ABILIFY (Page 8 of 14)
ABILIFY has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ABILIFY misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).
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.
MedDRA terminology has been used to classify the adverse reactions.
10.1 Human Experience
In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral ABILIFY have been reported worldwide. These include overdoses with oral ABILIFY alone and in combination with other substances. No fatality was reported with ABILIFY alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral ABILIFY (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 ABILIFY ingestions up to 195 mg with no fatalities.
Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral ABILIFY 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 ABILIFY 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 ABILIFY. 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 ABILIFY, 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 ABILIFY, 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 ABILIFY, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.
Aripiprazole is an atypical antipsychotic drug that is available as ABILIFY® (aripiprazole) Tablets, ABILIFY DISCMELT® (aripiprazole) Orally Disintegrating Tablets, ABILIFY® (aripiprazole) Oral Solution, and ABILIFY® (aripiprazole) Injection, a solution for intramuscular injection. Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. The empirical formula is C23 H27 Cl2 N3 O2 and its molecular weight is 448.38. The chemical structure is:
ABILIFY Tablets are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg strengths. Inactive ingredients include cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Colorants include ferric oxide (yellow or red) and FD&C Blue No. 2 Aluminum Lake.
ABILIFY DISCMELT Orally Disintegrating Tablets are available in 10 mg and 15 mg strengths. Inactive ingredients include acesulfame potassium, aspartame, calcium silicate, croscarmellose sodium, crospovidone, crème de vanilla (natural and artificial flavors), magnesium stearate, microcrystalline cellulose, silicon dioxide, tartaric acid, and xylitol. Colorants include ferric oxide (yellow or red) and FD&C Blue No. 2 Aluminum Lake.
ABILIFY Oral Solution is a clear, colorless to light-yellow solution available in a concentration of 1 mg/mL. The inactive ingredients for this solution include disodium edetate, fructose, glycerin, dl-lactic acid, methylparaben, propylene glycol, propylparaben, sodium hydroxide, sucrose, and purified water. The oral solution is flavored with natural orange cream and other natural flavors.
ABILIFY Injection is available in single-dose vials as a ready-to-use, 9.75 mg/1.3 mL (7.5 mg/mL) clear, colorless, sterile, aqueous solution for intramuscular use only. Inactive ingredients for this solution include 199.5 mg of sulfobutylether β-cyclodextrin (SBECD), 10.4 mg of tartaric acid, q.s. to pH 4.3 of sodium hydroxide, and q.s. to 1.33 mL of water for injection.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of aripiprazole in schizophrenia or bipolar mania, is unclear. However, the efficacy of aripiprazole in the listed indications could be mediated through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors.
Aripiprazole exhibits high affinity for dopamine D2 and D3 , serotonin 5-HT1A and 5-HT2A receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, 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 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki =98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC50 >1000 nM).
ABILIFY 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 is dose-proportional. Elimination of aripiprazole is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4. For CYP2D6 poor metabolizers, the mean elimination half-life for aripiprazole is about 146 hours.
Pharmacokinetic studies showed that ABILIFY DISCMELT Orally Disintegrating Tablets are bioequivalent to ABILIFY Tablets.
Tablet: Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within 3 hours to 5 hours; the absolute oral bioavailability of the tablet formulation is 87%. ABILIFY can be administered with or without food. Administration of a 15 mg ABILIFY 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.
Oral Solution: Aripiprazole is well absorbed when administered orally as the solution. At equivalent doses, the plasma concentrations of aripiprazole from the solution were higher than that from the tablet formulation. In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole as the oral solution to 30 mg aripiprazole tablets in healthy subjects, the solution to tablet ratios of geometric mean Cmax and AUC values were 122% and 114%, respectively [see Dosage and Administration (2.6)]. The single-dose pharmacokinetics of aripiprazole were linear and dose-proportional between the doses of 5 mg to 30 mg.
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.
Aripiprazole is metabolized primarily by three 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, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma.
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.
Drug Interaction Studies
Effect of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure 1 and Figure 2, respectively. Based on simulation, a 4.5 fold increase in mean Cmax and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. A 3 fold increase in mean Cmax and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors.
Figure 1: The Effect of Other Drugs on Aripiprazole Pharmacokinetics
Figure 2: The Effect of Other Drugs on Dehydro-Aripiprazole Pharmacokinetics
The effect of ABILIFY on the exposures of other drugs are summarized in Figure 3. A population PK analysis in patients with major depressive disorder showed no substantial change in plasma concentrations of fluoxetine (20 or 40 mg/day), paroxetine CR (37.5 or 50 mg/day), or sertraline (100 or 150 mg/day) dosed to steady-state. The steady-state plasma concentrations of fluoxetine and norfluoxetine increased by about 18% and 36%, respectively, and concentrations of paroxetine decreased by about 27%. The steady-state plasma concentrations of sertraline and desmethylsertraline were not substantially changed when these antidepressant therapies were coadministered with aripiprazole.
Figure 3: The Effect of ABILIFY on Pharmacokinetics of Other Drugs
Exposure of aripiprazole and dehydro-aripiprazole in specific populations are summarized in Figure 4 and Figure 5, respectively. In addition, in pediatric patients (10 to 17 years of age) administered with ABILIFY (20 mg to 30 mg), the body weight corrected aripiprazole clearance was similar to the adults.
Figure 4: Effect of Intrinsic Factors on Aripiprazole Pharmacokinetics
Figure 5: Effect of Intrinsic Factors on Dehydro-Aripiprazole Pharmacokinetics
In two pharmacokinetic studies of aripiprazole injection administered intramuscularly to healthy subjects, the median times to the peak plasma concentrations were at 1 hour and 3 hours. A 5 mg intramuscular injection of aripiprazole had an absolute bioavailability of 100%. The geometric mean maximum concentration achieved after an intramuscular dose was on average 19% higher than the Cmax of the oral tablet. While the systemic exposure over 24 hours was generally similar between aripiprazole injection given intramuscularly and after oral tablet administration, the aripiprazole AUC in the first 2 hours after an intramuscular injection was 90% greater than the AUC after the same dose as a tablet. In stable patients with schizophrenia or schizoaffective disorder, the pharmacokinetics of aripiprazole after intramuscular administration were linear over a dose range of 1 mg to 45 mg. Although the metabolism of aripiprazole injection was not systematically evaluated, the intramuscular route of administration would not be expected to alter the metabolic pathways.
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