Aripiprazole 003577
Categories, Drug
Classes, Brand Names & Cost Of Therapy
Categories: Schizophrenia; Pregnancy
Category C; FDA Approved 2002 Nov
Drug Classes: Antipsychotics
Brand Names: Abilify
DescriptionAbilify (aripiprazole) is a
psychotropic drug that is available as tablets for oral administration.
Aripiprazole is
7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. The
empirical formula is
C23H27Cl2N3O2 and its
molecular weight is 448.38.
Abilify tablets are available in 2, 5, 10, 15,
20, and 30 mg strengths. Inactive ingredients include lactose monohydrate,
cornstarch, microcrystalline cellulose, hydroxypropyl cellulose, and magnesium
stearate. Colorants include ferric oxide (yellow or red) and FD&C blue no.
2 aluminum lake.
Clinical PharmacologyPharmacodynamics
Aripiprazole exhibits high affinity for
dopamine D2 and D3, serotonin 5-HT1A and
5-HT2A receptors (Ki values of 0.34, 0.8, 1.7, and 3.4 nM,
respectively), moderate affinity for dopamine D4, serotonin
5-HT2C and 5-HT7, alpha1-adrenergic and
histamine H1 receptors (Ki values of 44, 15, 39, 57, and 61 nM,
respectively), and moderate affinity for serotonin reuptake site (Ki = 98 nM).
Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors
(IC50 >1000 nM). Aripiprazole functions as a partial agonist at
the dopamine D2 and the serotonin 5-HT1A receptors, and
as an antagonist at serotonin 5-HT2A receptor.
The mechanism of action of aripiprazole, as
with other drugs having efficacy in schizophrenia, is unknown. However, it has
been proposed that the efficacy of aripiprazole is mediated through a
combination of partial agonist activity at D2 and 5-HT1A
receptors and antagonist activity at 5-HT2A receptors. Actions at
receptors other than D2, 5-HT1A, and 5-HT2A
may explain some of the other clinical effects of aripiprazole,
e.g., the orthostatic hypotension
observed with aripiprazole may be explained by its antagonist activity at
adrenergic alpha 1 receptors.
Pharmacokinetics
Aripiprazole activity is presumably primarily
due to the parent drug, aripiprazole, and to a lesser extent, to its major
metabolite dehydro-aripiprazole, which has been shown to have affinities for
D2 receptors similar to the parent drug and represents 40% of the
parent drug exposure in plasma. The mean elimination half-lives are about 75
hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively.
Steady-state concentrations are attained within 14 days of dosing for both
active moieties. Aripiprazole accumulation is predictable from single-dose
pharmacokinetics. At steady state, the pharmacokinetics of aripiprazole are
dose-proportional. Elimination of aripiprazole is mainly through hepatic
metabolism involving two P450 isozymes, CYP2D6 and CYP3A4.
Absorption
Aripiprazole is well absorbed, with peak
plasma concentrations occurring within 3-5 hours; the absolute oral
bioavailability of the tablet formulation is 87%. Aripiprazole can be
administered with or without food. Administration of a 15 mg aripiprazole
tablet with a standard high-fat meal did not significantly affect the
Cmax or AUC of aripiprazole or its active metabolite,
dehydro-aripiprazole, but delayed Tmax by 3 hours for aripiprazole
and 12 hours for dehydro-aripiprazole.
Distribution
The steady-state volume of distribution of
aripiprazole following intravenous administration is high (404 L or 4.9 L/kg),
indicating extensive extravascular distribution. At therapeutic concentrations,
aripiprazole and its major metabolite are greater than 99% bound to serum
proteins, primarily to albumin. In healthy human volunteers administered 0.5 to
30 mg/day aripiprazole for 14 days, there was dose-dependent
D2-receptor occupancy indicating brain penetration of aripiprazole
in humans.
Metabolism and
Elimination
Aripiprazole is metabolized primarily by 3
biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation.
Based on in vitro studies, CYP3A4 and
CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of
aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the
predominant drug moiety in the systemic circulation. At steady state,
dehydroaripiprazole, the active metabolite, represents about 40% 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.
Coadministration of aripiprazole with known inhibitors of CYP2D6, like
quinidine in EMs results in a 112% increase in aripiprazole plasma exposure,
and dosing adjustment is needed (see DRUG INTERACTIONS). The mean elimination
half-lives are about 75 hours and 146 hours for aripiprazole in EMs and PMs,
respectively. Aripiprazole does not inhibit or induce the CYP2D6
pathway.
Following a single oral dose of [
14 C]-labeled aripiprazole, approximately 25% and 55%
of the administered radioactivity was recovered in the urine and feces,
respectively. Less than 1% of unchanged aripiprazole was excreted in the urine
and approximately 18% of the oral dose was recovered unchanged in the
feces.
Special Populations
In general, no dosage adjustment for
aripiprazole is required on the basis of a patient’s age, gender, race,
smoking status, hepatic function, or renal function (see DOSAGE AND
ADMINISTRATION, Dosing in Special Populations). The pharmacokinetics of
aripiprazole in special populations are described below.
Hepatic Impairment
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.
Renal Impairment
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
dehydroaripiprazole is less than 1% of the dose. No dosage adjustment is
required in subjects with renal impairment.
Elderly
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, Geriatric Use.)
Gender
Cmax and AUC of aripiprazole and
its active metabolite, dehydro-aripiprazole, are 30-40% 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
Although no specific pharmacokinetic study was
conducted to investigate the effects of race on the disposition of
aripiprazole, population pharmacokinetic evaluation revealed no evidence of
clinically significant race-related differences in the pharmacokinetics of
aripiprazole. No dosage adjustment is recommended based on race.
