February 28, 2017
Recommended Topic Related To:

Latuda

"July 10, 2015 -- People with schizophrenia are three times more likely to smoke than those who don't have the mental health condition, a study published in Lancet Psychiatry says.

Experts at King's College London say that although li"...

A A A

Latuda




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Increased Mortality In Elderly Patients With Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6-to 1.7-times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. LATUDA is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING].

Suicidal Thoughts And Behaviors In Children, Adolescents And Young Adults

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in patients aged 24 years and younger was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.

No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide.

Table 2: Risk Differences of the Number of Patients with Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients

Age Range (years) Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated
Increases Compared to Placebo
< 18 14 additional patients
18-24 5 additional patients
Decreases Compared to Placebo
25-64 1 fewer patient
≥ 65 6 fewer patients

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression.

Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing LATUDA, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Cerebrovascular Adverse Reactions, Including Stroke In Elderly Patients With Dementia-Related Psychosis

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. LATUDA is not approved for the treatment of patients with dementia-related psychosis [see also BOXED WARNING and Increased Mortality in Elderly Patients with Dementia-Related Psychosis].

Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including LATUDA.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. It is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. If reintroduced, the patient should be carefully monitored, since recurrences of NMS have been reported.

Tardive Dyskinesia

Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that can develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, LATUDA should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on LATUDA, drug discontinuation should be considered. However, some patients may require treatment with LATUDA despite the presence of the syndrome.

Metabolic Changes

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 treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because LATUDA was not marketed at the time these studies were performed, it is not known if LATUDA is associated with this increased risk.

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.

Schizophrenia

Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 3.

Table 3: Change in Fasting Glucose in Schizophrenia Studies

  LATUDA
Placebo 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day
Mean Change from Baseline (mg/dL)
  n=680 n=71 n=478 n=508 n=283 n=113
Serum Glucose -0.0 -0.6 +2.6 -0.4 +2.5 +2.5
Proportion of Patients with Shifts to ≥ 126 mg/dL
Serum Glucose ( ≥ 126 mg/dL) 8.3% (52/628) 11.7% (7/60) 12.7% ( 57/449) 6.8% (32/472) 10.0% (26/260) 5.6% (6/108)

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in glucose of +1.8 mg/dL at week 24 (n=355), +0.8 mg/dL at week 36 (n=299) and +2.3 mg/dL at week 52 (n=307).

Bipolar Depression

Monotherapy

Data from the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study are presented in Table 4.

Table 4: Change in Fasting Glucose in the Monotherapy Bipolar Depression Study

  Placebo LATUDA
20 to 60 mg/day 80 to 120 mg/day
Mean Change from Baseline (mg/dL)
  n=148 n=140 n=143
Serum Glucose +1.8 -0.8 +1.8
Proportion of Patients with Shifts to ≥ 126 mg/dL
Serum Glucose ( ≥ 126 mg/dL) 4.3% (6/141) 2.2% (3/138) 6.4% (9/141)
Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA 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 short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 5.

Table 5: Change in Fasting Glucose in the Adjunctive Therapy Bipolar Depression Studies

  Placebo LATUDA 20 to 120 mg/day
Mean Change from Baseline (mg/dL)
  n=302 n=319
Serum Glucose -0.9 +1.2
Proportion of Patients with Shifts to ≥ 126 mg/dL
Serum Glucose ( ≥ 126 mg/dL) 1.0% (3/290) 1.3% (4/316)
Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA 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).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Schizophrenia

Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 6.

Table 6: Change in Fasting Lipids in Schizophrenia Studies

  LATUDA
Placebo 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day
Mean Change from Baseline (mg/dL)
  n=660 n=71 n=466 n=499 n=268 n=115
Total Cholesterol -5.8 -12.3 -5.7 -6.2 -3.8 -6.9
Triglycerides -13.4 -29.1 -5.1 -13.0 -3.1 -10.6
Proportion of Patients with Shifts
Total Cholesterol( ≥ 240 mg/dL) 5.3% (30/571) 13.8% (8/58) 6.2% (25/402) 5.3% (23/434) 3.8% (9/238) 4.0% (4/101)
Triglycerides( ≥ 200 mg/dL) 10.1% (53/526) 14.3% (7/49) 10.8% (41/379) 6.3% (25/400) 10.5% (22/209) 7.0% (7/100)

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in total cholesterol and triglycerides of -3.8 (n=356) and -15.1 (n=357) mg/dL at week 24, -3.1 (n=303) and -4.8 (n=303) mg/dL at week 36 and -2.5 (n=307) and -6.9 (n=307) mg/dL at week 52, respectively.

