Lurastar Overdose

• Overdose of Lurastar in details
• Lurastar warnings
• Lurastar precautions
• Lurastar reviews

What happens if I overdose Lurastar?

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Lurastar:

Store Lurastar at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Lurastar out of the reach of children and away from pets.

Overdose of Lurastar in details

Human Experience

In premarketing clinical studies, accidental or intentional overdosage of Lurastar was identified in one patient who ingested an estimated 560 mg of Lurastar. This patient recovered without sequelae. This patient resumed Lurastar treatment for an additional two months.

Management of Overdosage

Consult a Certified Poison Control Center for up-to-date guidance and advice. There is no specific antidote to Lurastar, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Consider the possibility of multiple-drug overdose.

Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of Lurastar. Similarly, the alpha-blocking properties of bretylium might be additive to those of Lurastar, resulting in problematic hypotension.

Hypotension and circulatory collapse should be treated with appropriate measures. Epinephrine and dopamine should not be used, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of Lurastar-induced alpha blockade. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered.

Gastric lavage (after intubation if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.

The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

What should I avoid while taking Lurastar?

While you are taking Lurastar, you may be more sensitive to temperature extremes such as very hot or cold conditions. Avoid getting too cold, or becoming overheated or dehydrated. Drink plenty of fluids, especially in hot weather and during exercise. It is easier to become dangerously overheated and dehydrated while you are taking Lurastar.

Grapefruit and grapefruit juice may interact with Lurastar and lead to unwanted side effects. Avoid the use of grapefruit products while taking Lurastar.

Lurastar may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Avoid drinking alcohol. Dangerous side effects could occur.

Lurastar warnings

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. Lurastar is not approved for the treatment of patients with dementia-related psychosis.

Suicidal Thoughts and Behaviors in Adolescents and Young Adults

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.

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

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidal thoughts and behaviors, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Lurastar should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

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. Lurastar is not approved for the treatment of 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 Lurastar.

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, Lurastar 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 Lurastar, drug discontinuation should be considered. However, some patients may require treatment with Lurastar 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 Lurastar was not marketed at the time these studies were performed, it is not known if Lurastar 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.

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), Lurastar 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.

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

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

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), Lurastar 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 depression study are presented in Table 7.

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

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received Lurastar, 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 Lurastar-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, respectively. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 4.8% for Lurastar-treated patients versus 3.3% for placebo-treated patients.

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), Lurastar 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 Lurastar-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 Lurastar-treated patients versus 0.7% for placebo-treated patients.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received Lurastar 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 Lurastar-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 Lurastar-treated patients versus 0.3% for placebo-treated patients.

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

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 Lurastar carcinogenicity study conducted in rats and mice. 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 Lurastar-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.

The proportion of patients with prolactin elevations ≥ 5× upper limit of normal (ULN) was 2.8% for Lurastar-treated patients versus 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 5.7% for Lurastar-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), Lurastar 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 Lurastar 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.

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

The proportion of patients with prolactin elevations ≥ 5x upper limit of normal (ULN) was 0.0% for Lurastar-treated patients versus 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 0% for Lurastar-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 Lurastar, 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 Lurastar 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 Lurastar and have their WBC followed until recovery.

Orthostatic Hypotension and Syncope

Lurastar 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-naïve. 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 (Lurastar 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 Lurastar 40 mg, 2.1% with Lurastar 80 mg, 1.7% with Lurastar 120 mg and 0.8% with Lurastar 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 Lurastar 20 to 60 mg and 0.6% with Lurastar 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 Lurastar 20 to 120 mg compared to 0.9% with placebo.

Seizures

As with other antipsychotic drugs, Lurastar 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 Lurastar 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

Lurastar, 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 Lurastar does not affect them adversely.

In clinical studies with Lurastar, 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 Lurastar (15.5% Lurastar 20 mg, 15.6% Lurastar 40 mg, 15.2% Lurastar 80 mg, 26.5% Lurastar 120 mg and 8.3% Lurastar 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 Lurastar 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 depression studies, somnolence was reported by 11.4% (41/360) of patients treated with Lurastar 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 Lurastar 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.

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 Lurastar 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 Lurastar-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 Lurastar-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 Lurastar-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 Lurastar 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. Lurastar 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 sensitivity include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.

What should I discuss with my healthcare provider before taking Lurastar?

You should not use Lurastar if you are allergic to Lurastar.

Some medicines can interact with Lurastar and should not be used at the same time. Your doctor may need to change your treatment plan if you use certain other medicines, including:

• antifungal medicine such as ketoconazole or voriconazole;

• an antibiotic such as clarithromycin or rifampin;

• an antiviral such as ritonavir;

• St. John's wort; or

• seizure medicine such as carbamazepine or phenytoin.

