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2010年10月28日，美国食品药品管理局FDA批准Latuda(lurasidone HCL)用于治疗成人精神分裂症。
HIGHLIGHTS OF PRESCRIBING INFORMATION
LATUDA is contraindicated in any patient with a known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has been observed with lurasidone [see Adverse Reactions (6.6)]. LATUDA is contraindicated with strong CYP3A4 inhibitors (e.g., ketoconazole) and strong CYP3A4 inducers (e.g., rifampin) [see Drug Interactions (7.1)]. 5. WARNINGS AND PRECAUTIONS 5.1. 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. LATUDA is not approved for the treatment of dementia-related psychosis [see Boxed Warning]. 5.2. Cerebrovascular Adverse Reactions, Including Stroke 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 Warnings and Precautions (5.1)]. 5.3. 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 creatinine 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. 5.4. 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. 5.5. 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. Pooled data from short-term, placebo-controlled studies are presented in Table 2. Table 2: Change in Fasting Glucose
Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Pooled data from short-term, placebo-controlled studies are presented in Table 3. Table 3: Change in Fasting Lipids
Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Pooled data from short-term, placebo-controlled studies are presented in Table 4. The mean weight gain was 0.75 kg for LATUDA-treated patients compared to 0.26 kg for placebo-treated patients. In study 3 [see Clinical Studies (14.1)] change in weight from baseline for olanzapine was 4.15 kg. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 5.6% for LATUDA-treated patients versus 4.0% for placebo-treated patients. Table 4: Mean Change in Weight (kg) from Baseline
5.6. 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 (6)]. In short-term placebo-controlled studies, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was 1.1 ng/mL and was - 0.6 ng/mL in the placebo-treated patients. The increase in prolactin was greater in female patients; the median change from baseline to endpoint for females was 1.5 ng/mL and was 1.1 ng/mL in males. The increase in prolactin concentrations was dose-dependent (Table 5). Table 5: Median Change in Prolactin (ng/mL) from Baseline
In the uncontrolled longer-term studies (primarily open-label extension studies), LATUDA was associated with a median change in prolactin of -1.9 ng/mL at week 24 (n = 188), -5.4 ng/mL at week 36 (n=189) and -3.3 ng/mL at week 52 (n = 243). 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 (13)]. 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. 5.7. 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. 5.8. Orthostatic Hypotension and Syncope LATUDA may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. The incidence of orthostatic hypotension and syncope events from short-term, placebo-controlled studies was (LATUDA incidence, placebo incidence): orthostatic hypotension [0.4% (4/1004), 0.2 % (1/455)] and syncope [< 0.1% (1/1004), 0%]. Assessment of orthostatic hypotension defined by 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 positions). In short-term clinical trials orthostatic hypotension occurred with a frequency of 0.8% with LATUDA 40 mg, 1.4% with LATUDA 80 mg and 1.7% with LATUDA 120 mg compared to 0.9% with placebo. LATUDA should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction, ischemia, or conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension. 5.9. 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. In short-term placebo-controlled trials, seizures/convulsions occurred in < 0.1% (1/1004) of patients treated with LATUDA compared to 0.2% (1/455) placebo-treated patients. 5.10. Potential for Cognitive and Motor Impairment LATUDA, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. In short-term, placebo-controlled trials, somnolence was reported in 22.3% (224/1004) of patients treated with LATUDA compared to 9.9% (45/455) of placebo patients, respectively. The frequency of somnolence increases with dose; somnolence was reported in 26.5% (77/291) of patients receiving LATUDA 120 mg/day. In these short-term trials, somnolence included: hypersomnia, hypersomnolence, sedation and somnolence. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with LATUDA does not affect them adversely. 