Bipolar Depression

Monotherapy

Data from the short-term, flexible-dosed, placebo-controlled, monotherapy bipolar depressio n study are presented in Table 7.

Table 7: Change in Fasting Lipids in the Monotherapy Bipolar Depression Study

  Placebo LATUDA
20 to 60 mg/day 80 to 120 mg/day
Mean Change from Baseline (mg/dL)
  n=147 n=140 n=144
Total cholesterol -3.2 +1.2 -4.6
Triglycerides +6.0 +5.6 +0.4
Proportion of Patients with Shifts
Total cholesterol ( ≥ 240 mg/dL) 4.2% (5/118) 4.4% (5/113) 4.4% (5/114)
Triglycerides ( ≥ 200 mg/dL) 4.8% (6/126) 10.1% (12/119) 9.8% (12/122)
Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA 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 (n=130) and -1.0 (n=130) mg/dL at week 24, respectively.

Adjunctive Therapy With Lithium Or Valproate

Data from the short-term, flexible-dosed, placebo-controlled, adjunctive therapy bipolar depression studies are presented in Table 8.

Table 8: Change in Fasting Lipids in the Adjunctive Therapy Bipolar Depression Studies

  LATUDA
Placebo 20 to 120 mg/day
Mean Change from Baseline (mg/dL)
  n=303 n=321
Total cholesterol -2.9 -3.1
Triglycerides -4.6 +4.6
Proportion of Patients with Shifts
Total cholesterol ( ≥ 240 mg/dL) 5.7% (15/263) 5.4% (15/276)
Triglycerides ( ≥ 200 mg/dL) 8.6% (21/243) 10.8% (28/260)
Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA, 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.

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Schizophrenia

Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 9. The mean weight gain was +0.43 kg for LATUDA-treated patients compared to -0.02 kg for placebo-treated patients. Change in weight from baseline for olanzapine was +4.15 kg and for quetiapine extended-release was +2.09 kg in Studies 3 and 5 [see Clinical Studies], respectively. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 4.8% for LATUDA-treated patients versus 3.3% for placebo-treated patients.

Table 9: Mean Change in Weight (kg) from Baseline in Schizophrenia Studies

  LATUDA
Placebo
(n=696)
20 mg/day
(n=71)
40 mg/day
(n=484)
80 mg/day
(n=526)
120 mg/day
(n=291)
160 mg/day
(n=114)
All Patients -0.02 -0.15 +0.22 +0.54 +0.68 +0.60

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in weight of -0.69 kg at week 24 (n=755), -0.59 kg at week 36 (n=443) and -0.73 kg at week 52 (n=377).

Bipolar Depression

Monotherapy

Data from the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 10. The mean weight gain was +0.29 kg for LATUDA-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 LATUDA-treated patients versus 0.7% for placebo-treated patients.

Table 10: Mean Change in Weight (kg) from Baseline in the Monotherapy Bipolar Depression Study

  Placebo
(n=151)
LATUDA
20 to 60 mg/day
(n=143)
80 to 120 mg/day
(n=147)
All Patients -0.04 +0.56 +0.02
Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA 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 short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 11. The mean weight gain was +0.11 kg for LATUDA-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 LATUDA-treated patients versus 0.3% for placebo-treated patients.

Table 11: Mean Change in Weight (kg) from Baseline in the Adjunctive Therapy Bipolar Depression Studies

  Placebo
(n=307)
LATUDA 20 to 120 mg/day
(n=327)
All Patients +0.16 +0.11
Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA, 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).

Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, LATUDA elevates prolactin levels.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male patients [see ADVERSE REACTIONS].

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in a LATUDA carcinogenicity study conducted in rats and mice [see Nonclinical Toxicology]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.

Schizophrenia

In short-term, placebo-controlled schizophrenia studies, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was +0.4 ng/mL and was -1.9 ng/mL in the placebo-treated patients. The median change from baseline to endpoint for males was +0.5 ng/mL and for females was -0.2 ng/mL. Median changes for prolactin by dose are shown in Table 12.

