What safety concerns and monitoring requirements should be considered when prescribing Vraylar (cariprazine)?

Safety Concerns When Prescribing Vraylar (Cariprazine)

Exercise extreme caution with Vraylar in elderly patients with dementia-related psychosis, as it carries a black box warning for increased mortality risk and is not approved for this population. 1

Critical Black Box Warnings

Increased Mortality in Elderly with Dementia

• Vraylar is contraindicated in elderly patients with dementia-related psychosis due to increased risk of death 1
• Elderly patients with dementia taking atypical antipsychotics like cariprazine have higher incidence of stroke and transient ischemic attacks, including fatal stroke 1

Suicidal Thoughts and Behaviors

• Monitor closely for emergence of suicidal thoughts and behaviors, especially during initial treatment and dose adjustments 1
• Risk is particularly elevated in children and young adults within the first few months of treatment 1
• Advise patients and caregivers to report any new or sudden changes in mood, behavior, thoughts, or feelings immediately 1

Movement Disorders and Neurological Risks

Akathisia (Most Common Adverse Effect)

• Akathisia occurs in 14.6% of patients and is the most frequently reported adverse event 2
• Most cases are mild to moderate (97.5%), with >93% of patients remaining on treatment 2
• Manage with rescue medications (56.3% of cases) or dose reduction (18.3%) 2
• Monitor for akathisia continuously, as it can emerge several weeks after treatment initiation 1

Tardive Dyskinesia

• Prescribe at the lowest effective dose for the shortest duration to minimize risk of potentially irreversible tardive dyskinesia 1
• Risk is highest in elderly women but can occur in any patient 1
• Periodically reassess the need for continued treatment 1
• Consider drug discontinuation if signs of tardive dyskinesia appear, though some patients may require continued treatment despite symptoms 1

Neuroleptic Malignant Syndrome (NMS)

• Immediately discontinue Vraylar if NMS is suspected (hyperpyrexia, muscle rigidity, delirium, autonomic instability) 1
• This potentially fatal syndrome requires intensive symptomatic treatment and monitoring 1

Delayed Adverse Reactions

A critical pitfall is assuming early tolerability predicts long-term safety—adverse reactions may not appear until several weeks after initiation due to accumulation of cariprazine and its metabolites 1

• Monitor patients for several weeks after starting treatment and after each dose increase 1
• Plasma levels accumulate over time because cariprazine has active metabolites with long half-lives (didesmethyl-cariprazine half-life substantially exceeds parent drug) 3, 4
• Short-term trial data may not reflect rates of adverse reactions after longer-term exposure 1

Metabolic Monitoring Requirements

Hyperglycemia and Diabetes

• Assess fasting plasma glucose before or soon after initiation and monitor periodically during long-term treatment 1
• In long-term studies, 4-7% of patients with normal baseline hemoglobin A1c developed elevated levels (≥6.5% or >6%) 1
• Extreme hyperglycemia associated with ketoacidosis, hyperosmolar coma, or death has been reported with atypical antipsychotics 1

Weight Gain

• Mean weight gain is approximately 1 kg with cariprazine 2, 5
• Weight increased as an adverse event occurs in 5.1% of patients 2
• About 8% of patients gain ≥7% body weight (compared to 5% with placebo) 4
• Monitor weight regularly throughout treatment 1

Lipid Profile

• Monitor lipids periodically, though cariprazine demonstrates a generally neutral metabolic profile 2, 4

Hematologic Monitoring

Leukopenia/Neutropenia

• Patients with pre-existing low white blood cell count or history of drug-induced leukopenia/neutropenia require complete blood count monitoring 1
• Consider discontinuing Vraylar at first sign of clinically significant decline in WBC in absence of other causative factors 1

Cardiovascular Precautions

Orthostatic Hypotension and Syncope

• Risk is highest early in treatment, during re-initiation, or with dose increases 1
• Use caution in patients with cardiovascular disease, cerebrovascular disease, or conditions predisposing to hypotension 1

QT Prolongation

• QT prolongation occurs at ≤1% incidence 2
• No clinically meaningful ECG alterations have been observed in clinical trials 4

Drug Interactions

CYP3A4 Interactions (Critical)

• Cariprazine is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6 3, 4
• Strong CYP3A4 inhibitors require dose reduction of Vraylar 1
• Strong CYP3A4 inducers may reduce cariprazine efficacy 1
• Avoid grapefruit juice, which inhibits CYP3A4 1

Special Populations

Pregnancy and Lactation

• Third trimester use may cause extrapyramidal and/or withdrawal symptoms in neonates 1
• Advise patients to notify healthcare provider of known or suspected pregnancy 1
• Pregnancy exposure registry available for monitoring outcomes 1

Elderly Patients

• Beyond the dementia contraindication, use lower doses and monitor more closely for adverse effects 1

Hepatic and Renal Impairment

• Dose adjustments may be necessary based on severity of impairment 1

Common Adverse Events Requiring Monitoring

Beyond akathisia, the most common adverse events (>10%) include:

• Insomnia (14.0%) 2
• Headache (12.1%) 2
• Extrapyramidal symptoms (7.0%) 2
• Sedation (3.7%) and somnolence (3.1%) 2

Most adverse events are mild (71.0%) or moderate (26.5%) in severity 2

Cognitive and Motor Impairment

• Caution patients against operating hazardous machinery or motor vehicles until they know how Vraylar affects them 1
• Assess for interference with cognitive and motor performance 1

Heat Exposure and Dehydration

• Educate patients on avoiding overheating and dehydration, as antipsychotics can impair temperature regulation 1

Dosing Considerations for Safety

• Start at 1.5 mg/day, which is potentially therapeutic, rather than escalating unnecessarily 4
• Recommended dose range is 1.5-6 mg/day for schizophrenia 4
• Due to long half-life of metabolites, allow adequate time between dose adjustments 1