5.11. Body Temperature Regulation 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 Counseling Information (17.9)]. 5.12. 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. In short-term, placebo-controlled studies in patients with schizophrenia, the incidence of treatment-emergent suicidal ideation was 0.6% (6/1004) for LATUDA treated patients compared to 0.4% (2/455) on placebo. No suicide attempts or completed suicides were reported in these studies. 5.13. 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 is not indicated for the treatment of dementia-related psychosis, and should not be used in patients at risk for aspiration pneumonia. 5.14. Use in Patients with Concomitant Illness Clinical experience with LATUDA in patients with certain concomitant systemic illnesses is limited [see Use in Specific Populations (8.6, 8.7)]. LATUDA has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies [see Warnings and Precautions (5.1, 5.8)]. 6. ADVERSE REACTIONS 6.1. Overall Adverse Reaction Profile The following adverse reactions are discussed in more detail in other sections of the labeling: Use in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.1)] Cerebrovascular Adverse Reactions, Including Stroke [see Warnings and Precautions (5.2)] Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.3)] Tardive Dyskinesia [see Warnings and Precautions (5.4)] Hyperglycemia and Diabetes Mellitus [see Warnings and Precautions (5.5)] Hyperprolactinemia [see Warnings and Precautions (5.6)] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.7)] Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.8)] Seizures [see Warnings and Precautions (5.9)] Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.10)] Body Temperature Regulation [see Warnings and Precautions (5.11)] Suicide [see Warnings and Precautions (5.12)] Dysphagia [see Warnings and Precautions (5.13)] Use in Patients with Concomitant Illness [see Warnings and Precautions (5.14)] The information below is derived from a clinical study database for LATUDA consisting of over 2096 patients with schizophrenia exposed to one or more doses with a total experience of 624 patient-years. Of these patients, 1004 participated in short-term placebo-controlled schizophrenia studies with doses of 20 mg, 40 mg, 80 mg or 120 mg once daily. A total of 533 LATUDA-treated patients had at least 24 weeks and 238 LATUDA-treated patients had at least 52 weeks of exposure. Adverse events during exposure to study treatment were obtained by general inquiry and voluntarily reported adverse experiences, as well as results from physical examinations, vital signs, ECGs, weights and laboratory investigations. Adverse experiences were recorded by clinical investigators using their own terminology. In order to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology. The stated frequencies of adverse reactions represent the proportion of individuals who experienced at least once, a treatment-emergent adverse event of the type listed. Treatment-emergent adverse events were defined as adverse experiences, which started or worsened on or after the date of the first dose through seven days after study medication discontinuation. There was no attempt to use investigator causality assessments; i.e., all events meeting the defined criteria, regardless of investigator causality are included. It is important to emphasize that, although the reactions occurred during treatment with LATUDA, they were not necessarily caused by it. The label should be read in its entirety to gain an understanding of the safety profile of LATUDA. The figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatment, uses and investigators. The cited figures, however, do provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied. 6.2. Clinical Studies Experience The following findings are based on the short-term placebo-controlled premarketing studies for schizophrenia in which LATUDA was administered at daily doses ranging from 20 to 120 mg (n = 1004). Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in patients treated with LATUDA were somnolence, akathisia, nausea, parkinsonism and agitation. Adverse Reactions Associated with Discontinuation of Treatment: A total of 9.4% (94/1004) LATUDA-treated patients and 5.9% (27/455) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate. Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to 6-weeks in patients with schizophrenia) are shown in Table 6. Table 6: Adverse Reaction in 2% or More of LATUDA-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in Short-term Schizophrenia Studies
Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus 6.3. Dose-Related Adverse Reactions Based on the pooled data from the placebo-controlled, short-term, fixed-dose studies, among the adverse reactions that occurred with a greater than 5% incidence in the patients treated with LATUDA, the apparent dose-related adverse reactions were akathisia and somnolence (Table 7). Table 7: Dose-Related Adverse Events
6.4. Extrapyramidal Symptoms In the short-term, placebo-controlled schizophrenia studies, for LATUDA-treated patients, the incidence of reported EPS-related events, excluding akathisia and restlessness, was 14.7% versus 5.1% for placebo-treated patients; and the incidence of akathisia for LATUDA-treated patients was 15.0% versus 3.3% for placebo-treated patients. Akathisia appeared to be dose-related and the greatest frequency of parkinsonism and dystonia occurred with the highest dose of LATUDA, 120 mg/day (Table 8). Table 8: Percentage of EPS Compared to Placebo
Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. In the short-term, placebo-controlled clinical trials, dystonia occurred in 4.7% of LATUDA-treated subjects (0.0% LATUDA 20 mg, 4.2% LATUDA 40 mg, 4.6% LATUDA 80 mg and 6.5% LATUDA 120 mg) compared to 0.7% of subjects receiving placebo. Seven subjects (0.7%, 7/1004) discontinued clinical trials due to dystonic events – 4 were receiving LATUDA 80 mg/day and 3 were receiving LATUDA 120 mg/day. 6.5. Laboratory Test Abnormalities and ECG Changes in Clinical Studies Laboratory Test Abnormalities In a between-group comparison of the pooled data from short-term, placebo-controlled studies, there were no clinically important changes in total cholesterol measurements; triglycerides or glucose from Baseline to Endpoint [see Warnings and Precautions (5.5)]. There were also no clinically important differences between LATUDA and placebo in mean change from baseline to endpoint in routine hematology, urinalysis, or serum chemistry. LATUDA was associated with a dose-related increase in prolactin concentration [see Warnings and Precautions (5.6)] Creatinine: In short-term, placebo-controlled trials, the mean change from Baseline in creatinine was 0.06 mg/dL for LATUDA-treated patients compared to 0.03 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 3.1% (30/977) of LATUDA-treated patients and 1.4% (6/439) on placebo. The threshold for high creatinine value varied from ≥ 1.1 to ≥ 1.3 mg/dL based on the centralized laboratory definition for each study [see Dosage in Special Population (2.3); Use in Specific Populations (8)]. Transaminases: The mean changes in AST and ALT for LATUDA- and placebo-treated patients were similar. The proportion of patients with transaminases (AST and ALT) elevations ≥ 3 times ULN was similar for all LATUDA-treated patients (0.8% and 0.8%, respectively) to placebo-treated patients (0.9% and 1.1%, respectively). ECG Changes Electrocardiogram (ECG) measurements were taken at various time points during the LATUDA clinical trial program. No post-baseline QT prolongations exceeding 500 msec were reported in patients treated with LATUDA. Within a subset of patients defined as having an increased cardiac risk, no potentially important changes in ECG parameters were observed. No cases of torsade de pointes or other severe cardiac arrhythmias were observed in the pre-marketing clinical program. The effects of LATUDA on the QT/QTc interval were evaluated in a dedicated QT study involving 87 clinically stable patients with schizophrenia or schizoaffective disorder, who were treated with LATUDA doses of 120 mg daily, 600 mg daily, or ziprasidone 160 mg daily. Holter monitor-derived electrocardiographic assessments were obtained over an eight hour period at baseline and steady state. No patients treated with LATUDA experienced QTc increases > 60 msec from baseline, nor did any patient experience a QTc of > 500 msec. 6.6. Other Adverse Reactions Observed During the Premarketing Evaluation of LATUDA Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with LATUDA at multiple doses of ≥ 20 mg once daily during any phase of a study within the database of 2096 patients. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions listed in Table 6 are not included. Although the reactions reported occurred during treatment with LATUDA, they were not necessarily caused by it. Reactions are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent) (only those not already listed in the tabulated results from placebo-controlled studies appear in this listing); those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare). Blood and Lymphatic System Disorders: Infrequent: anemia; Rare: leukopenia, neutropenia Cardiac Disorders: Frequent: tachycardia; Infrequent: AV block 1st degree, angina pectoris, bradycardia Ear and Labyrinth Disorders: Infrequent: vertigo Eye disorders: Frequent: blurred vision Gastrointestinal Disorders: Frequent: abdominal pain, diarrhea; Infrequent: gastritis, dysphagia General Disorders and Administrative Site Conditions: Rare: Sudden death Investigations: Frequent: CPK increased Metabolic and Nutritional System Disorders: Frequent: decreased appetite Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis Nervous System Disorders: Infrequent: tardive dyskinesia, cerebrovascular accident, dysarthria, syncope; Rare: neuroleptic malignant syndrome, seizure Psychiatric Disorders: Infrequent: abnormal dreams, panic attack, sleep disorder; Rare: suicidal behavior Renal and Urinary Disorders: Infrequent: dysuria; Rare: renal failure Reproductive System and Breast Disorders: Infrequent: amenorrhea, dysmenorrhea; Rare: breast enlargement, breast pain, galactorrhea, erectile dysfunction Skin and Subcutaneous Tissue Disorders: Frequent: rash, pruritus; Rare: angioedema Vascular Disorders: Infrequent: hypertension, orthostatic hypotension 7. DRUG INTERACTIONS Given the primary CNS effects of LATUDA, caution should be used when it is taken in combination with other centrally acting drugs and alcohol. 7.1. Potential for Other Drugs to Affect LATUDA LATUDA is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes. This suggests that an interaction of LATUDA with drugs that are inhibitors or inducers of these enzymes is unlikely. LATUDA is predominantly metabolized by CYP3A4; interaction of LATUDA with strong and moderate inhibitors or inducers of this enzyme has been observed (Table 9). LATUDA should not be used in combination with strong inhibitors or inducers of this enzyme [see Contraindications (4)]. Table 9: Summary of Effect of Coadministered Drugs on Exposure to LATUDA in Healthy Subjects or Patients with Schizophrenia
Digoxin (P-gp substrate): Coadministration of LATUDA (120 mg/day) at steady state with a single dose of digoxin (0.25 mg) increased Cmax and AUC(0-24) for digoxin by approximately 9% and 13%, respectively relative to digoxin alone. Digoxin dose adjustment is not required when coadministered with LATUDA. Midazolam (CYP3A4 substrate): Coadministration of LATUDA (120 mg/day) at steady state with a single dose of 5 mg midazolam increased midazolam Cmax and AUC(0-24) by approximately 21% and 44%, respectively relative to midazolam alone. Midazolam dose adjustment is not required when coadministered with LATUDA. Oral Contraceptive (estrogen/progesterone): Coadministration of LATUDA (40 mg/day) at steady state with an oral contraceptive (OC) containing ethinyl estradiol and norelgestimate resulted in equivalent AUC(0-24) and Cmax of ethinyl estradiol and norelgestromin relative to OC administration alone. Also, sex hormone binding globulin levels were not meaningfully affected by coadministration of LATUDA and OC. Dose adjustment of OC dose is not required when coadministered with LATUDA. 8. USE IN SPECIFIC POPULATIONS 8.1. Pregnancy Teratogenic Effects Pregnancy Category B Lurasidone was not teratogenic in rats and rabbits. There are no adequate and well-controlled studies of LATUDA in pregnant women. 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 3 and 12 times, in rats and rabbits respectively, the maximum recommended human dose (MRHD) of 80 mg/day based on body surface area. No adverse developmental effects were seen 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; this dose is approximately equal to the MRHD based on body surface area. Non-teratogenic Effects 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. 8.2. Labor and Delivery The effect of LATUDA on labor and delivery in humans is unknown. 8.3. 