Smoking
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.
Drug-Drug Interactions
Potential for
Other Drugs to Affect Aripiprazole
Aripiprazole is not a substrate of CYP1A1,
CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes.
Aripiprazole also does not undergo direct glucuronidation. This suggests that
an interaction of aripiprazole with inhibitors or inducers of these enzymes, or
other factors, like smoking, is unlikely.
Both CYP3A4 and CYP2D6 are responsible for
aripiprazole metabolism. Agents that induce CYP3A4 (e.g., carbamazepine) could cause an increase
in aripiprazole clearance and lower blood levels. Inhibitors of CYP3A4 (
e.g., ketoconazole) or CYP2D6 (
e.g., quinidine, fluoxetine, or
paroxetine) can inhibit aripiprazole elimination and cause increased blood
levels.
Potential for
Aripiprazole to Affect Other Drugs
Aripiprazole is unlikely to cause clinically
important pharmacokinetic interactions with drugs metabolized by cytochrome
P450 enzymes. In in vivo studies, 10-30
mg/day doses of aripiprazole had no significant effect on metabolism by CYP2D6
(dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and
CYP3A4 (dextromethorphan) substrates. Additionally, aripiprazole and
dehydroaripiprazole did not show potential for altering CYP1A2-mediated
metabolism in vitro (see DRUG
INTERACTIONS).
Aripiprazole had no clinically
important interactions with the following drugs:
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Famotidine:
Coadministration of aripiprazole (given in a
single dose of 15 mg) with a 40 mg single dose of the H2 antagonist
famotidine, a potent gastric acid blocker, decreased the solubility of
aripiprazole and, hence, its rate of absorption, reducing by 37% and 21% the
Cmax of aripiprazole and dehydro-aripiprazole, respectively, and by
13% and 15%, respectively, the extent of absorption (AUC). No dosage adjustment
of aripiprazole is required when administered concomitantly with
famotidine. |
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Valproate:
When valproate (500-1500 mg/day) and
aripiprazole (30 mg/day) were coadministered at steady state, the
Cmax and AUC of aripiprazole were decreased by 25%. No dosage
adjustment of aripiprazole is required when administered concomitantly with
valproate. |
|
Lithium:
A pharmacokinetic interaction of aripiprazole
with lithium is unlikely because lithium is not bound to plasma proteins, is
not metabolized, and is almost entirely excreted unchanged in urine.
Coadministration of therapeutic doses of lithium (1200-1800 mg/day) for 21 days
with aripiprazole (30 mg/day) did not result in clinically significant changes
in the pharmacokinetics of aripiprazole or its active metabolite,
dehydro-aripiprazole (Cmax and AUC increased by less than 20%). No
dosage adjustment of aripiprazole is required when administered concomitantly
with lithium. |
|
Dextromethorphan:
Aripiprazole at doses of 10-30 mg/day for 14
days had no effect on dextromethorphan’s O-dealkylation to its major
metabolite, dextrorphan, a pathway known to be dependent on CYP2D6 activity.
Aripiprazole also had no effect on dextromethorphan’s N-demethylation to
its metabolite 3-methyoxymorphan, a pathway known to be dependent on CYP3A4
activity. No dosage adjustment of dextromethorphan is required when
administered concomitantly with aripiprazole. |
|
Warfarin:
Aripiprazole 10 mg/day for 14 days had no
effect on the pharmacokinetics of R- and S-warfarin or on the pharmacodynamic
end point of International Normalized Ratio, indicating the lack of a
clinically relevant effect of aripiprazole on CYP2C9 and CYP2C19 metabolism or
the binding of highly protein-bound warfarin. No dosage adjustment of warfarin
is required when administered concomitantly with aripiprazole.
|
|
Omeprazole:
Aripiprazole 10 mg/day for 15 days had no
effect on the pharmacokinetics of a single 20 mg dose of omeprazole, a CYP2C19
substrate, in healthy subjects. No dosage adjustment of omeprazole is required
when administered concomitantly with aripiprazole. |
Clinical StudiesThe efficacy of
aripiprazole in the treatment of schizophrenia was evaluated in four short-term
(4 and 6 week), placebo-controlled trials of acutely relapsed inpatients who
predominantly met DSM-III/IV criteria for schizophrenia. Three of the four
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 three positive trials for aripiprazole,
four primary measures were used for assessing psychiatric signs and symptoms.
The Positive and Negative Syndrome Scale (PANSS) is a multi-item inventory of
general psychopathology used to evaluate the effects of drug treatment in
schizophrenia. The PANSS positive subscale is a subset of items in the PANSS
that rates 7 positive symptoms of schizophrenia (delusions, conceptual
disorganization, hallucinatory behavior, excitement, grandiosity,
suspiciousness/persecution, and hostility). The PANSS negative subscale is a
subset of items in the PANSS that rates 7 negative symptoms of schizophrenia
(blunted affect, emotional withdrawal, poor rapport, passive apathetic
withdrawal, difficulty in abstract thinking, lack of spontaneity/flow of
conversation, stereotyped thinking). 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 2 fixed
doses of aripiprazole (15 or 30 mg/day) and haloperidol (10 mg/day) to placebo,
both doses of aripiprazole were superior to placebo in the PANSS total score,
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 2 fixed
doses of aripiprazole (20 or 30 mg/day) and risperidone (6 mg/day) to placebo,
both doses of aripiprazole were superior to placebo in the PANSS total score,
PANSS positive subscale, PANSS negative subscale, and CGI-severity
score.
