Drug Safety-related Labeling Changes (SrLC)

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LATUDA (NDA-200603)

(LURASIDONE HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/04/2019 (SUPPL-35)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Metabolic Changes

(additions underlined)

Pediatric Patients (6 to 17 years)

In a 104-week, open-label study in pediatric patients with schizophrenia, bipolar depression, or autistic disorder, 7 % of patients with a normal baseline fasting glucose experienced a shift to high at endpoint while taking lurasidone.

Pediatric Patients (6 to 17 years)

In a 104-week, open-label study of pediatric patients with schizophrenia, bipolar depression, or autistic disorder, shifts in baseline fasting cholesterol from normal to high at 27% (HDL cholesterol) of patients taking lurasidone. Of patients with normal baseline fasting triglycerides, 12% experienced shifts to high.

Pediatric Patients (6 to 17 years)

In a long-term, open-label study that enrolled pediatric patients with schizophrenia, bipolar depression, or autistic disorder from three short-term, placebo-controlled trials, 54% (378/701) received lurasidone for 104 weeks. The mean increase in weight from open-label baseline to Week 104 was 5.85 kg. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of children and adolescents by comparisons to age- and sex-matched population standards. A z-score change <0.5 SD is considered not clinically significant. In this trial, the mean change in z-score from open-label baseline to Week 104 was -0.06 SD for body weight and -0.13 SD for body mass index (BMI), indicating minimal deviation from the normal curve for weight gain.

5.7 Hyperprolactinemia

(additions underlined)

 

Pediatric Patients (6 to 17 years)

In a 104-week, open-label study of pediatric patients with schizophrenia, bipolar depression, or autistic disorder, the median changes from baseline to endpoint in serum prolactin levels were

-0.20 ng/mL (all patients), -0.30 ng/mL (females), and -0.05 ng/mL (males). The proportions of patients with a markedly high prolactin level (greater than or equal to 5 times the upper limit of normal) at any time during open-label treatment were 2% (all patients), 3% (females), and 1% (males).

Adverse events among females in this trial that are potentially prolactin-related include galactorrhea (0.6%). Among male patients in this study, decreased libido was reported in one patient (0.2%) and there were no reports of impotence, gynecomastia, or galactorrhea.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

breast enlargement, breast pain, galactorrhea, erectile dysfunction, priapism

 

Pediatric Patients (6 to 17 years)

In a 104-week, open-label study in pediatric patients with schizophrenia, bipolar depression, or autistic disorder, the mean change from baseline to Week 104 in serum creatinine was +0.07 mg/dL. In patients with a normal serum creatinine at baseline, 6% experienced a shift to high at endpoint.

8 Use in Specific Populations

8.4 Pediatric Use

(additions underlined)

In a long-term, open-label study that enrolled pediatric patients (age 6 to 17 years) with schizophrenia, bipolar depression, or autistic disorder from three short-term, placebo-controlled trials, 54% (378/701) received lurasidone for 104 weeks. There was one adverse event in this trial that was considered possibly drug-related and has not been reported in adults receiving lurasidone: a 10 year old male experienced a prolonged, painful erection, consistent with priapism, that led to treatment discontinuation.


In this trial, the mean increase in height from open-label baseline to Week 104 was 4.94 cm. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of children and adolescents by comparisons to age- and sex- matched population standards. A z-score change <0.5 SD is considered not clinically significant. In this trial, the mean change in height z-score from open-label baseline to Week 104 was +0.05 SD, indicating minimal deviation from the normal growth curve.

03/05/2018 (SUPPL-29)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.11 Seizures

(additions underlined)

Bipolar Depression Monotherapy

In the adult and pediatric 6-week, flexible-dose, placebo-controlled monotherapy bipolar depression studies, no patients experienced seizures/convulsions.

5.12 Potential for Cognitive and Motor Impairment

(additions underlined)

Bipolar Depression

Adults

 Monotherapy

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, somnolence was reported by 11.4% (20/175) of patients treated with LATUDA 20 to 80 mg/day compared to 5.8% (10/172) of placebo treated patients.

