Cariprazine

Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low white blood cell count (WBC)/absolute neutrophil count (ANC) or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count 3.

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

Has been reported with atypical antipsychotics; risk profile may differ between agents. In clinical trials, lipid changes observed with cariprazine monotherapy were similar to those observed with placebo.

Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk for aspiration pneumonia (eg, Alzheimer dementia) (Maddalena 2004).

May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics; frequencies reported are similar to placebo). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Lehman 2004]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.

May increase the risk for falls due to somnolence, orthostatic hypotension and motor or sensory instability. Complete fall risk assessments at baseline and periodically during treatment in patients with diseases, conditions, or on medications that may also increase fall risk.

Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. All patients should be monitored for symptoms of hyperglycemia (eg, polydipsia, polyuria, polyphagia, weakness). Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control.

Use may be associated with neuroleptic malignant syndrome (NMS); monitor for mental status changes, fever, muscle rigidity, autonomic instability, increased creatine phosphokinase, rhabdomyolysis, and/or acute renal failure. If NMS is suspected, discontinue immediately, provide symptomatic treatment, and monitor patient. NMS can recur. Following recovery from NMS, reintroduction of drug therapy should be carefully considered; if an antipsychotic agent is resumed, monitor closely for NMS (APA [Lehman 2004]).

May cause orthostatic hypotension; risk is increased at initial dose titration and when increasing the dose. Use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (patients who are antipsychotic-naive or have cerebrovascular disease, cardiovascular disease, hypovolemia, dehydration, or are taking concurrent medication use which may predispose to hypotension/bradycardia). Consider using lower starting dosages and slower titrations in these patients.

Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.

Significant weight gain (>7% of baseline weight) has been observed with antipsychotic therapy; incidence varies with product. Monitor waist circumference and BMI. Disease-related concerns:

Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death. (APA [Reus 2016]). Cariprazine is not approved for the treatment of dementia-related psychosis.

Use with caution in patients with Parkinson disease; antipsychotics may aggravate motor disturbances (APA [Lehman 2004; Reus 2016]).

Use with caution in patients at risk of seizures or with conditions that potentially lower the seizure threshold. Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Other warnings/precautions:

When discontinuing antipsychotic therapy, the American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid physical withdrawal symptoms, including anorexia, anxiety, diaphoresis, diarrhea, dizziness, dyskinesia, headache, myalgia, nausea, paresthesia, restlessness, tremulousness, and vomiting (APA [Lehman 2004]; CPA [Addington 2005]; Lambert 2007; WFSBP [Hasan 2012]). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anti-cholinergic or dopaminergic antipsychotics (Cerovecki 2013). Additional factors such as duration of antipsychotic exposure, the indication for use, medication half-life, and risk for relapse should be considered. In schizophrenia, there is no reliable indicator to differentiate the minority who will not from the majority who will relapse with drug discontinuation. However, studies in which the medication of well-stabilized patients were discontinued indicate that 75% of patients relapse within 6 to 24 months. Indefinite maintenance antipsychotic medication is generally recommended, and especially for patients who have had multiple prior episodes or 2 episodes within 5 years (APA [Lehman 2004]).

Plasma levels of cariprazine and its major metabolites accumulate over time. Adverse reactions may not appear until several weeks after initiation of treatment. Monitor response and for adverse reactions several weeks after the patient has begun treatment and after each dose increase. With treatment discontinuation the plasma concentration of cariprazine and active metabolites declines by 50% in ~1 week; therefore, the decline of plasma concentrations of active drug and metabolite may not be immediately reflected in the patient's clinical symptoms.