In a 6 week trial (n=420) comparing 3 fixed
doses of aripiprazole (10, 15 or 20 mg/day) to placebo, all 3 doses of
aripiprazole were superior to placebo in the PANSS total score, PANSS positive
subscale, and the PANSS negative subscale.
In a fourth study, a 4 week trial (n=103)
comparing aripiprazole in a range of 5-30 mg/day or haloperidol 5-20 mg/day to
placebo, haloperidol was superior to placebo, in the Brief Psychiatric Rating
Scale (BPRS), a multi-item inventory of general psychopathology traditionally
used to evaluate the effects of drug treatment in psychosis, and in a responder
analysis based on the CGI-severity score, the primary outcomes for that trial.
Aripiprazole was only significantly different compared to placebo in a
responder analysis based on the CGI-severity score.
Thus, the efficacy of 15, 20, and 30 mg daily
doses was established in two studies for each dose whereas the efficacy of the
10 mg dose was established in one study. There was no evidence in any study
that the higher dose groups offered any advantage over the lowest dose
group.
An examination of population subgroups did not
reveal any clear evidence of differential responsiveness on the basis of age,
gender, or race.
Indications And UsageAripiprazole is
indicated for the treatment of schizophrenia. The efficacy of aripiprazole in
the treatment of schizophrenia was established in short-term (4 and 6 week)
controlled trials of schizophrenic inpatients (see CLINICAL STUDIES).
The long-term efficacy of aripiprazole in the
treatment of schizophrenia has not been established. The physician who elects
to use aripiprazole for extended periods should periodically re-evaluate the
long-term usefulness of the drug for the individual patient.
ContraindicationsAripiprazole is
contraindicated in patients with a known hypersensitivity to the product.
WarningsNeuroleptic Malignant Syndrome
(NMS)
A potentially fatal symptom complex sometimes
referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in
association with administration of antipsychotic drugs, including aripiprazole.
Two possible cases of NMS occurred during aripiprazole treatment in the
premarketing 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, etc.) 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.
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.
There is no known treatment for established
cases of tardive dyskinesia, although the syndrome 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.
PrecautionsGeneral
Orthostatic
Hypotension
Aripiprazole may be associated with
orthostatic hypotension, perhaps due to its α1-adrenergic receptor
antagonism. The incidence of orthostatic hypotension associated events from
five short-term, placebo-controlled trials in schizophrenia (n=926) on
aripiprazole included: orthostatic hypotension (placebo 1%, aripiprazole 1.9%),
orthostatic lightheadedness (placebo 1%, aripiprazole 0.9%), and syncope
(placebo 1%, aripiprazole 0.6%). The incidence of a significant orthostatic
change in blood pressure (defined as a decrease of at least 30 mm Hg in
systolic blood pressure when changing from a supine to standing position) for
aripiprazole was not statistically different from placebo (14% among
aripiprazole-treated patients and 12% among placebo-treated patients).
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).
Seizure
Seizures occurred in 0.1% (1/926) of
aripiprazole-treated patients in short-term, placebo-controlled trials. 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,
e.g., Alzheimer’s dementia.
Conditions that lower the seizure threshold may be more prevalent in a
population of 65 years or older.
Potential for Cognitive
and Motor Impairment
In short-term, placebo-controlled trials,
somnolence was reported in 11% of patients on aripiprazole compared to 8% of
patients on placebo; somnolence led to discontinuation in 0.1% (1/926) of
patients on aripiprazole in short-term, placebo-controlled trials. Despite the
relatively modest increased incidence of somnolence compared to placebo,
aripiprazole, like other antipsychotics, 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 therapy with aripiprazole does not affect them adversely.
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.
Dysphagia
Esophageal dysmotility and aspiration have
been associated with antipsychotic drug use. 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 Use
in Patients With Concomitant Illness).
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 of tablets consistent with good patient management in
order to reduce the risk of overdose.
Use in Patients With
Concomitant Illness
Safety
Experience in Elderly Patients With Psychosis Associated With Alzheimer’s
Disease
In a flexible dose (2-15 mg/day), 10 week,
placebo-controlled study of aripiprazole in elderly patients (mean age: 81.5
years; range: 56-95) with psychosis associated with Alzheimer’s dementia,
4 of 105 patients (3.8%) who received aripiprazole died compared to no deaths
among 102 patients who received placebo during or within 30 days after
termination of the double-blind portion of the study. Three of the patients
(age 92, 91, and 87 years) died following the discontinuation of aripiprazole
in the double-blind phase of the study (causes of death were pneumonia, heart
failure, and shock). The fourth patient (age 78 years) died following hip
surgery while in the double-blind portion of the study. The treatment-emergent
adverse events that were reported at an incidence of ≥5% and having a
greater incidence than placebo in this study were accidental injury,
somnolence, and bronchitis. Eight percent (8%) of the aripiprazole treated
patients reported somnolence compared to 1% of placebo patients. In a small
pilot, open-label, ascending-dose, cohort study (n=30) in elderly patients with
dementia, aripiprazole was associated in a dose-related fashion with
somnolence.
The safety and efficacy of aripiprazole in the
treatment of patients with psychosis associated with dementia has not been
established. If the prescriber elects to treat such patients with aripiprazole,
vigilance should be exercised, particularly for the emergence of difficulty
swallowing or excessive somnolence, which could predispose to accidental injury
or aspiration.
Clinical experience with aripiprazole in
patients with certain concomitant systemic illnesses (see CLINICAL
PHARMACOLOGY, Special Populations: Renal Impairment and Hepatic Impairment) is
limited.