5.14 Activation of Mania/Hypomania

(addition underlined)

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

5.4 Neuroleptic Malignant Syndrome

(additions underlined)

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. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

If NMS is suspected, immediately discontinue LATUDA and provide intensive symptomatic treatment and monitoring.

5.5 Tardive Dyskinesia


Additions underlined)

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 or may even arise after discontinuation of treatment.

5.6 Metabolic Changes

Bipolar Depression

Adults

Monotherapy

Pediatric Patients (10 to 17 years)

In studies of pediatric patients 10 to 17 years and adults with bipolar depression, changes in fasting glucose were similar. In the 6-week, placebo-controlled study of pediatric patients with bipolar depression, mean change in fasting glucose was +1.6 mg/dL for LATUDA 20 to 80 mg/day (n=145) and -0.5 mg/dL for placebo (n=145).

 

 

Bipolar Depression

Adults

 Monotherapy

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, mean change in fasting cholesterol was -6.3 mg/dL for LATUDA 20 to 80 mg/day (n=144) and -

1.4 mg/dL for placebo (n=145), and mean change in fasting triglyceride was -7.6 mg/dL for LATUDA 20 to 80 mg/day (n=144) and +5.9 mg/dL for placebo (n=145).

5.7 Hyperprolactinemia

(additions underlined)

Adjunctive Therapy with Lithium or Valproate

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was +1.10 ng/mL and was +0.50 ng/mL for placebo-treated patients. For LATUDA-treated patients, the median change from baseline to endpoint for males was +0.85 ng/mL and for females was +2.50 ng/mL. Median changes for prolactin are shown in Table 18.

(please refer to label to view Table 8)

The proportion of patients with prolactin elevations greater than or equal to 5x ULN was 0% for LATUDA-treated patients and 0.6% for placebo-treated patients. The proportion of female patients with prolactin elevations greater than or equal to 5x ULN was 0% for LATUDA-treated patients and 1.3% for placebo-treated female patients. No male patients in the placebo or LATUDA treatment groups had prolactin elevations greater than or equal to 5x ULN.

5.9 Orthostatic Hypotension and Syncope

(additions underlined)

Bipolar Depression

 Adults

 Monotherapy

 

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, there were no reported adverse events of orthostatic hypotension or syncope.

Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with LATUDA 20 to 80 mg/day, compared to 0.6% with placebo.

6 Adverse Reactions

6.1 Clinical Trials Experience

(extensive additions, please refer to label)

6.2 Postmarketing Experience

(additions underlined)

Hypersensitivity Reactions: Urticaria, throat swelling, tongue swelling, dyspnea, and rash. Metabolism and Nutrition Disorders: Hyponatremia

8 Use in Specific Populations

8.4 Pediatric Use

(additions underlined)

The safety and effectiveness of LATUDA has not been established in pediatric patients less than 13 years of age with schizophrenia.

Bipolar Depression

The safety and effectiveness of LATUDA 20 to 80 mg/day for the treatment of bipolar depression in pediatric patients (10 to 17 years) was established in a 6-week, placebo-controlled clinical study in 347 pediatric patients.

The safety and effectiveness of LATUDA has not been established in pediatric patients less than 10 years of age with bipolar depression.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(additions and revisions, please refer to label)

PATIENT COUNSELING INFORMATION

(additions underlined)

Pregnancy

Advise patients that LATUDA may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LATUDA during pregnancy

09/25/2017 (SUPPL-30)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(addition underlined)

The following adverse reactions have been identified during postapproval use of Latuda. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity Reactions: Urticaria, throat swelling, tongue swelling, and dyspnea. Hyponatremia.

02/23/2017 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Falls

(Newly added subsection)

Latuda may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

6 Adverse Reactions

6.2 Postmarketing Experience

(Newly added subsection)

The  following  adverse  reactions  have  been  identified  during  postapproval use  of  Latuda. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity Reactions: Urticaria, throat swelling, tongue swelling, and dyspnea.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE LATUDA (luh-TOO-duh) (lurasidone hydrochloride) tablets

(Additions and/or revisions are underlined)

Do not take LATUDA if you are:

  • allergic to lurasidone hydrochloride or any of the ingredients in LATUDA. See the end of this Medication Guide for a complete list of ingredients in LATUDA.