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. Breast feeding in women receiving LATUDA should be considered only if the potential benefit justifies the potential risk to the child. 8.4. Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5. Geriatric Use Clinical studies of LATUDA in the treatment of schizophrenia 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), lurasidone concentrations (20 mg/day) were similar to those in young subjects [see Clinical Pharmacology (12.3)]. No dose adjustment is necessary in elderly patients. 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]. 8.6. Renal Impairment It is recommended that LATUDA dose should not exceed 40 mg/day in patients with moderate and severe renal impairment (Clcr ≥ 10 mL/min to < 50 mL/min). After administration of a single dose of 40 mg LATUDA to patients with mild, moderate and severe renal impairment, mean Cmax increased by 40%, 92% and 54%, respectively and mean AUC(0-∞) increased by 53%, 91% and 2- times, respectively compared to healthy matched subjects. 8.7. Hepatic Impairment It is recommended that LATUDA dose should not exceed 40 mg/day in patients with moderate and severe hepatic impairment (Child-Pugh Class B and C). In a single-dose study of LATUDA 20 mg, lurasidone mean AUC(0-last) was 1.5-times higher in subjects with mild hepatic impairment (Child-Pugh Class A), 1.7-times higher in subjects with moderate hepatic impairment (Child-Pugh Class B) and 3-times higher in subjects with severe hepatic impairment (Child-Pugh Class C) compared to the values for healthy matched subjects. Mean Cmax was 1.3, 1.2 and 1.3-times higher for mild, moderate and severe hepatically impaired patients respectively, compared to the values for healthy matched subjects. 8.8. Gender Population pharmacokinetic evaluation indicated that the mean AUC of LATUDA was 18% higher in women than in men, and correspondingly, the apparent oral clearance of LATUDA was lower in women. Mean Cmax of LATUDA was similar between women and men. No dosage adjustment of LATUDA is recommended based on gender. 8.9. Race Although no specific pharmacokinetic study was conducted to investigate the effects of race on the disposition of LATUDA, population pharmacokinetic evaluation revealed no evidence of clinically significant race-related differences in the pharmacokinetics of LATUDA. No dosage adjustment of LATUDA is recommended based on race. 8.10. Smoking Status Based on in vitro studies utilizing human liver enzymes, LATUDA is not a substrate for CYP1A2; smoking is therefore not expected to have an effect on the pharmacokinetics of LATUDA. 9. DRUG ABUSE AND DEPENDENCE 9.1. Controlled substance LATUDA is not a controlled substance. 9.2. Abuse LATUDA has not been systematically studied in humans for its potential for abuse or physical dependence or its ability to induce tolerance. While clinical studies with LATUDA did not reveal any tendency for drug-seeking behavior, these observations were not systematic and it is not possible to predict the extent to which a CNS-active drug will be misused, diverted and/or abused once it is marketed. Patients should be evaluated carefully for a history of drug abuse, and such patients should be observed carefully for signs of LATUDA misuse or abuse (e.g., development of tolerance, drug-seeking behavior, increases in dose). 10. OVERDOSAGE 10.1. Human Experience In premarketing clinical studies involving more than 2096 patients and/or healthy subjects, accidental or intentional overdosage of LATUDA was identified in one patient who ingested an estimated 560 mg of LATUDA. This patient recovered without sequelae. This patient resumed LATUDA treatment for an additional two months. 10.2. Management of Overdosage Consult a Certified Poison Control Center for up-to-date guidance and advice. There is no specific antidote to LATUDA, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. 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 LATUDA. Similarly the alpha-blocking properties of bretylium might be additive to those of LATUDA, 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 LATUDA-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. 