Aripiprazole 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.
Information
for the Patient
Physicians are
advised to discuss the following issues with patients for whom they prescribe
Aripiprazole:
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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.
|
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Pregnancy:
Patients should be advised to notify their
physician if they become pregnant or intend to become pregnant during therapy
with aripiprazole. |
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Nursing:
Patients should be advised not to breast-feed
an infant if they are taking aripiprazole. |
|
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. |
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Alcohol:
Patients should be advised to avoid alcohol
while taking aripiprazole. |
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Heat exposure and
dehydration: Patients should be advised
regarding appropriate care in avoiding overheating and dehydration.
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Carcinogenesis, Mutagenesis, and
Impairment of Fertility
Carcinogenesis
Lifetime carcinogenicity studies were
conducted in ICR mice and in Sprague-Dawley (SD) and 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). In addition, SD rats were dosed
orally for 2 years at 10, 20, 40, and 60 mg/kg/day (3-19 times the MRHD based
on mg/m2 ). Aripiprazole did not induce tumors 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
3-30 mg/kg/day (0.1-0.9 times human exposure at 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 human
exposure at 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 dose
of 60 mg/kg/day (14 times human exposure at MRHD based on AUC and 19 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.
However, increases in serum prolactin levels were observed in female mice in a
13 week dietary study at the doses associated with mammary gland and pituitary
tumors. Serum prolactin was not increased in female rats in 4 and 13 week
dietary studies at the dose associated with mammary gland tumors. The relevance
for human risk of the findings of prolactin-mediated endocrine tumors in
rodents is unknown.
Mutagenesis
The mutagenic potential of aripiprazole was
tested in the in vitro bacterial
reverse-mutation assay, the in vitro
bacterial DNA repair assay, the in
vitro forward gene mutation assay in mouse lymphoma cells, the
in vitro chromosomal aberration assay
in Chinese hamster lung (CHL) cells, the in
vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay
in rats. Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the
in vitro chromosomal aberration assay
in CHL cells with and without metabolic activation. The metabolite, 2,3-DCPP,
produced increases in numerical aberrations in the
in vitro assay in CHL cells in the
absence of metabolic activation. A positive response was obtained in the
in vivo micronucleus assay in mice,
however, the response was shown to be due to a mechanism not considered
relevant to humans.
Impairment of
Fertility
Female rats were treated with oral doses of 2,
6, and 20 mg/kg/day (0.6, 2, and 6 times the maximum recommended human dose
[MRHD] on a mg/m2 basis) of aripiprazole from 2 weeks prior to mating
through Day 7 of gestation. Estrus cycle irregularities and increased corpora
lutea were seen at all doses, but no impairment of fertility was seen.
Increased pre-implantation loss was seen at 6 and 20 mg/kg, and decreased fetal
weight was seen at 20 mg/kg.
Male rats were treated with oral doses of 20,
40, and 60 mg/kg/day (6, 13, and 19 times the MRHD on a mg/m2
basis) of aripiprazole from 9 weeks prior to mating through mating.
Disturbances in spermatogenesis were seen at 60 mg/kg, and prostate atrophy was
seen at 40 and 60 mg/kg, but no impairment of fertility was seen.
Pregnancy
Category C
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 10 times the maximum recommended human dose
[MRHD] on a mg/m2
basis) of aripiprazole during the
period of organogenesis. Gestation was slightly prolonged at 30 mg/kg.
Treatment caused a slight delay in fetal development as evidenced by decreased
fetal weight (30 mg/kg), undescended testes (30 mg/kg), and delayed skeletal
ossification (10 and 30 mg/kg). There were no adverse effects on embryofetal or
pup survival. Delivered offspring had decreased bodyweights (10 and 30 mg/kg),
and increased incidences of hepatodiaphragmatic nodules and diaphragmatic
hernia at 30 mg/kg (the other dose groups were not examined for these
findings). (A low incidence of diaphragmatic hernia was also seen in the
fetuses exposed to 30 mg/kg.) Postnatally, delayed vaginal opening was seen at
10 and 30 mg/kg and impaired reproductive performance (decreased fertility
rate, corpora lutea, implants, and live fetuses, and increased
post-implantation loss, likely mediated through effects on female offspring)
was seen at 30 mg/kg. Some maternal toxicity was seen at 30 mg/kg, however,
there was no evidence to suggest that these developmental effects were
secondary to maternal toxicity.
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 6, 19, and 65 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 fetal mortality (100 mg/kg), decreased fetal weight (30 and 100
mg/kg), increased incidence of a skeletal abnormality (fused sternebrae at 30
and 100 mg/kg) and minor skeletal variations (100 mg/kg).
In a study in which rats were treated with
oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 10 times the MRHD on a
mg/m2
basis) of aripiprazole perinatally and
postnatally (from Day 17 of gestation through Day 21 postpartum), slight
maternal toxicity and slightly prolonged gestation were seen at 30 mg/kg. An
increase in stillbirths, and decreases in pup weight (persisting into
adulthood) and survival, were seen at this dose.
There are no adequate and well-controlled
studies in pregnant women. It is not known whether aripiprazole can cause fetal
harm when administered to a pregnant woman or can affect reproductive capacity.
Aripiprazole should be used during pregnancy only if the potential benefit
outweighs the potential risk to the fetus.
Labor and
Delivery
The effect of aripiprazole on labor and
delivery in humans is unknown.
Nursing
Mothers
Aripiprazole was excreted in milk of rats
during lactation. It is not known whether aripiprazole or its metabolites are
excreted in human milk. It is recommended that women receiving aripiprazole
should not breast-feed.