01/27/2017 (SUPPL-26)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA?RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS

Suicidal Thoughts and Behaviors

LATUDA is not approved for use in pediatric patients with depression.

5 Warnings and Precautions

5.10 Seizures

(Additions and/or revisions are underlined)

Schizophrenia

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

 

Bipolar Depression

Monotherapy

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

Adjunctive Therapy with Lithium or Valproate

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

5.11 Potential for Cognitive and Motor Impairment

(Additions and/or revisions are underlined)

Schizophrenia

Adolescents

In the short-term, placebo-controlled adolescent schizophrenia study, somnolence was reported by 14.5% (31/214) of patients treated with LATUDA (15.5% LATUDA 40 mg and 13.5% LATUDA 80 mg,/day) compared to 7.1% (8/112) of placebo patients.

 

Bipolar Depression

Monotherapy

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

Adjunctive Therapy with Lithium or Valproate

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

5.2. Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

(Additions and/or revisions are underlined)

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000  adult patients, and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. 

LATUDA is not approved for use in pediatric patients with depression.

5.6 Metabolic Changes

(Additions and/or revisions are underlined)

Schizophrenia

Adults

Table 3: Change in Fasting Glucose in Adult Schizophrenia Studies

 

Adolescents

In studies of adolescents and adults with schizophrenia, changes in fasting glucose were similar. In the short-term, placebo-controlled study of adolescents, fasting serum glucose mean values were -+1.3 for placebo (n=95), +0.1 for 40mg (n=90), and +1.8 for 80mg (n=92).

 

Bipolar Depression

Monotherapy

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

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

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 5.

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

 

Dyslipidemia

Schizophrenia

Adults

Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 6: Change in Fasting Lipids in Adult Schizophrenia Studies

Table 6: Change in Fasting Lipids in Adult Schizophrenia Studies

Adolescents

In the adolescent short-term, placebo-controlled study, fasting serum cholesterol mean values were -9.6 for placebo (n=95), -4.4 for 40mg (n=89), and +1.6 for 80mg (n=92), and fasting serum triglyceride mean values were +0.1 for placebo (n=95), -0.6 for 40mg (n=89), and +8.5 for 80mg (n=92).

 

Bipolar Depression

Monotherapy

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

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

Adjunctive Therapy with Lithium or Valproate

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

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

 

Weight Gain

Schizophrenia

Adults

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

Adolescents

Data from the short-term, placebo-controlled adolescent schizophrenia study are presented in Table 10. The mean weight gain was +0.5 kg for LATUDA-treated patients compared to +0.2 kg for placebo-treated patients. The proportion of patients with a greater than or equal to 7% increase in body weight (at Endpoint) was 3.3% for LATUDA-treated patients versus 4.5% for placebo-treated patients.

Table 10: Mean Change in Weight (kg) from Baseline in the Adolescent Schizophrenia Study  (Table revised; please refer to label)

 

Bipolar Depression

Monotherapy

Data from the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 11.

Table 11: Mean Change in Weight (kg) from Baseline in the Adult Monotherapy Bipolar Depression Study

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 12.

Table 12: Mean Change in Weight (kg) from Baseline in the Adult Adjunctive Therapy Bipolar Depression Studies

5.7 Hyperprolactinemia

(Additions and/or revisions are underlined)

Schizophrenia

Adults

…Median changes for prolactin by dose are shown in Table 13.

Table 13: Median Change in Prolactin (ng/mL) from Baseline in Adult Schizophrenia Studies

Adolescents

In the short-term, placebo-controlled adolescent schizophrenia study, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was +1.1 ng/mL and was +0.1 ng/mL for placebo-treated patients. For LATUDA-treated patients, the median change from baseline to endpoint for males was +1.0 ng/mL and for females was +2.6 ng/mL. Median changes for prolactin by dose are shown in Table 14.

