Cariprazine

Cariprazine is an atypical antipsychotic agent. The precise mechanism of action is unknown, but efficacy is thought to be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors. Cariprazine forms two major metabolites, desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR), which have in vitro receptor binding profiles similar to the parent drug.

Cariprazine is indicated for schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder, bipolar depression, and as adjunctive therapy to antidepressants for major depressive disorder (MDD) in adults.

• Schizophrenia in adults
• Acute treatment of manic or mixed episodes associated with bipolar I disorder
• Depressive episodes associated with bipolar I disorder (bipolar depression)
• Adjunctive therapy to antidepressants for major depressive disorder (MDD)

Schizophrenia:
Starting dose: 1.5 mg once daily. May be increased to 3 mg/day on Day 2. Further adjustments in 1.5-3 mg increments based on clinical response and tolerability. Dosage range: 1.5-6 mg/day. Maximum: 6 mg/day. Doses above 6 mg/day do not confer increased effectiveness.

Bipolar I Disorder (Manic/Mixed Episodes):
Starting dose: 1.5 mg/day; increase to 3 mg/day on Day 2. Dosage range: 3-6 mg/day. Maximum: 6 mg/day.

Bipolar Depression:
Starting dose: 1.5 mg/day. May be increased to 3 mg/day on Day 15 based on clinical response and tolerability. Maximum: 3 mg/day.

MDD (Adjunctive Therapy):
Starting dose: 1.5 mg/day. May be increased to 3 mg/day on Day 15. Clinical trials showed higher adverse reaction incidence with titration intervals <14 days. Maximum: 3 mg/day.

Hepatic impairment: Mild-moderate (Child-Pugh 5-9): No adjustment; Severe (Child-Pugh 10-15): Not recommended.

Renal impairment: Mild-moderate (CrCl ≥30 mL/min): No adjustment; Severe (CrCl <30 mL/min): Not recommended (safety and efficacy not established).

Note: Due to the long half-life of cariprazine and its active metabolites, changes in dose will not be fully reflected in plasma for several weeks. Monitor for several weeks after starting and after each dosage change.

Schizophrenia (>10%): Extrapyramidal symptoms (24-33%), Parkinsonism (13-18%), Headache (9-18%), Akathisia (9-14%), Insomnia (11-13%).

Schizophrenia (1-10%): Constipation (6-10%), Somnolence (5-10%), Nausea (5-8%), Abdominal pain (3-7%), Restlessness (4-6%), Anxiety (3-6%), Toothache (3-6%), Hypertension (2-6%), Dyspepsia (4-5%), Vomiting (4-5%), Dizziness (3-5%), Agitation (3-5%), Diarrhea (1-5%), Pain in extremity (2-4%), Cough (1-4%), Tachycardia (2-3%), Weight increased (2-3%), Decreased appetite (1-3%), Dry mouth (1-3%), Fatigue (1-3%), Increased CPK (1-3%), Musculoskeletal stiffness (1-3%), Back pain (1-3%), Dystonia (2%), Arthralgia (1-2%), Increased LFTs (1-2%), Nasopharyngitis (1-2%), Urinary tract infections (1-2%), Rash (1-2%).

Bipolar Disorder (>10%): Extrapyramidal symptoms (41-45%), Parkinsonism (21-26%), Akathisia (20-21%), Headache (13-14%), Nausea (11-13%), Constipation (6-11%).

Bipolar Disorder (1-10%): Vomiting (8-10%), Insomnia (8-9%), Dyspepsia (7-9%), Somnolence (7-8%), Abdominal pain (6-8%), Restlessness (7%), Dizziness (6-7%), Diarrhea (5-6%), Hypertension (4-5%), Fatigue (4-5%), Dystonia (3-5%), Blurred vision (4%), Decreased appetite (3-4%), Toothache (3-4%), Pain in extremity (2-4%), Pyrexia (1-4%), Weight increased (2-3%), Increased CPK (2-3%), Dry mouth (2-3%), Oropharyngeal pain (1-3%), Back pain (1-3%), Increased LFTs (1-3%), Musculoskeletal stiffness (2%).

MDD (Adjunctive): Akathisia, restlessness, fatigue, constipation, nausea, insomnia, increased appetite, dizziness, extrapyramidal symptoms.

Serious (rare): Neuroleptic malignant syndrome (NMS), tardive dyskinesia, seizures, orthostatic hypotension, syncope, leukopenia, neutropenia, agranulocytosis, angioedema.

• Antipsychotic drugs increase the all-cause risk of death in elderly patients with dementia-related psychosis; higher incidence of stroke and TIA observed (Black Box Warning).
• Hypersensitivity reactions (rash, pruritus, urticaria, angioedema - swollen tongue/lip, facial/pharyngeal edema) may occur.
• Neuroleptic malignant syndrome (NMS): Monitor for hyperpyrexia, muscle rigidity, delirium, autonomic instability; increased CPK, myoglobinuria (rhabdomyolysis), acute renal failure may occur; if NMS suspected, immediately discontinue treatment.
• Tardive dyskinesia: Potentially irreversible, involuntary dyskinetic movements may develop in patients treated with antipsychotics.
• Seizures: Risk is greatest with history of seizures or conditions that lower seizure threshold.
• Cognitive and motor impairment: May cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and fractures.
• Metabolic changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain.
• Leukopenia, neutropenia, agranulocytosis: Monitor CBC in patients with pre-existing low WBC or history; consider discontinuation if clinically significant WBC decline occurs.
• Neonates exposed to antipsychotics during third trimester are at risk for extrapyramidal and withdrawal symptoms.
• Use caution when operating machinery (may cause cognitive and motor impairment).

• History of hypersensitivity to cariprazine (reactions include rash, pruritus, urticaria, angioedema - swollen tongue/lip, facial edema, pharyngeal edema)

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin): Increase cariprazine and its active metabolite DDCAR exposure; reduce dose by half.
• CYP3A4 inducers (rifampin, carbamazepine, phenytoin): May decrease cariprazine levels; concomitant use is not recommended.