Pediatric
Use
Safety and effectiveness in pediatric and
adolescent patients have not been established.
Geriatric Use
Of the 5592 patients treated with aripiprazole
in premarketing clinical trials, 659 (12%) were ≥65 years old and 525 (9%)
were ≥75 years old. The majority (91%) of the 659 patients were diagnosed
with dementia of the Alzheimer’s type.
Placebo-controlled studies of aripiprazole in
schizophrenia did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. There was
no effect of age on the pharmacokinetics of a single 15 mg dose of
aripiprazole. Aripiprazole clearance was decreased by 20% in elderly subjects
(≥65 years) compared to younger adult subjects (18-64 years), but there was
no detectable effect of age in the population pharmacokinetic analysis in
schizophrenia patients.
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 Use in Patients With Concomitant Illness). The safety
and efficacy of aripiprazole in the treatment of patients with psychosis
associated with Alzheimer’s disease has not been established. If the
prescriber elects to treat such patients with aripiprazole, vigilance should be
exercised.
Drug InteractionsGiven the primary CNS
effects of aripiprazole, caution should be used when aripiprazole is taken in
combination with other centrally acting drugs and alcohol. Due to its
α1-adrenergic receptor antagonism, aripiprazole has the
potential to enhance the effect of certain antihypertensive agents.
Potential for
Other Drugs to Affect Aripiprazole
Aripiprazole is not a substrate of CYP1A1,
CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes.
Aripiprazole also does not undergo direct glucuronidation. This suggests that
an interaction of aripiprazole with inhibitors or inducers of these enzymes, or
other factors, like smoking, is unlikely.
Both CYP3A4 and CYP2D6 are responsible for
aripiprazole metabolism. Agents that induce CYP3A4 (e.g., carbamazepine) could cause an increase
in aripiprazole clearance and lower blood levels. Inhibitors of CYP3A4 (
e.g., ketoconazole) or CYP2D6 (
e.g., quinidine, fluoxetine, or
paroxetine) can inhibit aripiprazole elimination and cause increased blood
levels.
|
Ketoconazole:
Coadministration of ketoconazole (200 mg/day
for 14 days) with a 15 mg single dose of aripiprazole increased the AUC of
aripiprazole and its active metabolite by 63% and 77%, respectively. The effect
of a higher ketoconazole dose (400 mg/day) has not been studied. When
concomitant administration of ketoconazole with aripiprazole occurs,
aripiprazole dose should be reduced to one-half of its normal dose. Other
strong inhibitors of CYP3A4 (itraconazole) would be expected to have similar
effects and need similar dose reductions; weaker inhibitors (erythromycin,
grapefruit juice) have not been studied. When the CYP3A4 inhibitor is withdrawn
from the combination therapy, aripiprazole dose should then be
increased. |
|
Quinidine:
Coadministration of a 10 mg single dose of
aripiprazole with quinidine (166 mg/day for 13 days), a potent inhibitor of
CYP2D6, increased the AUC of aripiprazole by 112% but decreased the AUC of its
active metabolite, dehydroaripiprazole, by 35%. Aripiprazole dose should be
reduced to one-half of its normal dose when concomitant administration of
quinidine with aripiprazole occurs. Other significant inhibitors of CYP2D6,
such as fluoxetine or paroxetine, would be expected to have similar effects
and, therefore, should be accompanied by similar dose reductions. When the
CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose
should then be increased. |
|
Carbamazepine:
Coadministration of carbamazepine (200 mg
bid), a potent CYP3A4 inducer, with aripiprazole (30 mg qd) resulted in an
approximate 70% decrease in Cmax and AUC values of both aripiprazole
and its active metabolite, dehydro-aripiprazole. When carbamazepine is added to
aripiprazole therapy, aripiprazole dose should be doubled. Additional dose
increases should be based on clinical evaluation. When carbamazepine is
withdrawn from the combination therapy, aripiprazole dose should then be
reduced. |
|
No clinically significant effect of
famotidine, valproate, or lithium was seen on the pharmacokinetics of
aripiprazole (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions).
|
Potential for
Aripiprazole to Affect Other Drugs
Aripiprazole is unlikely to cause clinically
important pharmacokinetic interactions with drugs metabolized by cytochrome
P450 enzymes. In in vivo studies, 10-30
mg/day doses of aripiprazole had no significant effect on metabolism by CYP2D6
(dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and
CYP3A4 (dextromethorphan) substrates. Additionally, aripiprazole and
dehydroaripiprazole did not show potential for altering CYP1A2-mediated
metabolism in vitro (see CLINICAL
PHARMACOLOGY, Drug-Drug Interactions).
|
Alcohol:
There was no significant difference between
aripiprazole coadministered with ethanol and placebo coadministered with
ethanol on performance of gross motor skills or stimulus response in healthy
subjects. As with most psychoactive medications, patients should be advised to
avoid alcohol while taking aripiprazole. |
Adverse ReactionsAripiprazole has been
evaluated for safety in 5592 patients who participated in multiple-dose,
premarketing trials in schizophrenia, bipolar mania, and dementia of the
Alzheimer’s type, and who had approximately 3639 patient-years of
exposure. A total of 1887 aripiprazole-treated patients were treated for at
least 180 days and 1251 aripiprazole-treated patients had at least 1 year of
exposure.
The conditions and duration of treatment with
aripiprazole 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 volunteered 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, modified COSTART
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. There was no attempt to use
investigator causality assessments; i.e., all reported events are included.