Table 12: Median Change in Prolactin (ng/mL) from Baseline in Schizophrenia Studies

  LATUDA
Placebo 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day
All Patients -1.9 (n=672) -1.1 (n=70) -1.4 (n=476) -0.2 (n=495) +3.3 (n=284) +3.3 (n=115)
Females -5.1 (n=200) -0.7 (n=19) -4.0 (n=149) -0.2 (n=150) +6.7 (n=70) +7.1 (n=36)
Males -1.3 (n=472) -1.2 (n=51) -0.7 (n=327) -0.2 (n=345) +3.1 (n=214) +2.4 (n=79)

The proportion of patients with prolactin elevations ≥ 5x upper limit of normal (ULN) was 2.8% for LATUDA-treated patients versus 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 5.7% for LATUDA-treated patients versus 2.0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN was 1.6% versus 0.6% for placebo-treated male patients.

In the uncontrolled longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a median change in prolactin of -0.9 ng/mL at week 24 (n=357), -5.3ng/mL at week 36 (n=190) and -2.2 ng/mL at week 52 (n=307).

Bipolar Depression

Monotherapy

The median change from baseline to endpoint in prolactin levels, in the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, was +1.7 ng/mL and +3.5 ng/mL with LATUDA 20 to 60 mg/day and 80 to 120 mg/day, respectively compared to +0.3 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +1.5 ng/mL and for females was +3.1 ng/mL. Median changes for prolactin by dose range are shown in Table 13.

Table 13: Median Change in Prolactin (ng/mL) from Baseline in the Monotherapy Bipolar Depression Study

  Placebo LATUDA
20 to 60 mg/day 80 to 120 mg/day
All Patients +0.3 (n=147) +1.7 (n=140) +3.5 (n=144)
Females 0.0 (n=82) +1.8 (n=78) +5.3 (n=88)
Males +0.4 (n=65) +1.2 (n=62) +1.9 (n=56)
Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo

The proportion of patients with prolactin elevations ≥ 5x upper limit of normal (ULN) was 0.4% for LATUDA-treated patients versus 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 0.6% for LATUDA-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN was 0% versus 0% for placebo-treated male patients.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA as monotherapy in the short-term and continued in the longer-term study, had a median change in prolactin of -1.15 ng/mL at week 24 (n=130).

Adjunctive Therapy With Lithium Or Valproate

The median change from baseline to endpoint in prolactin levels, in the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/mL with LATUDA 20 to 120 mg/day compared to 0.0 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +2.4 ng/mL and for females was +3.2 ng/mL. Median changes for prolactin across the dose range are shown in Table 14.

Table 14: Median Change in Prolactin (ng/mL) from Baseline in the Adjunctive Therapy Bipolar Depression Studies

  Placebo LATUDA 20 to 120 mg/day
All Patients 0.0 (n=301) +2.8 (n=321)
Females +0.4 (n=156) +3.2 (n=162)
Males -0.1 (n=145) +2.4 (n=159)
Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

The proportion of patients with prolactin elevations ≥ 5x upper limit of normal (ULN) was 0.0% for LATUDA-treated patients versus 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 0% for LATUDA-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN was 0% versus 0% for placebo-treated male patients.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA, as adjunctive therapy with either lithium or valproate, in the short-term and continued in the longer-term study, had a median change in prolactin of -2.9 ng/mL at week 24 (n=88).

Leukopenia, Neutropenia And Agranulocytosis

Leukopenia/neutropenia has been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in the class.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and LATUDA should be discontinued at the first sign of decline in WBC, in the absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm³) should discontinue LATUDA and have their WBC followed until recovery.

Orthostatic Hypotension And Syncope

LATUDA may cause orthostatic hypotension and syncope, perhaps due to its α1-adrenergic receptor antagonism. Associated adverse reactions can include dizziness, lightheadedness, tachycardia, and bradycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-nave. In such patients, consider using a lower starting dose and slower titration, and monitor orthostatic vital signs.

Orthostatic hypotension, as assessed by vital sign measurement, was defined by the following vital sign changes: ≥ 20 mm Hg decrease in systolic blood pressure and ≥ 10 bpm increase in pulse from sitting to standing or supine to standing position.