11. DESCRIPTION LATUDA is a psychotropic agent belonging to the chemical class of benzoisothiazol derivatives. Its chemical name is (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride. Its molecular formula is C28H36N4O2S·HCl and its molecular weight is 529.14. The chemical structure is: Lurasidone hydrochloride is a white to off-white powder. It is very slightly soluble in water, practically insoluble or insoluble in 0.1 N HCl, slightly soluble in ethanol, sparingly soluble in methanol, practically insoluble or insoluble in toluene and very slightly soluble in acetone. LATUDA tablets are intended for oral administration only. Each tablet contains 40 mg, or 80 mg of lurasidone hydrochloride. Inactive ingredients are mannitol, pregelatinized starch, croscarmellose sodium, hypromellose, magnesium stearate, Opadry® and carnauba wax. Additionally, the 80 mg tablet contains yellow ferric oxide and FD&C Blue No.2 Aluminum Lake. 12. CLINICAL PHARMACOLOGY 12.1. Mechanism of Action The mechanism of action of lurasidone, as with other drugs having efficacy in schizophrenia, is unknown. It has been suggested that the efficacy of lurasidone in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism. 12.2. Pharmacodynamics In vitro receptor binding studies revealed that lurasidone is an antagonist with high affinity at dopamine D2 receptors (Ki = 0.994 nM) and the 5-hydroxytryptamine (5-HT, serotonin) receptors 5-HT2A (Ki = 0.47 nM) and 5-HT7 (Ki = 0.495 nM), is an antagonist with moderate affinity at human α2C adrenergic receptors (Ki = 10.8 nM), is a partial agonist at serotonin 5-HT1A (Ki = 6.38 nM) receptors, and is an antagonist at α2A adrenergic receptors (Ki = 40.7 nM). Lurasidone exhibits little or no affinity for histamine H1 and muscarinic M1 receptors (IC50 ≥ 1,000 nM and > 1,000 nM, respectively). 12.3. Pharmacokinetics The activity of lurasidone is primarily due to the parent drug. The pharmacokinetics of lurasidone is dose-proportional within a total daily dose range of 20 mg to 160 mg. Steady-state concentrations of lurasidone are reached within 7 days of starting LATUDA. Following administration of 40 mg of LATUDA, the mean (%CV) elimination half-life was 18 (7) hours. Absorption and Distribution: Lurasidone is absorbed and reaches peak serum concentrations in approximately 1-3 hours. It is estimated that 9-19% of an administered dose is absorbed. Following administration of 40 mg of LATUDA, the mean (%CV) apparent volume of distribution was 6173 (17.2) L. Lurasidone is highly bound (~99%) to serum proteins. In a food effect study, lurasidone mean Cmax and AUC were about 3-times and 2-times, respectively, when administered with food compared to the levels observed under fasting conditions. Lurasidone exposure was not affected as meal size was increased from 350 to 1000 calories and was independent of meal fat content [see Dosage and Administration (2.2)]. In clinical studies, establishing the safety and efficacy of LATUDA, patients were instructed to take their daily dose with food [see Dosage and Administration (2.2)]. Metabolism and Elimination: Lurasidone is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation. Lurasidone is metabolized into two active metabolites (ID-14283 and ID-14326) and two major non-active metabolites (ID-20219 and ID-20220). Total excretion of radioactivity in urine and feces combined was approximately 89%, with about 80% recovered in feces and 9% recovered in urine, after a single dose of [14C]-labeled lurasidone. Following administration of 40 mg of LATUDA, the mean (%CV) apparent clearance was 3902 (18.0) mL/min. 13. NONCLINICAL TOXICOLOGY Carcinogenesis: Lifetime carcinogenicity studies were conducted in ICR mice and Sprague-Dawley rats. Lurasidone was administered orally at doses of 30, 100, 300, or 650 (the high dose was reduced from 1200 in males) mg/kg/day to ICR mice and 3, 12, or 36 (high dose reduced from 50) mg/kg/day to Sprague-Dawley rats. In the mouse study, there were increased incidences of malignant mammary gland tumors and pituitary gland adenomas in females at all doses; the lowest dose tested produced plasma levels (AUC) 2 times those in humans receiving the maximum recommended human dose (MRHD) of 80 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 15-25 times those in humans receiving the MRHD. In rats, an increased incidence of mammary gland carcinomas was seen in females at the two higher doses; the no-effect dose of 3 mg/kg produced plasma levels (AUC) 0.7 times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to highest dose tested, which produced plasma levels (AUC) 10 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 in terms of human risk is unknown [see Warnings and Precautions (5.6)]. Mutagenesis: Lurasidone was not genotoxic in the Ames test, the in vitro chromosomal aberration test in Chinese Hamster Lung (CHL) cells, or the in vivo mouse bone marrow micronucleus test. Impairment of Fertility: Lurasidone was administered orally to female rats at doses of 0.1, 1.5, 15, or 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through day 7 of gestation. Estrus cycle irregularities were seen at 1.5 mg/kg and above; the no-effect dose of 0.1 mg/kg is approximately 0.01 times the maximum recommended human dose (MRHD) of 80 mg/day based on body surface area. Fertility was reduced only at the highest dose and this was shown to be reversible after a 14 day drug-free period. The no-effect dose for reduced fertility was 15 mg/kg, which is 1.8 times the MRHD based on body surface area. Fertility was not affected in male rats treated orally with lurasidone for 64 consecutive days prior to mating and during the mating period at doses up to 150 mg/kg/day (12 times the MRHD based on body surface area). 14. CLINICAL STUDIES 14.1. Schizophrenia The efficacy of LATUDA for the treatment of schizophrenia was established in four short-term (6-week), placebo-controlled studies in adult patients (mean age of 38.8 years, range 18-72) who met DSM-IV criteria for schizophrenia. One study included an active-control arm (olanzapine) to assess assay sensitivity. Several instruments were used for assessing psychiatric signs and symptoms in these studies: 1.Positive and Negative Syndrome Scale (PANSS), is a multi-item inventory of general psychopathology used to evaluate the effects of drug treatment in schizophrenia. PANSS total scores may range from 30 to 210. 2.Brief Psychiatric Rating Scale derived (BPRSd), derived from the PANSS, is a multi-item inventory primarily focusing on positive symptoms of schizophrenia, whereas the PANSS includes a wider range of positive, negative and other symptoms of schizophrenia. BPRSd scores may range from 18 to 126. 3.The Clinical Global Impression severity scale (CGI-S) is a validated clinician-rated scale that measures the subject's current illness state on a 1 to 7-point scale. The endpoint associated with each instrument is change from baseline in the total score to the end of week 6. These changes are then compared to placebo changes for the drug and control groups. The results of the studies follow: 1.In a 6-week, placebo-controlled trial (N=145) involving two fixed doses of LATUDA (40 or 120 mg/day), both doses of LATUDA at Endpoint were superior to placebo on the BPRSd total score, and the CGI-S. 2.In a 6-week, placebo-controlled trial (N=180) involving a fixed dose of LATUDA (80 mg/day), LATUDA at Endpoint was superior to placebo on the BPRSd total score, and the CGI-S. 3.In a 6-week, placebo and active-controlled trial (N=473) involving two fixed doses of LATUDA (40 or 120 mg/day) and an active control (olanzapine), both LATUDA doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S. 4.In a 6-week, placebo-controlled trial (N=489) involving three fixed doses of LATUDA (40, 80 or 120 mg/day), only the 80 mg/day dose of LATUDA at Endpoint was superior to placebo on the PANSS total score, and the CGI-S. Thus, the efficacy of LATUDA at doses of 40, 80 and 120 mg/day was established in two studies for each dose. However, the 120 mg dose did not appear to add additional benefit over the 40 mg dose (Table 10). Table 10: Summary of Results for Primary Efficacy Endpoints
a Least Squares Mean (Standard Error) Examination of population subgroups based on age (there were few patients over 65), gender and race did not reveal any clear evidence of differential responsiveness. 16. HOW SUPPLIED/STORAGE AND HANDLING LATUDA tablets are white to off-white, round (40 mg), or pale green, oval (80 mg) and identified with strength specific one-sided debossing , “L40” (40 mg), or “L80” (80 mg). Tablets are supplied in the following strengths and package configurations (Table 11): Table 11: Package Configuration for LATUDA Tablets Tablet Strength Package Configuration NDC Code 40 mg Drum of 1,517,754 51148-001-01 80 mg Drum of 754,561 51148-002-01 Storage Store LATUDA tablets at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [See USP Controlled Room Temperature]. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=88a244d1-eddb-499c-bee2-e1f49056e78f Sunovion制药公司宣布，FDA核准Latuda®（盐酸鲁拉西酮）单药及辅助治疗用于双相抑郁成人患者 2013年7月2日，美国食品药品管理局(FDA)核准了Latuda®（盐酸鲁拉西酮）的两个新适应证，一是作为单药治疗、二是作为锂盐或丙戊酸的辅助治疗，用于成人患者中双相I型障碍（双相抑郁）相关的重性抑郁发作。 大日本住友制药株式会社董事长、总裁兼首席执行官多田正世说：“这两项核准不仅对Sunovion和DSP、而且对成百万上千万罹患双相障碍、与双相抑郁症状斗争的美国人来说，都是一个重大的里程碑。我们期待着在美国启动的强大根基上，将LATUDA推向世界其他市场。此外，我们正在日本准备开展治疗双相I型障碍（双相抑郁）的3期临床试验，日本是我们的重要市场，治疗精神分裂症的3期临床试验已在进行中。这是Sunovion和DSP为精神疾病患者研发和商业化新药的持续承诺的一部分。” 两项双盲、随机、安慰剂对照、为期6周的临床试验获得阳性结果，支持了LATUDA单药（PREVAIL 2研究）和（添加至锂盐或丙戊酸背景治疗）辅助（PREVAIL 1研究）治疗双相抑郁成人患者的两项新适应证。这两项研究中，预设的主要终点是抑郁症状的减轻，衡量指标是《蒙哥马利-阿斯博格抑郁量表》(MADRS)总分基线至第6周的变化。关键的次要终点（即按多重比较进行校正）是《临床总评量表-双相版-病情严重程度》(CGI-BP-S)评分基线至第6周的变化。其他次要终点包括：有效率、痊愈率、《汉密尔顿焦虑量表》(HAM-A)、《席罕残疾量表》(SDS)、《抑郁症状快速自评问卷》(QIDS-SR16)和《生活质量、愉悦度和满意度简明问卷》(Q-LES-Q-SF)基线至第6周的变化。 这两项研究均显示，研究终点时，LATUDA治疗组的MADRS减分与安慰剂组有统计学显著差异，两组的显著差异早在治疗第2周就已显现。此外，这两项研究的次要终点均显示，第6周时，LATUDA组患者的改善与安慰剂组有统计学显著差异，这些次要终点包括CGI-BP-S、有效率、痊愈率、焦虑症状、抑郁自评，以及功能发挥、生活质量和生活愉悦感的指标。 LATUDA单药组患者最常见的不良反应（任何剂量组中发生率≥5%且发生率至少比安慰剂组高2倍）有静坐不能、锥体外系症状、嗜睡、恶心、呕吐、腹泻和焦虑；任何不良反应所致的停药率，LATUDA组为6.0%，安慰剂组为5.4%。LATUDA辅助组患者最常见的不良反应（任何剂量组中发生率≥5%且发生率至少比安慰剂组高2倍）有静坐不能和嗜睡；任何不良反应所致的停药率，LATUDA组为5.8%，安慰剂组为4.8%。LATUDA组患者还可出现体重、体重指数(BMI)、血脂参数和血糖控制指标的变化，但发生率较低。 Case Western Reserve大学医疗中心精神病学教授兼心境障碍课题负责人Joseph Calabrese, M.D.说：“双相障碍患者有症状时，多数为抑郁相。该相常导致功能受损、生活质量严重下降，可能导致自杀企图的风险增高。不幸的是，专门获准治疗双相抑郁症状的药物很少，因此患者及其家属有很大一部分医疗需求未获满足。” Sunovion制药公司执行副总裁兼首席医学官Antony Loebel, M.D.说：“LATUDA的药理特性、连同临床前和初步的临床结果，提示它对双相障碍相关的抑郁发作可能有效。治疗双相抑郁的药物在临床试验中历来难以显现有效性，但鉴于未获满足的大量需求，我们坚信这是正确的道路。确凿证据证明，LATUDA单药及辅助治疗双相抑郁有效、安全，我们很高兴它获得了这两个新适应证。” 关于双相抑郁 双相障碍是一种精神疾病，特点是致残性的心境波动，美国约有1040万成人患者。2,3 双相I型障碍的特点是一生中至少有一次躁狂或混合型发作；患者也常有一次或多次重性抑郁发作。4多数双相障碍患者有症状时，多为抑郁相，而躁狂相较少。5 双相抑郁是指双相障碍的抑郁相。4 双相抑郁相关的重性抑郁发作症状包括：心境低落、活动时丧失兴趣或愉悦感、体重大幅减轻、失眠、疲乏、无价值感、注意力难以集中、反复出现死亡意念或自杀企图。4 双相障碍时，患者因各类内科疾病而过早死亡的风险翻倍，这些疾病包括肥胖、糖尿病和心血管疾病。6,7,8 双相障碍是全球第六大致残病因，也位居美国十大致残病因之列。9,10 关于LATUDA LATUDA是一种处方药，用于治疗： •单用或与锂盐或丙戊酸合用治疗双相I型障碍成人患者的抑郁发作 •成人精神分裂症 一项为期6周的单药治疗对照研究和一项为期6周的辅助治疗对照研究确立了LATUDA作为①单药治疗和②锂盐或丙戊酸的辅助治疗用于成人患者中双相I型障碍（双相抑郁）相关的重性抑郁发作的有效性。五项为期6周的对照研究确立了LATUDA治疗精神分裂症成人患者的有效性。LATUDA长期用药的疗效，即6周以上的疗效，尚未经对照研究确立。因此，医生若选用LATUDA作为长期用药，必须定期重新评估该药对该个例患者的长期效用。LATUDA治疗双相障碍相关的躁狂的有效性尚未确立。 LATUDA作为单药治疗或锂盐或丙戊酸的辅助治疗用于双相抑郁成人患者的推荐起始剂量为20毫克/天，与食物（至少350卡路里）同服，无需递增初始剂量。研究显示，LATUDA治疗双相抑郁患者的有效剂量范围介于20毫克/天至120毫克/天。双相抑郁患者的最大推荐剂量为120毫克/天。单药治疗研究中，平均而言，与LATUDA剂量介于20毫克/天至60毫克/天的患者相比，LATUDA剂量介于80毫克/天至120毫克/天的患者未见额外的有效性。 LATUDA治疗精神分裂症成人患者的推荐起始剂量为40毫克/天，与食物（至少350卡路里）同服，无需递增初始剂量。研究显示，LATUDA治疗精神分裂症患者的有效剂量范围介于40毫克/天至160毫克/天。精神分裂症患者的最大推荐剂量为160毫克/天。 中重度肝肾损害患者的推荐起始剂量为20毫克/天。中重度肾脏损害患者和中度肝损患者的剂量不得超过80毫克/天，重度肝损患者的剂量不得超过40毫克/天。LATUDA不得与强效CYP3A4抑制剂（例如酮康唑、克拉霉素、利托那韦、伏立康唑、米贝拉地尔）合用。若先处方LATUDA、然后添加中效CYP3A4抑制剂（例如地尔硫卓、阿扎那韦、红霉素、氟康唑、维拉帕米），则LATUDA剂量必须减至原初剂量水平的一半。若先处方中效CYP3A4抑制剂、然后添加LATUDA，则LATUDA的推荐起始剂量为20毫克/天。最大推荐剂量为80毫克/天。服用LATUDA的患者应避免食用葡萄柚和葡萄柚汁。LATUDA不得与强效CYP3A4诱导剂（例如利福平、阿伐麦布、贯叶连翘、苯妥英、卡马西平）合用。若LATUDA与中效CYP3A4诱导剂合用，在CYP3A4诱导剂慢性（7天或更长）治疗后，LATUDA的剂量可能需要增加。 LATUDA的重要安全性信息和适应证 警示语： 罹患痴呆相关精神病的老年患者死亡率升高；自杀意念和行为增多 •罹患痴呆相关精神病（因意识模糊和记忆力丧失而失去现实接触）的老年患者使用此类药物治疗时，死亡风险高于服用安慰剂（糖丸）的患者。LATUDA未获准用于治疗此类患者。 •部分儿童、青少年和低龄成人服用抗抑郁药时，自杀意念和举动的风险升高。所有年龄段的患者在启用药物时，均应密切观察抑郁恶化、自杀意念或举动、行为异常变化、兴奋和激惹。患者、家属和照料者应密切留意任何变化，尤其是心境、行为、思维或感觉的突然变化。抗抑郁药启用或变换剂量时，此举极为重要。此类症状的任何变化均应立即报告医生。LATUDA未获准用于18岁以下患者。 神经阻滞剂恶性综合征(NMS)：NMS是LATUDA及类似药物用药中罕见的、可能致命的副作用。患者若出现高热、肌肉僵硬、意识模糊、脉搏、心率或血压变化、或肌肉疼痛和无力，必须立即致电医生。患者若出现NMS，必须停用LATUDA。 迟发性运动障碍(TD)：TD是LATUDA及类似药物用药中出现的一种严重的、有时永久性的副作用。患者用药中若出现无法控制面部、舌头或身体其他部分的运动，有可能是TD的体征，必须告知医生。LATUDA即使停药，TD也不一定会消退。TD也可能在LATUDA停药后出现。 代谢变化 高血糖：LATUDA及类似药物用药中会出现高血糖和糖尿病。患者若有糖尿病或糖尿病的危险因素，必须在LATUDA启用时和用药中检测血糖。糖尿病的并发症后果可能很严重，甚至危及生命。患者若有血糖问题或糖尿病的体征，例如全天口渴、频繁排尿或感觉虚弱或饥饿，必须告知其健康保健提供者。 高胆固醇和甘油三酯：LATUDA用药中可出现甘油三酯和LDL（坏）胆固醇升高和HDL（好）胆固醇降低。 体重增加：部分患者服用LATUDA中可能出现体重增加。处方医生应定期测量患者的体重。 其他重要警示 •其他风险可能包括：站起时感觉头晕或头重脚轻、白细胞减少（可能致命）或吞咽困难。患者若出现上述情况中任何一项，应告知医生。 •LATUDA及类似药物可升高催乳素水平。患者若出现停经、泌乳或乳房增大或阳痿，应告知医生。 •患者若有癫痫史、既往有过癫痫或罹患增加癫痫风险的疾病，应告知医生。 •患者若有长时间的肌肉异常痉挛或收缩，有可能是运动障碍的体征，应告知其健康保健提供者。 •LATUDA可影响患者的判断力、思维和运动技能。患者在知晓LATUDA对身体的影响之前，不得开车或操纵有危险的机器。 •LATUDA可增加热敏感性。患者有可能难以降温。锻炼或从事有可能引起脱水或体温升高的活动时应谨慎。 •患者若正在或打算服用任何处方药和非处方药，应告知其健康保健提供者，因为LATUDA可能有药物相互作用的风险。服用LATUDA期间应避免饮酒。 •患者若正在妊娠或打算妊娠，应告知其健康保健提供者。服用LATUDA期间应避免哺乳。 临床研究中LATUDA最常见的副作用： •双相抑郁成人中包括：坐立不安或需要活动的内在感觉（静坐不能）；难以移动、移动缓慢、肌肉僵硬或震颤；以及嗜睡 •精神分裂症成人中包括：嗜睡；坐立不安或需要活动的内在感觉（静坐不能）；难以移动、移动缓慢、肌肉僵硬或震颤；以及恶心 此处并非安全性信息的完整总结。患者请与其医生讨论处方LATUDA的完整处方信息。 鼓励患者向FDA上报处方药的负面副作用。请访问www.fda.gov/medwatch or call 1-800-FDA-1088。 适应证 LATUDA用于治疗： •单用或与锂盐或丙戊酸合用治疗双相I型障碍（双相抑郁）成人患者的抑郁发作 •成人精神分裂症 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