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
Findings Observed in Short-Term, Placebo-Controlled Trials of Patients With
Schizophrenia
The following findings are based on a pool of
five placebo-controlled trials (four 4-week and one 6-week) in which
aripiprazole was administered in doses ranging from 2-30 mg/day.
Adverse Events
Associated With Discontinuation of Treatment in Short-Term, Placebo-Controlled
Trials
Overall, there was no difference in the
incidence of discontinuation due to adverse events between aripiprazole-treated
(7%) and placebo-treated (9%) patients. The types of adverse events that led to
discontinuation were similar between the aripiprazole and placebo-treated
patients.
Adverse Events
Occurring at an Incidence of 2% or More Among Aripiprazole-Treated Patients and
Greater Than Placebo in Short-Term Placebo-Controlled Trials
TABLE 1 enumerates the incidence, rounded to
the nearest percent, of treatment-emergent adverse events that occurred during
acute therapy (up to 6 weeks), including only those events that occurred in 2%
or more of patients treated with aripiprazole (doses ≥2 mg/day) and for
which the incidence in patients treated with aripiprazole was greater than the
incidence in patients treated with placebo.
TABLE 1 Treatment-Emergent Adverse Events in
Short-Term, Placebo-Controlled Trials*
|
Body System |
Aripiprazole |
Placebo |
| |
Adverse Event |
(n=926) |
(n=413) |
|
Body as a Whole |
| |
Headache |
32% |
25% |
| |
Asthenia |
7% |
5% |
| |
Fever |
2% |
1% |
|
Digestive System |
| |
Nausea |
14% |
10% |
| |
Vomiting |
12% |
7% |
| |
Constipation |
10% |
8% |
|
Nervous System |
| |
Anxiety |
25% |
24% |
| |
Insomnia |
24% |
19% |
| |
Lightheadedness |
11% |
7% |
| |
Somnolence |
11% |
8% |
| |
Akathisia |
10% |
7% |
| |
Tremor |
3% |
2% |
|
Repiratory System |
| |
Rhinitis |
4% |
3% |
| |
Coughing |
3% |
2% |
|
Skin and Appendages
|
| |
Rash |
6% |
5% |
|
Special Senses |
| |
Blurred vision |
3% |
1% |
|
*
Events reported by at least 2% of patients
treated with aripiprazole, except the following events, which had an incidence
equal to or less than placebo: abdominal pain, accidental injury, back pain,
dental pain, dyspepsia, diarrhea, dry mouth, myalgia, agitation, psychosis,
extrapyramidal syndrome, hypertonia, pharyngitis, upper respiratory tract
infection, dysmenorrhea, vaginitis. |
An examination of population subgroups did not
reveal any clear evidence of differential adverse event incidence on the basis
of age, gender, or race.
Dose-Related
Adverse Events
Dose response relationships for the incidence
of treatment-emergent adverse events were evaluated from four trials comparing
various fixed doses (2, 10, 15, 20, and 30 mg/day) of aripiprazole 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 (placebo, 7.7%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg,
15.3%).
Extrapyramidal
Symptoms
In the short-term, placebo-controlled trials,
the incidence of reported EPS for aripiprazole-treated patients was 6% vs 6%
for placebo. Objectively collected data from those trials on the Simpson Angus
Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the
Assessments of Involuntary Movement Scales (for dyskinesias) also did not show
a difference between aripiprazole and placebo, with the exception of the Barnes
Akathisia Scale (aripiprazole, 0.08; placebo, -0.05).
Laboratory Test
Abnormalities
A between group comparison for 4-6 week
placebo-controlled trials revealed no medically important differences between
the aripiprazole and placebo groups in the proportions of patients experiencing
potentially clinically significant changes in routine serum chemistry,
hematology, or urinalysis parameters. Similarly, there were no
aripiprazole/placebo differences in the incidence of discontinuations for
changes in serum chemistry, hematology, or urinalysis.
Weight
Gain
In short-term trials, there was a slight
difference in mean weight gain between aripiprazole and placebo patients (+0.7
kg vs -0.05 kg, respectively), and also a difference in the proportion of
patients meeting a weight gain criterion of >7% of body weight [aripiprazole
(8%) compared to placebo (3%)]. TABLE 2 provides the weight change results from
a long-term (52 week) study of aripiprazole, both mean change from baseline and
proportions of patients meeting a weight gain criterion of >7% of body
weight relative to baseline, categorized by BMI at baseline (see TABLE
2).
TABLE 2 Weight Change Results Categorized by BMI at
Baseline
| |
BMI <23 |
BMI 23-27 |
BMI >27 |
|
Mean change from baseline |
2.6 kg |
1.4 kg |
-1.2 kg |
|
% With ≥7% increase BW |
30% |
19% |
8% |
ECG
Changes
Between group comparisons for pooled,
placebo-controlled trials revealed no significant differences between
aripiprazole and placebo in the proportion of patients experiencing potentially
important changes in ECG parameters; in fact, within the dose range of 10-30
mg/day, aripiprazole tended to slightly shorten the QTc interval. Aripiprazole
was associated with a median increase in heart rate of 4 beats/min compared to
a 1 beat/min increase among placebo patients.
Other Adverse
Events Observed During the Premarketing Evaluation of Aripiprazole
Following is a list of modified COSTART terms
that reflect treatment-emergent adverse events as defined in the introduction
to ADVERSE REACTIONS reported by patients treated with aripiprazole at multiple
doses ≥2 mg/day during any phase of a trial within the database of 5592
patients. All reported events are included except those already listed in TABLE
1, or other parts of ADVERSE REACTIONS, those considered in WARNINGS or
PRECAUTIONS, those event terms which were so general as to be uninformative,
events reported with an incidence of <0.05% and which did not have a
substantial probability of being acutely life-threatening, events that are
otherwise common as background events, and events considered unlikely to be
drug related. It is important to emphasize that, although the events reported
occurred during treatment with aripiprazole, they were not necessarily caused
by it.
