed 26 weeks of therapy with aripiprazole.
After 26 weeks, 32.8% of patients gained ≥7% of their body weight, not adjusted for normal growth.
To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of pediatric patients and adolescents by comparisons to age- and gender-matched population standards.
A z-score change <0.5 SD is considered not clinically significant.
After 26 weeks, the mean change in z-score was 0.09 SD.
In an open-label trial that enrolled patients from two short-term, placebo-controlled trials, patients (6 to 17 years) with irritability associated with autistic disorder, as well as de novo patients, 60.3% (199/330) completed one year of therapy with aripiprazole.
The mean change in weight z-score was 0.26 SDs for patients receiving >9 months of treatment.
When treating pediatric patients for any indication, weight gain should be monitored and assessed against that expected for normal growth.
5.7 Pathological Gambling and Other Compulsive Behaviors Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole.
Other compulsive urges, reported less frequently, include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors.
Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, 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.
In some cases, although not all, urges were reported to have stopped when the dose was reduced or the medication was discontinued.
Compulsive behaviors 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.
5.8 Orthostatic Hypotension Aripiprazole may cause orthostatic hypotension, perhaps due to its α 1 -adrenergic receptor antagonism.
The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral aripiprazole (n=2467) included (aripiprazole incidence, placebo incidence) orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%); of pediatric patients 6 to 18 years of age (n=732) on oral aripiprazole included orthostatic hypotension (0.5%, 0%), postural dizziness (0.4%, 0%), and syncope (0.2%, 0%) [see Adverse Reactions (6.1) ].
The incidence of a significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 bpm when comparing standing to supine values) for aripiprazole was not meaningfully different from placebo (aripiprazole incidence, placebo incidence): in adult oral aripiprazole-treated patients (4%, 2%), or in pediatric oral aripiprazole-treated patients aged 6 to 18 years (0.4%, 1%).
Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) [see Drug Interactions (7.1) ] .
5.9 Falls Antipsychotics, including aripiprazole, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.
For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
5.10 Leukopenia, Neutropenia, and Agranulocytosis In clinical trials and/or post-marketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including aripiprazole.
Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia.
In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy.
In such patients, consider discontinuation of aripiprazole at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur.
Discontinue aripiprazole in patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) and follow their WBC counts until recovery.
5.11 Seizures/Convulsions In short-term, placebo-controlled trials, patients with a history of seizures excluded seizures/convulsions occurred in 0.1% (3/2467) of undiagnosed adult patients treated with oral aripiprazole and in 0.1% (1/732) of pediatric patients (6 to 18 years).
As with other antipsychotic drugs, aripiprazole should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold.
Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
5.12 Potential for Cognitive and Motor Impairment Aripiprazole, like other antipsychotics, may have the potential to impair judgment, thinking, or motor skills.
For example, in short-term, placebo-controlled trials, somnolence (including sedation) was reported as follows (aripiprazole incidence, placebo incidence): in adult patients (n=2467) treated with oral aripiprazole (11%, 6%), and in pediatric patients ages 6 to 17 (n=611) (24%, 6%).
Somnolence (including sedation) led to discontinuation in 0.3% (8/2467) of adult patients and 3% (20/732) of pediatric patients (6 to 18 years) on oral aripiprazole 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 aripiprazole does not affect them adversely.
5.13 Body Temperature Regulation Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents.
Appropriate care is advised when prescribing aripiprazole 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) [see Adverse Reactions (6.2) ] .
5.14 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 aripiprazole should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose [see Adverse Reactions (6.1 , 6.2 )] .
5.15 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including aripiprazole.
Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia.
Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Warnings and Precautions (5.1) and Adverse Reactions (6.2) ] .
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Discuss the following issues with patients prescribed aripiprazole: Clinical Worsening of Depression and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down.
Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt.
Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see Warnings and Precautions (5.3) ] .
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with aripiprazole and should counsel them in its appropriate use.
A patient Medication Guide including information about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for aripiprazole.
The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents.
Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.
It should be noted that aripiprazole is not approved as a single agent for treatment of depression and has not been evaluated in pediatric major depressive disorder.
Pathological Gambling and Other Compulsive Behaviors Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking aripiprazole.
In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped [see Warnings and Precautions (5.7) ] .
Interference with Cognitive and Motor Performance Because aripiprazole may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that aripiprazole therapy does not affect them adversely [see Warnings and Precautions (5.12) ] .
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 Drug Interactions (7) ] .
Heat Exposure and Dehydration Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.13) ] .
Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with aripiprazole.
Advise patients that aripiprazole may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate.
Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to aripiprazole during pregnancy [see Use in Specific Populations (8.1) ].
Manufactured by: Amneal Pharmaceuticals Pvt.
Ltd.
Ahmedabad, 382220 INDIA Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev.