Schizophrenia

The incidence of orthostatic hypotension and syncope reported as adverse events from short-term, placebo-controlled schizophrenia studies was (LATUDA incidence, placebo incidence): orthostatic hypotension [0.3% (5/1508), 0.1% (1/708)] and syncope [0.1% (2/1508), 0% (0/708)].

In short-term schizophrenia clinical studies, orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.8% with LATUDA 40 mg, 2.1% with LATUDA 80 mg, 1.7% with LATUDA 120 mg and 0.8% with LATUDA 160 mg compared to 0.7% with placebo.

Bipolar Depression

Monotherapy

In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, there were no reported adverse events of orthostatic hypotension and syncope.

Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.6% with LATUDA 20 to 60 mg and 0.6% with LATUDA 80 to 120 mg compared to 0% with placebo.

Adjunctive Therapy with Lithium or Valproate

In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression therapy studies, there were no reported adverse events of orthostatic hypotension and syncope. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with LATUDA 20 to 120 mg compared to 0.9% with placebo.

Seizures

As with other antipsychotic drugs, LATUDA should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold, e.g., Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

Schizophrenia

In short-term, placebo-controlled schizophrenia studies, seizures/convulsions occurred in 0.1% (2/1508) of patients treated with LATUDA compared to 0.1% (1/708) placebo-treated patients.

Bipolar Depression

Monotherapy

In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, no patient experienced seizures/convulsions.

Adjunctive Therapy with Lithium or Valproate

In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, no patient experienced seizures/convulsions.

Potential For Cognitive And Motor Impairment

LATUDA, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with LATUDA does not affect them adversely.

In clinical studies with LATUDA, somnolence included: hypersomnia, hypersomnolence, sedation and somnolence.

Schizophrenia

In short-term, placebo-controlled schizophrenia studies, somnolence was reported by 17.0% (256/1508) of patients treated with LATUDA (15.5% LATUDA 20 mg, 15.6% LATUDA 40 mg, 15.2% LATUDA 80 mg, 26.5% LATUDA 120 mg and 8.3% LATUDA 160 mg/day) compared to 7.1% (50/708) of placebo patients.

Bipolar Depression

Monotherapy

In the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, somnolence was reported by 7.3% (12/164) and 13.8% (23/167) with LATUDA 20 to 60 mg and 80 to120 mg, respectively compared to 6.5% (11/168) of placebo patients.

Adjunctive Therapy with Lithium or Valproate

In the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depressio n studies, somnolence was reported by 11.4% (41/360) of patients treated with LATUDA 20-120 mg compared to 5.1% (17/334) of placebo patients.

Body Temperature Dysregulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing LATUDA for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration [see PATIENT INFORMATION].

Suicide

The possibility of a suicide attempt is inherent in psychotic illness and close supervision of high-risk patients should accompany drug therapy. Prescriptions for LATUDA should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.

Schizophrenia

In short-term, placebo-controlled schizophrenia studies, the incidence of treatment-emergent suicidal ideation was 0.4% (6/1508) for LATUDA-treated patients compared to 0.8% (6/708) on placebo. No suicide attempts or completed suicides were reported in these studies.

Bipolar Depression

Monotherapy

In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, the incidence of treatment-emergent suicidal ideation was 0.0% (0/331) with LATUDA-treated patients compared to 0.0% (0/168) with placebo-treated patients. No suicide attempts or completed suicides were reported in this study.

Adjunctive Therapy with Lithium or Valproate

In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, the incidence of treatment-emergent suicidal ideation was 1.1% (4/360) for LATUDA-treated patients compared to 0.3% (1/334) on placebo. No suicide attempts or completed suicides were reported in these studies.

Activation Of Mania/Hypomania

Antidepressant treatment can increase the risk of developing a manic or hypomanic episode, particularly in patients with bipolar disorder. Monitor patients for the emergence of such episodes.

In the bipolar depression monotherapy and adjunctive therapy (with lithium or valproate) studies, less than 1% of subjects in the LATUDA and placebo groups developed manic or hypomanic episodes.

