If signs and symptoms of tardive dyskinesia appear in a patient on lurasidone hydrochloride, drug discontinuation should be considered. However, some patients may require treatment with lurasidone hydrochloride despite the presence of the syndrome.
Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
Hyperglycemia and Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse events in patients treated with the atypical antipsychotics.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Data from the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study are presented in Table 4.
Table 4: Change in Fasting Glucose in the Adult Monotherapy Bipolar Depression Study
In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride as monotherapy in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.2 mg/dL at week 24 (n=129).
Adjunctive Therapy with Lithium or Valproate
Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 5.
Table 5: Change in Fasting Glucose in the Adult Adjunctive Therapy Bipolar Depression Studies
In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.7 mg/dL at week 24 (n=88).
Pediatric Patients (10 to 17 years)
In studies of pediatric patients 10 to 17 years and adults with bipolar depression, changes in fasting glucose were similar. In the 6-week, placebo-controlled study of pediatric patients with bipolar depression, mean change in fasting glucose was +1.6 mg/dL for lurasidone hydrochloride 20 to 80 mg/day (n=145) and -0.5 mg/dL for placebo (n=145).
Pediatric Patients (6 to 17 years)
In a 104-week, open-label study in pediatric patients with bipolar depression, autistic disorder, or another indication, 7 % of patients with a normal baseline fasting glucose experienced a shift to high at endpoint while taking lurasidone.
Dyslipidemia
Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
Data from the adult short-term, flexible-dosed, placebo-controlled, monotherapy bipolar depression study are presented in Table 7.
Table 7: Change in Fasting Lipids in the Adult Monotherapy Bipolar Depression Study
In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride as monotherapy in the short-term and continued in the longer-term study had a mean change in total cholesterol and triglycerides of -0.5 mg/dL (n=130) and -1.0 mg/dL (n=130) at week 24, respectively.
Adjunctive Therapy with Lithium or Valproate
Data from the adult short-term, flexible-dosed, placebo-controlled, adjunctive therapy bipolar depression studies are presented in Table 8.
Table 8: Change in Fasting Lipids in the Adult Adjunctive Therapy Bipolar Depression Studies
In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride, as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in total cholesterol and triglycerides of -0.9 (n=88) and +5.3 (n=88) mg/dL at week 24, respectively.
Pediatric Patients (10 to 17 years)
In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, mean change in fasting cholesterol was -6.3 mg/dL for lurasidone hydrochloride 20 to 80 mg/day (n=144) and -1.4 mg/dL for placebo (n=145), and mean change in fasting triglyceride was -7.6 mg/dL for lurasidone hydrochloride 20 to 80 mg/day (n=144) and +5.9 mg/dL for placebo (n=145).
Pediatric Patients (6 to 17 years)
In a 104-week, open-label study of pediatric patients with bipolar depression, autistic disorder, or another indication, shifts in baseline fasting cholesterol from normal to high at endpoint were reported in 12% (total cholesterol), 3% (LDL cholesterol), and shifts in baseline from normal to low were reported in 27% (HDL cholesterol) of patients taking lurasidone. Of patients with normal baseline fasting triglycerides, 12% experienced shifts to high.
Weight Gain
Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
Data from the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 11. The mean change in weight gain was +0.29 kg for lurasidone hydrochloride-treated patients compared to -0.04 kg for placebo-treated patients. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 2.4% for lurasidone hydrochloride-treated patients and 0.7% for placebo-treated patients.
Table 11: Mean Change in Weight (kg) from Baseline in the Adult Monotherapy Bipolar Depression Study
In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride as monotherapy in the short-term and continued in the longer-term study had a mean change in weight of -0.02 kg at week 24 (n=130).
Adjunctive Therapy with Lithium or Valproate
Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 12. The mean change in weight gain was +0.11 kg for lurasidone hydrochloride-treated patients compared to +0.16 kg for placebo-treated patients. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 3.1% for lurasidone hydrochloride-treated patients and 0.3% for placebo-treated patients.
Table 12: Mean Change in Weight (kg) from Baseline in the Adult Adjunctive Therapy Bipolar Depression Studies
In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with lurasidone hydrochloride, as adjunctive therapy with either lithium or valproate in the short-term and continued in the longer-term study, had a mean change in weight of +1.28 kg at week 24 (n=86).
Pediatric Patients (10 to 17 years)
Data from the 6-week, placebo-controlled bipolar depression study in patients 10 to 17 years are presented in Table 13. The mean change in weight gain was +0.7 kg for lurasidone hydrochloride-treated patients compared to +0.5 kg for placebo-treated patients. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 4.0% for lurasidone hydrochloride-treated patients and 5.3% for placebo-treated patients.
Table 13: Mean Change in Weight (kg) from Baseline in the Bipolar Depression Study in Pediatric Patients (10 to 17 years)
Pediatric Patients (6 to 17 years)
In a long-term, open-label study that enrolled pediatric patients with bipolar depression, autistic disorder or another indication, from three short-term, placebo-controlled trials, 54% (378/701) received lurasidone for 104 weeks. The mean increase in weight from open-label baseline to Week 104 was 5.85 kg. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of children and adolescents by comparisons to age- and sex-matched population standards. A z-score change < 0.5 SD is considered not clinically significant. In this trial, the mean change in z-score from open-label baseline to Week 104 was -0.06 SD for body weight and -0.13 SD for body mass index (BMI), indicating minimal deviation from the normal curve for weight gain.