05-2023-12 Dispense with Medication Guide available at: documents.amneal.com/mg/aripiprazole.pdf
DOSAGE AND ADMINISTRATION
2 Initial Dose Recommended Dose Maximum Dose Schizophrenia – adults (2.1) 10 to 15 mg/day 10 to 15 mg/day 30 mg/day Schizophrenia – adolescents (2.1) 2 mg/day 10 mg/day 30 mg/day Irritability associated with autistic disorder – pediatric patients (2.4) 2 mg/day 5 to 10 mg/day 15 mg/day Tourette’s disorder – (2.5) Patients <50 kg 2 mg/day 5 mg/day 10 mg/day Patients ≥50 kg 2 mg/day 10 mg/day 20 mg/day Oral formulations: Administer once daily without regard to meals.
( 2 ) Known CYP2D6 poor metabolizers: Half of the usual dose.
( 2.7 ) 2.1 Schizophrenia Adults The recommended starting and target dose for aripiprazole tablets is 10 mg/day or 15 mg/day administered on a once-a-day schedule without regard to meals.
Aripiprazole tablets have been systematically evaluated and shown to be effective in a dose range of 10 mg/day to 30 mg/day, when administered as the tablet formulation; however, doses higher than 10 mg/day or 15 mg/day were not more effective than 10 mg/day or 15 mg/day.
Dosage increases should generally not be made before 2 weeks, the time needed to achieve steady-state [see Clinical Studies (14.1) ] .
Maintenance Treatment: Maintenance of efficacy in schizophrenia was demonstrated in a trial involving patients with schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of 3 months or longer.
These patients were discontinued from those medications and randomized to either aripiprazole tablets 15 mg/day or placebo, and observed for relapse [see Clinical Studies (14.1) ] .
Patients should be periodically reassessed to determine the continued need for maintenance treatment.
Adolescents The recommended target dose of aripiprazole tablets is 10 mg/day.
Aripiprazole was studied in adolescent patients 13 to 17 years of age with schizophrenia at daily doses of 10 mg and 30 mg.
The starting daily dose of the tablet formulation in these patients was 2 mg, which was titrated to 5 mg after 2 days and to the target dose of 10 mg after 2 additional days.
Subsequent dose increases should be administered in 5 mg increments.
The 30 mg/day dose was not shown to be more efficacious than the 10 mg/day dose.
Aripiprazole tablets can be administered without regard to meals [see Clinical Studies (14.1) ] .
Patients should be periodically reassessed to determine the need for maintenance treatment.
Switching from Other Antipsychotics There are no systematically collected data to specifically address switching patients with schizophrenia from other antipsychotics to aripiprazole tablets or concerning concomitant administration with other antipsychotics.
While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others.
In all cases, the period of overlapping antipsychotic administration should be minimized.
2.4 Irritability Associated with Autistic Disorder Pediatric Patients (6 to 17 years) The recommended dosage range for the treatment of pediatric patients with irritability associated with autistic disorder is 5 mg/day to 15 mg/day.
Dosing should be initiated at 2 mg/day.
The dose should be increased to 5 mg/day, with subsequent increases to 10 mg/day or 15 mg/day if needed.
Dose adjustments of up to 5 mg/day should occur gradually, at intervals of no less than one week [see Clinical Studies (14.4) ] .
Patients should be periodically reassessed to determine the continued need for maintenance treatment.
2.5 Tourette’s Disorder Pediatric Patients (6 to 18 years) The recommended dosage range for Tourette’s Disorder is 5 mg/day to 20 mg/day.
For patients weighing less than 50 kg, dosing should be initiated at 2 mg/day with a target dose of 5 mg/day after 2 days.
The dose can be increased to 10 mg/day in patients who do not achieve optimal control of tics.
Dosage adjustments should occur gradually at intervals of no less than one week.
For patients weighing 50 kg or more, dosing should be initiated at 2 mg/day for 2 days, and then increased to 5 mg/day for 5 days, with a target dose of 10 mg/day on Day 8.
The dose can be increased up to 20 mg/day for patients who do not achieve optimal control of tics.
Dosage adjustments should occur gradually in increments of 5 mg/day at intervals of no less than one week [see Clinical Studies (14.5) ] .
Patients should be periodically reassessed to determine the continued need for maintenance treatment.
2.7 Dosage Adjustments for Cytochrome P450 Considerations Dosage adjustments are recommended in patients who are known CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers (see Table 2).
When the co-administered drug is withdrawn from the combination therapy, aripiprazole tablets dosage should then be adjusted to its original level.
When the co-administered CYP3A4 inducer is withdrawn, aripiprazole tablets dosage should be reduced to the original level over 1 to 2 weeks.
Patients who may be receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (e.g., a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be reduced to one-quarter (25%) of the usual dose initially and then adjusted to achieve a favorable clinical response.
Table 2: Dose Adjustments for Aripiprazole Tablets in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers Factors Dosage Adjustments for Aripiprazole Tablets Known CYP2D6 Poor Metabolizers Administer half of usual dose Known CYP2D6 Poor Metabolizers taking concomitant strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin) Administer a quarter of usual dose Strong CYP2D6 (e.g., quinidine, fluoxetine, paroxetine) or CYP3A4 inhibitors (e.g., itraconazole, clarithromycin) Administer half of usual dose Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose Strong CYP3A4 inducers (e.g., carbamazepine, rifampin) Double usual dose over 1 to 2 weeks