CARIPRAZINE HYDROCHLORIDE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for CARIPRAZINE HYDROCHLORIDE (CARIPRAZINE HYDROCHLORIDE).
Cariprazine is a partial agonist at dopamine D3 and D2 receptors, with higher affinity for D3 receptors, and a partial agonist at serotonin 5-HT1A receptors; it is an antagonist at 5-HT2A and 5-HT2B receptors.
| Metabolism | Primarily metabolized by CYP3A4 and CYP2D6 to active metabolites (desmethylcariprazine and didesmethylcariprazine). |
| Excretion | Primarily hepatic metabolism via CYP3A4 and CYP2D6, with 60% excreted in feces (mostly as metabolites) and 30% in urine (mostly as metabolites). Less than 1% excreted unchanged. |
| Half-life | Terminal elimination half-life: 2–5 days (48–120 hours) for cariprazine and its major active metabolites (desmethylcariprazine, didesmethylcariprazine). The long half-life supports once-daily dosing and allows for gradual dose titration. |
| Protein binding | Approximately 91–97% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution (Vd) is approximately 9 L/kg, indicating extensive extravascular distribution. |
| Bioavailability | Oral bioavailability: Estimated to be high due to good absorption, though absolute bioavailability not determined; peak plasma concentrations reached in 3–6 hours post-dose. Food (high-fat meal) does not significantly affect AUC or Cmax of cariprazine. |
| Onset of Action | Oral administration: Onset of antipsychotic effect typically within 1–2 weeks, with full therapeutic effect often requiring 3–6 weeks due to slow dose titration and accumulation of active metabolites. |
| Duration of Action | Single oral dose: Antipsychotic effects persist for at least 24 hours due to the long half-lives of parent drug and its active metabolites, allowing once-daily dosing. Therapeutically, steady state is reached after 2–3 weeks. |
| Molecular Weight | 461.47 |
| Action Class | Atypical Antipsychotic |
1.5 mg orally once daily, with a recommended titration starting at 1.5 mg on day 1, increased to 3 mg on day 2, then 4.5 mg on day 3, and 6 mg on day 4; target dose range: 1.5–6 mg once daily, with a maximum of 6 mg/day.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for GFR ≥30 mL/min/1.73 m2. For GFR <30 mL/min/1.73 m2 or end-stage renal disease, use is not recommended due to lack of data. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: maximum recommended dose is 3 mg once daily. Child-Pugh Class C: use is not recommended. |
| Pediatric use | Safety and efficacy in pediatric patients (<18 years) have not been established; no specific dosing recommendations available. |
| Geriatric use | No specific dose adjustment required; however, elderly patients may be more sensitive to adverse effects (e.g., orthostatic hypotension, somnolence). Initiate at lower end of dosing range and titrate slowly. |
| 1st trimester | Insufficient human data; animal studies show developmental toxicity. Use only if potential benefit justifies risk to fetus. Consider alternative agents with more established safety profiles. |
| 2nd trimester | Insufficient human data; animal studies show developmental toxicity. Use only if potential benefit justifies risk to fetus. Consider alternative agents with more established safety profiles. |
| 3rd trimester | Insufficient human data; animal studies show developmental toxicity. Potential risk of extrapyramidal symptoms and/or withdrawal symptoms in neonates following exposure during third trimester. Use only if potential benefit justifies risk. |
Clinical note
Comprehensive clinical and safety monograph for CARIPRAZINE HYDROCHLORIDE (CARIPRAZINE HYDROCHLORIDE).
| Placental transfer | Cariprazine and its active metabolites are expected to cross the placenta due to molecular weight <500 Da, but no direct human placental transfer studies available. |
| Breastfeeding |
■ FDA Black Box Warning
Increased mortality in elderly patients with dementia-related psychosis.
| Common Effects | Akathisia, Somnolence, Sedation, Extrapyramidal symptoms (EPS), Nausea, Vomiting, Constipation, Dizziness, Fatigue, Increased appetite, Weight gain, Dry mouth, Insomnia, Anxiety |
| Serious Effects | Neuroleptic Malignant Syndrome (NMS), Tardive Dyskinesia, Increased mortality in elderly patients with dementia-related psychosis, Suicidal thoughts or behaviors, Seizures, Leukopenia, neutropenia, agranulocytosis, Orthostatic hypotension and syncope, QT prolongation, Hyperglycemia and diabetes mellitus, Dyslipidemia, Weight gain |
Hypersensitivity to cariprazine or any component of the formulation
| Precautions | Increased mortality in elderly patients with dementia-related psychosis, Suicidal thoughts and behaviors, Neuroleptic malignant syndrome (NMS), Tardive dyskinesia, Metabolic changes (hyperglycemia, dyslipidemia, weight gain), Leukopenia, neutropenia, agranulocytosis, Orthostatic hypotension and syncope, Seizures, Body temperature dysregulation, Dysphagia, Cognitive and motor impairment |
Loading safety data…
| Cariprazine is excreted into animal milk; no human data. Since small molecular weight and long half-life, monitor infant for sedation, irritability, and feeding problems. Consider alternative agents if possible. |
| Lactation Rating | L4 (Limited Data - Possibly Hazardous) |
| Teratogenic Risk | Limited human data; first trimester: insufficient evidence for major malformations; second/third trimester: risk of extrapyramidal symptoms (EPS) and neonatal withdrawal (e.g., agitation, hypertonia, tremors) with late-gestation exposure. Animal studies show no teratogenicity at clinically relevant doses. |
| Fetal Monitoring | Monitor maternal for EPS, akathisia, metabolic changes (weight, glucose, lipids); fetal/neonatal: monitor for EPS, withdrawal (lethargy, feeding difficulty, hypertonia), and adverse pregnancy outcomes (e.g., preterm birth, low birth weight). Consider therapeutic drug monitoring if available. |
| Fertility Effects | Animal studies show no significant impairment of fertility; however, hyperprolactinemia (dose-dependent) may occur, potentially affecting menstrual cycle and fertility in females. Human data limited. |
| Food/Dietary | Avoid grapefruit juice as it may increase cariprazine exposure. No other significant food interactions; administer with or without food. However, high-fat meals may slightly reduce absorption, but no dose adjustment is needed. |
| Clinical Pearls | Cariprazine hydrochloride is a dopamine D3-preferring D2/D3 receptor partial agonist, which may confer advantages in negative symptoms and cognitive deficits of schizophrenia. Titrate slowly to minimize akathisia and restlessness; initial dose 1.5 mg/day, increase by 1.5 mg increments. Monitor for orthostatic hypotension, especially early in treatment. Avoid use in patients with dementia-related psychosis due to increased mortality risk. |
| Patient Advice | Take this medication exactly as prescribed; do not change dose without consulting your doctor. · You may experience dizziness or lightheadedness upon standing; rise slowly from sitting or lying positions. · Notify your doctor immediately if you develop uncontrollable muscle movements, especially of the face, tongue, or jaw. · Avoid alcohol and grapefruit juice while taking this medication. · If you become pregnant or plan to become pregnant, inform your doctor; this medication may cause extrapyramidal symptoms in the newborn. · Do not drive or operate heavy machinery until you know how this drug affects you; it may cause drowsiness or dizziness. |