Lurastar is not approved for use in psychotic conditions related to dementia. Lurastar may increase the risk of death in older adults with dementia-related conditions.

To make sure Lurastar is safe for you, tell your doctor if you have:

• heart disease, high blood pressure;

• high cholesterol or triglycerides (a type of fat in the blood);

• seizures or epilepsy;

• liver disease;

• kidney disease;

• low white blood cell (WBC) counts;

• personal or family history of diabetes (Lurastar may raise your blood sugar);

• a history of abnormal hormone function tests (thyroid, pituitary gland);

• a history of breast cancer;

• a history of depression or bipolar disease (unless you are taking Lurastar to treat depressive episodes);

• a history of suicidal thoughts or actions; or

• if you have ever had a stroke.

Some young people have thoughts about suicide when first taking medicine to treat depression. Your doctor should check your progress at regular visits. Your family or other caregivers should also be alert to changes in your mood or symptoms.

This medicine is not expected to harm an unborn baby. However, taking antipsychotic medication during the last 3 months of pregnancy may cause problems in the newborn, such as withdrawal symptoms, breathing problems, feeding problems, fussiness, tremors, and limp or stiff muscles. However, you may have withdrawal symptoms or other problems if you stop taking your medicine during pregnancy. If you become pregnant while taking Lurastar, do not stop taking it without your doctor's advice.

It is not known whether Lurastar passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Lurastar is not approved for use by anyone younger than 18 years old.

Lurastar 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. Lurastar is not approved for the treatment of patients with dementia-related psychosis.

Suicidal Thoughts and Behaviors in Adolescents and Young Adults

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.

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

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidal thoughts and behaviors, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Lurastar should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

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. Lurastar is not approved for the treatment of 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 Lurastar.

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, Lurastar 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 Lurastar, drug discontinuation should be considered. However, some patients may require treatment with Lurastar 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 Lurastar was not marketed at the time these studies were performed, it is not known if Lurastar 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.

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), Lurastar 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.

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

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

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), Lurastar 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 depression study are presented in Table 7.

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

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received Lurastar, 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 Lurastar-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, respectively. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 4.8% for Lurastar-treated patients versus 3.3% for placebo-treated patients.

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), Lurastar 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 Lurastar-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 Lurastar-treated patients versus 0.7% for placebo-treated patients.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received Lurastar 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 Lurastar-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 Lurastar-treated patients versus 0.3% for placebo-treated patients.

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

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 Lurastar carcinogenicity study conducted in rats and mice. 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 Lurastar-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.

The proportion of patients with prolactin elevations ≥ 5× upper limit of normal (ULN) was 2.8% for Lurastar-treated patients versus 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 5.7% for Lurastar-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), Lurastar 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 Lurastar 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.

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

The proportion of patients with prolactin elevations ≥ 5x upper limit of normal (ULN) was 0.0% for Lurastar-treated patients versus 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 0% for Lurastar-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 Lurastar, 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 Lurastar 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 Lurastar and have their WBC followed until recovery.

Orthostatic Hypotension and Syncope

Lurastar 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-naïve. 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 (Lurastar 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 Lurastar 40 mg, 2.1% with Lurastar 80 mg, 1.7% with Lurastar 120 mg and 0.8% with Lurastar 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 Lurastar 20 to 60 mg and 0.6% with Lurastar 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 Lurastar 20 to 120 mg compared to 0.9% with placebo.

Seizures

As with other antipsychotic drugs, Lurastar 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 Lurastar 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

Lurastar, 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 Lurastar does not affect them adversely.

In clinical studies with Lurastar, 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 Lurastar (15.5% Lurastar 20 mg, 15.6% Lurastar 40 mg, 15.2% Lurastar 80 mg, 26.5% Lurastar 120 mg and 8.3% Lurastar 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 Lurastar 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 depression studies, somnolence was reported by 11.4% (41/360) of patients treated with Lurastar 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 Lurastar 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.

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 Lurastar 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 Lurastar-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 Lurastar-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 Lurastar-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 Lurastar 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. Lurastar 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 sensitivity include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.

What happens if I miss a dose of Lurastar?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

References

1. DailyMed. "LURASIDONE HYDROCHLORIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
2. DrugBank. "Lurasidone". http://www.drugbank.ca/drugs/DB08815 (accessed September 17, 2018).
3. MeSH. "Antipsychotic Agents". https://www.ncbi.nlm.nih.gov/mesh/68... (accessed September 17, 2018).

Reviews

Consumer reviews

Information checked by Dr. Sachin Kumar, MD Pharmacology