ARIPIPRAZOLE
Clinical safety rating: safe
Animal studies have demonstrated safety
Partial agonist at D2 and 5-HT1A receptors; antagonist at 5-HT2A receptors.
| Metabolism | Primarily hepatic via CYP2D6 and CYP3A4. |
| Excretion | Aripiprazole is extensively metabolized primarily by the liver via CYP2D6 and CYP3A4. Approximately 25% of the dose is excreted unchanged in urine, and about 55% in feces. The major metabolite, dehydro-aripiprazole, accounts for about 40% of the AUC and is also excreted in urine and feces. |
| Half-life | Aripiprazole has a terminal elimination half-life of approximately 75 hours in extensive CYP2D6 metabolizers and about 146 hours in poor metabolizers. The active metabolite, dehydro-aripiprazole, has a half-life of about 94 hours. This long half-life allows for once-daily dosing and gradual achievement of steady state (14 days in extensive metabolizers). |
| Protein binding | Aripiprazole is >99% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. High protein binding means that changes in protein levels (e.g., hypoalbuminemia) can affect free drug concentration. |
| Volume of Distribution | The volume of distribution (Vd) for aripiprazole is approximately 4.9 L/kg, indicating extensive tissue distribution (well beyond total body water). This large Vd suggests significant partitioning into tissues, which contributes to the long half-life. |
| Bioavailability | Oral: The absolute bioavailability of aripiprazole tablets is approximately 87%. Bioavailability is not significantly affected by food. Intramuscular immediate-release: Bioavailability is 100% for the IM formulation relative to oral. The long-acting injectable (aripiprazole lauroxil) has a bioavailability of about 100% compared to oral aripiprazole after reaching steady state. |
| Onset of Action | Oral: Therapeutic effects on positive and negative symptoms of schizophrenia may be seen within 1-2 weeks, but full response may take several weeks. Intramuscular (IM) immediate-release: Onset of agitation relief occurs within 30-60 minutes. Oral long-acting injectable (aripiprazole lauroxil): Not applicable for immediate onset; steady state achieved after several injections. |
| Duration of Action | Oral: With once-daily dosing, steady-state concentrations are maintained over 24 hours due to long half-life. The clinical effect persists for the entire dosing interval. IM immediate-release: A single dose provides symptom relief for about 24 hours. Long-acting injectable: Aripiprazole lauroxil provides therapeutic levels for 4-6 weeks per injection. |
Oral: 10-15 mg once daily; initial and target dose 10-15 mg; maximum 30 mg/day. IM: 9.75 mg single dose, then 5.25-9.75 mg every 2 hours if needed; maximum 30 mg/day.
| Dosage form | TABLET, ORALLY DISINTEGRATING |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥15 mL/min). For severe renal impairment (CrCl <15 mL/min), use with caution; limited data suggests no adjustment needed, but monitor tolerability. |
| Liver impairment | Child-Pugh Class A (mild): no adjustment. Child-Pugh Class B (moderate): start at 10 mg/day; titrate cautiously. Child-Pugh Class C (severe): avoid use; if unavoidable, start at 5 mg/day and titrate slowly. |
| Pediatric use | Schizophrenia (≥13 years): 10-15 mg/day initially; target 15 mg/day; max 30 mg/day. Irritability associated with autistic disorder (6-17 years): 5-10 mg/day; start at 2.5 mg/day for ≥30 kg and 5 mg/day for <30 kg; titrate gradually. Tourette's disorder (6-18 years): 5-10 mg/day; start at 2.5 mg/day for <50 kg and 5 mg/day for ≥50 kg; max 10 mg/day. |
| Geriatric use | Initiate at 10 mg/day; titrate slowly due to increased sensitivity and risk of hypotension, sedation, and extrapyramidal symptoms. Maximum 15 mg/day in elderly patients with psychosis. Consider lower initial doses (2-5 mg/day) in frail patients. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP3A4 inhibitors (eg ketoconazole) or inducers (eg carbamazepine) require dose adjustment May cause suicidal thoughts and metabolic changes including weight gain and dyslipidemia.
| Breastfeeding | Aripiprazole is excreted into breast milk; estimated relative infant dose is 1-8% of maternal weight-adjusted dose. M/P ratio not established. Monitor infant for sedation, poor feeding, and extrapyramidal symptoms. Consider benefits of breastfeeding vs. potential risks. |
| Teratogenic Risk | First trimester: Limited human data; animal studies show no teratogenicity at therapeutic doses, but increased risk of neural tube defects at high doses. Second/third trimesters: Possible risk of extrapyramidal symptoms or withdrawal in neonates; risk of gestational diabetes and weight gain. Overall, not a major human teratogen but risk-benefit assessment required. |
■ FDA Black Box Warning
Increased risk of death in elderly patients with dementia-related psychosis.
| Common Effects | Akathisia inability to stay still Anxiety Blurred vision Constipation Dizziness Fatigue Headache Increased saliva production Indigestion Insomnia difficulty in sleeping Nausea Parkinsonism Restlessness Sleepiness Tremors Vomiting |
| Serious Effects |
Hypersensitivity to aripiprazole or any components of the formulation.
| Precautions | Increased risk of cerebrovascular events in elderly with dementia, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes (hyperglycemia, dyslipidemia, weight gain), orthostatic hypotension, leukopenia/neutropenia, seizures, cognitive and motor impairment, and body temperature dysregulation. |
| Food/Dietary |
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| Fetal Monitoring | Maternal: Weight, blood pressure, blood glucose, lipid profile, and signs of extrapyramidal symptoms. Fetal: Ultrasound for growth and anatomy; neonatal monitoring for extrapyramidal symptoms, sedation, or withdrawal after delivery. |
| Fertility Effects | May cause hyperprolactinemia leading to menstrual irregularities, galactorrhea, and reduced fertility due to dopamine D2 receptor antagonism. However, effects are variable and dose-dependent. |
| No significant food interactions. Absorption unaffected by food. Avoid grapefruit juice as it may increase aripiprazole levels via CYP3A4 inhibition. |
| Clinical Pearls | Aripiprazole is a partial dopamine agonist, distinguishing it from typical antipsychotics. Monitor for akathisia, especially during titration. QT prolongation risk is lower than with other antipsychotics, but ECG is recommended in patients with cardiac risk. Tardive dyskinesia risk exists but may be lower than with typical agents. Avoid abrupt discontinuation to prevent withdrawal dyskinesias. Metabolized by CYP2D6 and CYP3A4; dose adjustments needed with CYP2D6 inhibitors or poor metabolizers. May cause orthostatic hypotension; titrate slowly. Weight gain and metabolic effects are less pronounced than with olanzapine or clozapine, but still monitor weight, lipids, and glucose. |
| Patient Advice | Take once daily without regard to meals. Swallow tablets whole, do not crush or chew. · May cause dizziness or drowsiness, especially when starting; avoid driving until you know how it affects you. · Do not stop taking suddenly without consulting your doctor, as this may cause withdrawal symptoms. · Report any restlessness, muscle stiffness, fever, or unusual movements to your doctor immediately. · Limit alcohol intake as it can increase side effects like drowsiness. · Inform your doctor of all medications you take, including over-the-counter drugs and supplements. · If you miss a dose, take it as soon as you remember unless it is almost time for the next dose; do not double up. · Regular blood tests may be needed to check for effects on blood sugar and cholesterol. |