Events are further
categorized by body system and listed in order of decreasing frequency
according to the following definitions:
Frequent
adverse events are those occurring in at
least 1/100 patients (only those not already listed in the tabulated results
from placebo-controlled trials appear in this listing);
infrequent adverse events are those
occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than
1/1000 patients.
|
Body as a Whole:
Frequent:
Flu syndrome, peripheral edema, chest pain,
neck pain, neck rigidity; Infrequent: Pelvic pain,
suicide attempt, face edema, malaise, photosensitivity, arm rigidity, jaw pain,
chills, bloating, jaw tightness, enlarged abdomen, chest tightness;
Rare: Throat pain, back
tightness, head heaviness, moniliasis, throat tightness, leg rigidity, neck
tightness, Mendelson’s syndrome, heat stroke. |
|
Cardiovascular System:
Frequent:
Hypertension, tachycardia, hypotension,
bradycardia; Infrequent: Palpitation,
hemorrhage, myocardial infarction, prolonged QT interval, cardiac arrest,
atrial fibrillation, heart failure, AV block, myocardial ischemia, phlebitis,
deep vein thrombosis, angina pectoris, extrasystoles;
Rare: Vasovagal
reaction, cardiomegaly, atrial flutter, thrombophlebitis. |
|
Digestive System:
Frequent:
Anorexia, nausea and vomiting;
Infrequent: Increased
appetite, gastroenteritis, dysphagia, flatulence, gastritis, tooth caries,
gingivitis, hemorrhoids, gastroesophageal reflux, gastrointestinal hemorrhage,
periodontal abscess, tongue edema, fecal incontinence, colitis, rectal
hemorrhage, stomatitis, mouth ulcer, cholecystitis, fecal impaction, oral
monliasis, cholelithiasis, eructation, intestinal obstruction, peptic ulcer;
Rare: Esophagitis, gum
hemorrhage, glossitis, hematemesis, melena, duodenal ulcer, cheilitis,
hepatitis, hepatomegaly, pancreatitis, intestinal perforation.
|
|
Endocrine System:
Infrequent:
Hypothyroidism;
Rare: Goiter,
hyperthyroidism. |
|
Hemic/Lymphatic System:
Frequent:
Ecchymosis, anemia;
Infrequent: Hypochromic
anemia, leukopenia, leukocytosis, lymphadenopathy, thrombocytopenia;
Rare: Eosinophilia,
thrombocythemia, macrocytic anemia. |
|
Metabolic and Nutritional
Disorders:
Frequent:
Weight loss, creatine phosphokinase increased;
Infrequent:
Dehydration, edema, hypercholesteremia, hyperglycemia, hypokalemia, diabetes
mellitus, SGPT increased, hyperlipemia, hypoglycemia, thirst, BUN increased,
hyponatremia, SGOT increased, alkaline phosphatase increased, iron deficiency
anemia, creatinine increased, bilirubinemia, lactic dehydrogenase increased,
obesity; Rare:
Hyperkalemia, gout, hypernatremia, cyanosis, hyperuricemia, hypoglycemic
reaction. |
|
Musculoskeletal System:
Frequent:
Muscle cramp;
Infrequent: Arthralgia,
bone pain, myasthenia, arthritis, arthrosis, muscle weakness, spasm, bursitis;
Rare: Rhabdomyolysis,
tendonitis, tenosynovitis, rheumatoid arthritis, myopathy. |
|
Nervous System:
Frequent:
Depression, nervousness, increased salivation,
hostility, suicidal thought, manic reaction, abnormal gait, confusion, cogwheel
rigidity; Infrequent:
Dystonia, twitch, impaired concentration, paresthesia, vasodilation,
hypesthesia, extremity tremor, impotence, bradykinesia, decreased libido, panic
attack, apathy, dyskinesia, hypersomnia, vertigo, dysarthria, tardive
dyskinesia, ataxia, impaired memory, stupor, increased libido, amnesia,
cerebrovascular accident, hyperactivity, depersonalization, hypokinesia,
restless leg, myoclonus, dysphoria, neuropathy, increased reflexes, slowed
thinking, hyperkinesia, hyperesthesia, hypotonia, oculogyric crisis;
Rare: Delirium,
euphoria, buccoglossal syndrome, akinesia, blunted affect, decreased
consciousness, incoordination, cerebral ischemia, decreased reflexes, obsessive
thought, intracranial hemorrhage. |
|
Respiratory System:
Frequent:
Dyspnea, pneumonia;
Infrequent: Asthma,
epistaxis, hiccup, laryngitis; Rare: Hemoptysis, aspiration
pneumonia, increased sputum, dry nasal passages, pulmonary edema, pulmonary
embolism, hypoxia, respiratory failure, apnea. |
|
Skin and Appendages:
Frequent:
Dry skin, pruritus, sweating, skin ulcer;
Infrequent: Acne,
vesiculobullous rash, eczema, alopecia, psoriasis, seborrhea;
Rare: Maculopapular
rash, exfoliative dermatitis, urticaria. |
|
Special Senses:
Frequent:
Conjunctivitis, ear pain;
Infrequent: Dry eye,
eye pain, tinnitus, otitis media, cataract, altered taste, blepharitis;
Rare: Increased
lacrimation, frequent blinking, otitis externa, amblyopia, deafness, diplopia,
eye hemorrhage, photophobia. |
|
Urogenital System:
Frequent:
Urinary incontinence;
Infrequent: Cystitis,
urinary frequency, leukorrhea, urinary retention, hematuria, dysuria,
amenorrhea, abnormal ejaculation, vaginal hemorrhage, vaginal moniliasis,
kidney failure, uterus hemorrhage, menorrhagia, albuminuria, kidney calculus,
nocturia, polyuria, urinary urgency;
Rare: Breast pain,
cervicitis, female lactation, anorgasmy, urinary burning, glycosuria,
gynecomastia, urolithiasis, priapism. |
Drug Abuse And DependenceControlled
Substance
Aripiprazole is not a controlled
substance.