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. LATUDA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Neurological Adverse Reactions In Patients With Parkinson's Disease Or Dementia With Lewy Bodies

Patients with Parkinson's Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivit y include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

Suicidal Thoughts And Behavior

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down and instruct them to report such symptoms to the healthcare provider [see BOXED WARNING, WARNINGS AND PRECAUTIONS].

Neuroleptic Malignant Syndrome

Counsel patients about a potentially fatal adverse reaction referred to as Neuroleptic Malignant Syndrome (NMS). Advise patients, family members, or caregivers to contact healthcare provider or to report to the emergency room if they experience signs and symptoms of NMS [see WARNINGS AND PRECAUTIONS].

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see WARNINGS AND PRECAUTIONS].

Metabolic Changes

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see WARNINGS AND PRECAUTIONS].

Hyperprolactinemia

Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of LATUDA. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males [see WARNINGS AND PRECAUTIONS].

Leukopenia/Neutropenia

Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia that they should have their CBC monitored while taking LATUDA [see WARNINGS AND PRECAUTIONS].

Orthostatic Hypotension

Educate patients about the risk of orthostatic hypotension, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see WARNINGS AND PRECAUTIONS].

Interference With Cognitive And Motor Performance

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that LATUDA therapy does not affect them adversely [see WARNINGS AND PRECAUTIONS].

Heat Exposure And Dehydration

Educate patients regarding appropriate care in avoiding overheating and dehydrating [see WARNINGS AND PRECAUTIONS].

Activation Of Mania Or Hypomania

Advise patients and their caregivers to observe for signs of activation of mania/hypomania [see WARNINGS AND PRECAUTIONS].

Pregnancy And Nursing

Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy with LATUDA [see Use in Specific Populations].

Concomitant Medication

Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, because there is potential for drug interactions [see DRUG INTERACTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Lurasidone increased incidences of malignant mammary gland tumors and pituitary gland adenomas in female mice orally dosed with 30, 100, 300, or 650 mg/kg/day. The lowest dose produced plasma levels (AUC) approximately equal to those in humans receiving the MRHD of 160 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 14-times those in humans receiving the MRHD.

Lurasidone increased the incidence of mammary gland carcinomas in females rats orally dosed at 12 and 36 mg/kg/day: the lowest dose; 3 mg/kg/day is the no-effect dose which produced plasma levels (AUC) 0.4-times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to the highest dose tested, which produced plasma levels (AUC) 6-times those in humans receiving the MRHD.

Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin-mediated. The relevance of this increased incidence of prolactin-mediated pituitary or mammary gland tumors in rodents to humans is unknown [see WARNINGS AND PRECAUTIONS].

Mutagenesis

Lurasidone did not cause mutation or chromosomal aberration when tested in vitro and in vivo. LATUDA was negative in the Ames gene mutation test, the Chinese Hamster Lung (CHL) cells, and in the in vivo mouse bone marrow micronucleus test up to 2000 mg/kg (61 times the MRHD of 160 mg/day based on mg/m² body surface area).

Impairment Of Fertility

Estrus cycle irregularities were seen in rats orally administered Lurasidone at 1.5, 15 and 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through day 7 of gestation. The no-effect dose is 0.1 mg/kg which is approximately 0.006-times the MRHD of 160 mg/day based on body surface area. Fertility was reduced only at the highest dose, which was reversible after a 14-day drug-free period. The no-effect dose for reduced fertility was 15 mg/kg, which is approximately equal to the MRHD based on body surface area.

Lurasidone had no effect on fertility in male rats treated orally with LATUDA for 64 consecutive days prior to mating and during the mating period at doses up to 150 mg/kg/day (9-times the MRHD based on mg/m² body surface area).

Use In Specific Populations

Pregnancy

Pregnancy Category B

Risk Summary

There are no adequate and well controlled studies of LATUDA use in pregnant women. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

LATUDA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Human Data

Safe use of LATUDA during pregnancy or lactation has not been established; therefore, use of LATUDA in pregnancy, in nursing mothers, or in women of childbearing potential requires that the benefits of treatment be weighed against the possible risks to mother and child.

Animal Data

No adverse developmental effects were observed in a study in which pregnant rats were given lurasidone during the period of organogenesis and continuing through weaning at doses up to 10 mg/kg/day, which is approximately half of the maximum recommended human dose (MRHD) of 160 mg/day, based on mg/m² body surface area.