Abuse and
Dependence
Aripiprazole has not been systematically
studied in humans for its potential for abuse, tolerance, or physical
dependence. In physical dependence studies in monkeys, withdrawal symptoms were
observed upon abrupt cessation of dosing. While the clinical trials did not
reveal any tendency for any drug-seeking behavior, 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 aripiprazole misuse or abuse (e.g., development of tolerance, increases in
dose, drug-seeking behavior).
OverdosageHuman Experience
In premarketing clinical studies, involving
more than 5500 patients, accidental or intentional acute overdosage of
aripiprazole was identified in 7 patients. In the 2 patients taking the largest
identified amount, 180 mg, the only symptoms reported were somnolence and
vomiting in 1 of the 2 patients. In the patients who were evaluated in hospital
settings, including the 2 patients taking 180 mg, there were no observations
indicating an adverse change in vital signs, laboratory assessments or ECG. An
uneventful, accidental overdose (15 mg) occurred in a non-patient, an
18-month-old child, with concomitant ingestion of Ativan (2 mg).
Management of
Overdose
No specific information is available on the
treatment of overdose with aripiprazole. An electrocardiogram should be
obtained in case of overdosage and, if QTc 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, 1
hour after a single 15 mg oral dose of aripiprazole, decreased the mean AUC and
Cmax 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. |
Dosage And AdministrationUsual Dose
The recommended starting and target dose for
aripiprazole is 10 or 15 mg/day administered on a once-a-day schedule without
regard to meals. Aripiprazole has been systematically evaluated and shown to be
effective in a dose range of 10-30 mg/day, however, doses higher than 10 or 15
mg/day, the lowest doses in these trials, were not more effective than 10 or 15
mg/day. Dosage increases should not be made before 2 weeks, the time needed to
achieve steady state.
Dosing in Special
Populations
Dosage adjustments are not routinely indicated
on the basis of age, gender, race, or renal or hepatic impairment status (see
CLINICAL PHARMACOLOGY, Special Populations).
|
Dosage adjustment
for patients taking aripiprazole concomitantly with potential CYP3A4
inhibitors: When concomitant
administration of ketoconazole with aripiprazole occurs, aripiprazole dose
should be reduced to one-half of the usual dose. When the CYP3A4 inhibitor is
withdrawn from the combination therapy, aripiprazole dose should then be
increased. |
|
Dosage adjustment
for patients taking aripiprazole concomitantly with potential CYP2D6
inhibitors: When concomitant
administration of potential CYP2D6 inhibitors such as quinidine, fluoxetine, or
paroxetine with aripiprazole occurs, aripiprazole dose should be reduced at
least to one-half of its normal dose. When the CYP2D6 inhibitor is withdrawn
from the combination therapy, aripiprazole dose should then be
increased. |
|
Dosage adjustment
for patients taking potential CYP3A4 inducers:
When potential CYP3A4 inducer such as
carbamazepine is added to aripiprazole therapy, aripiprazole dose should be
doubled (to 20 or 30 mg). Additional dose increases should be based on clinical
evaluation. When carbamazepine is withdrawn from the combination therapy,
aripiprazole dose should be reduced to 10-15 mg. |
Maintenance
Therapy
There is no body of evidence available from
controlled trials to answer the question of how long a patient treated with
aripiprazole should remain on it. It is generally agreed, however, that
pharmacological treatment for episodes of acute schizophrenia should continue
for up to 6 months or longer. 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 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.
Aripiprazole produced retinal degeneration in albino
rats in a 26 week chronic toxicity study at a dose of 60 mg/kg and in a 2 year
carcinogenicity study at doses of 40 and 60 mg/kg. The 40 and 60 mg/kg doses
are 13 and 19 times the maximum recommended human dose (MRHD) based on
mg/m2
and 7-14 times human exposure at MRHD
based on AUC. Evaluation of the retinas of albino mice and of monkeys did not
reveal evidence of retinal degeneration. Additional studies to further evaluate
the mechanism have not been performed. The relevance of this finding to human
risk is unknown.
How SuppliedAbilify (aripiprazole) tablets
are available in the following strengths and packages:
|
2 mg:
Green, modified rectangular, scored tablets,
debossed on one side with "A-006" and "2". |
|
5 mg:
Blue, modified rectangular, scored tablets,
debossed on one side with "A-007" and "5". |
|
10 mg:
Pink, modified rectangular tablets, debossed
on one side with "A-008" and "10". |
|
15 mg:
Yellow, round tablets, debossed on one side
with "A-009" and "15". |
|
20 mg:
White, round tablets, debossed on one side
with "A-010" and "20". |
|
30 mg:
Pink, round tablets, debossed on one side with
"A-011" and "30". |
Storage:
Store at 25°C (77°F); excursions
permitted to 15-30°C (59-86°F).
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