No teratogenic effects were seen in studies in which pregnant rats and rabbits were given lurasidone during the period of organogenesis at doses up to 25 and 50 mg/kg/day, respectively. These doses are 1.5-and 6-times, in rats and rabbits, respectively, the MRHD of 160 mg/day based on mg/m² body surface area.

Nursing Mothers

LATUDA was excreted in milk of rats during lactation. It is not known whether LATUDA or its metabolites are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, considering the risk of drug discontinuation to the mother.

Pediatric Use

The safety and effectiveness of LATUDA in pediatric patients have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

Juvenile Animal Studies

Lurasidone was orally administered to juvenile rats at doses of 3, 30, and 150 (males) or 300 (females) mg/kg/day which are 0.2 to 10 times (males) and 0.2 to 20 times (females) the maximum recommended adult human dose (MRHD) of 160 mg/day (on mg/m² basis), from postnatal days 21 through 91 (this period corresponds to childhood, adolescence, and young adulthood in humans). Adverse effects were seen on physical growth and development as well as on neurobehavior at doses as low as 0.2 times the MRHD on mg/m² basis. These effects included dose-dependent decrease in femoral length, bone mineral content, body and brain weights at 2 times the MRHD of 160 mg/day on mg/m² basis in both sexes, as well as motor hyperactivity in males and females at 2 and 0.2 times the MRHD, respectively. In females, there was a delay in attainment of sexual maturity at 2 times the MRHD, associated with decreased serum estradiol. Mortality occurred in both sexes during early post-weaning period and some of the male weanlings died after only 4 treatments at doses as low as 2 times the MRHD of 160 mg/day on mg/m² basis. Histopathological findings included increased colloid in the thyroids and inflammation of the prostate in males at 10 times MRHD of 160 mg/day on mg/m² basis and mammary gland hyperplasia, increased mucification of the vagina, and increased ovarian atretic follicles in females at doses as low as 0.2 times the MRHD of 160 mg/day on mg/m² basis. Some of these findings were attributed to transiently elevated serum prolactin which was seen in both sexes at all doses. However, there were no changes in reproductive parameters (fertility, conception indices, spermatogenesis, estrous cycle, gestation length, parturition, number of pups born) at any dose level. The no effect dose for neurobehavioral changes (motor hyperactivity) in males is 3 mg/kg/day which is 0.2 times the MHRD on mg/m² basis and could not be determined in females. The no effect dose for growth and physical development for males and females is 3 mg/kg/day which is 0.2 times the MRHD of 160 mg/day on mg/m² basis.

Geriatric Use

Clinical studies with LATUDA did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. In elderly patients with psychosis (65 to 85), LATUDA concentrations (20 mg/day) were similar to those in young subjects. It is unknown whether dose adjustment is necessary on the basis of age alone.

Elderly patients with dementia-related psychosis treated with LATUDA are at an increased risk of death compared to placebo. LATUDA is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS].

Renal Impairment

Reduce the maximum recommended dosage in patients with moderate or severe renal impairment (CLcr < 50 mL/minute). Patients with impaired renal function (CLcr < 50 mL/minute) had higher exposure to lurasidone than patients with normal renal function [see CLINICAL PHARMACOLOGY]. Greater exposure may increase the risk of LATUDA-associated adverse reactions [see DOSAGE AND ADMINISTRATION]

Hepatic Impairment

Reduce the maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score ≥ 7). Patients with moderate to severe hepatic impairment (Child-Pugh score ≥ 7) generally had higher exposure to lurasidone than patients with normal hepatic function [see CLINICAL PHARMACOLOGY]. Greater exposure may increase the risk of LATUDA-associated adverse reactions [see DOSAGE AND ADMINISTRATION].

Other Specific Populations

No dosage adjustment for LATUDA is required on the basis of a patient's sex, race, or smoking status [see CLINICAL PHARMACOLOGY].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 1/30/2017

Warnings
Precautions

Latuda - User Reviews

Latuda User Reviews

Now you can gain knowledge and insight about a drug treatment with Patient Discussions.

Here is a collection of user reviews for the medication Latuda sorted by most helpful. Patient Discussions FAQs

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Emotional Wellness

Get tips on therapy and treatment.