Table 14: Median Change in Prolactin (ng/mL) from Baseline in the Adolescent Schizophrenia Study

(New table added; please refer to label)

The proportion of patients with prolactin elevations ?5x ULN was 0.5% for LATUDA-treated patients  versus 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 1.3% for LATUDA-treated patients versus 0% for placebo- treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% versus 1.6% for placebo-treated male patients.

 

Bipolar Depression

Monotherapy

The median change from baseline to endpoint in prolactin levels, in the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study… 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 15.

Table 15: Median Change in Prolactin (ng/mL) from Baseline in the Adult Monotherapy Bipolar Depression Study

Adjunctive Therapy with Lithium or Valproate

The median change from baseline to endpoint in prolactin levels, in the  adult  short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/mL with LATUDA 20 to 120 mg/day compared to 0.0 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +2.4 ng/mL and for females was +3.2 ng/mL. Median changes for prolactin across the dose range are shown in Table 16.

Table 16: Median Change in Prolactin (ng/mL) from Baseline in the Adult Adjunctive Therapy Bipolar Depression Studies

5.9 Orthostatic Hypotension and Syncope

(Additions and/or revisions are underlined)

Schizophrenia

Adolescents

The incidence of orthostatic hypotension reported as adverse events from the short-term, placebo-controlled adolescent schizophrenia study was 0.5% (1/214) in LATUDA-treated patients and 0% (0/112) in placebo-treated patients. No syncope event was reported.

Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0% with LATUDA 40 mg and 2.9% with LATUDA 80 mg, compared to 1.8% with placebo.

 

Bipolar Depression

Monotherapy

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

Adjunctive Therapy with Lithium or Valproate

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

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive revisions; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LATUDA during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and- researchprograms/pregnancyregistry/.

 

Risk Summary

There are no studies of LATUDA use in pregnant women. The limited available data are not sufficient to inform a drug-associated risk of birth defects or miscarriage. In animal reproduction studies, no teratogenic effects were seen in pregnant rats and rabbits given lurasidone during the period of organogenesis at doses approximately 1.5- and 6-times, the maximum recommended human dose (MRHD) of 160 mg/day, respectively based on mg/m2 body surface area.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.


Clinical Considerations

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.

 

Data

Animal Data

Pregnant rats were treated with oral lurasidone at doses of 3, 10, and 25 mg/kg/day during the period of organogenesis. These doses are 0.2, 0.6, and 1.5 times the MRHD of 160 mg/day based on mg/m2 body surface area. No teratogenic or embryo-fetal effects were observed up to 1.5 times the MHRD of 160 mg/day, based on mg/m2.

Pregnant rabbits were treated with oral lurasidone at doses of 2, 10, and 50 mg/kg/day during the period of organogenesis. These doses are 0.2, 1.2 and 6 times the MRHD of 160 mg/day based on mg/m2 No teratogenic or embryo-fetal effects were observed up to 6 times the MHRD of 160 mg/day based on mg/m2.

Pregnant rats were treated with oral lurasidone at doses of 0.4, 2, and 10 mg/kg/day during the periods of organogenesis and lactation. These doses are 0.02, 0.1 and 0.6 times the MRHD of 160 mg/day based on mg/m2. No pre- and postnatal developmental effects were observed up to 0.6 times the MRHD of 160 mg/day, based on mg/m2.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

Lactation studies have not been conducted to assess the presence of lurasidone in human milk, the effects on the breastfed infant, or the effects on milk production. Lurasidone is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for LATUDA and any potential adverse effects on the breastfed infant from LATUDA or from the underlying maternal condition.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

Schizophrenia

The safety and effectiveness of LATUDA 40-mg/day and 80-mg/day for the treatment of schizophrenia in adolescents (13 to 17 years) was established in a 6-week, placebo-controlled clinical study in 326 adolescent  patients.

 

Depression

The safety and effectiveness of LATUDA have not been established with depression.

 

Irritability Associated with Autistic Disorder

The effectiveness of LATUDA in pediatric patients for the treatment of irritability associated with autistic disorder has not been established.

Efficacy was not demonstrated in a 6-week study   evaluating LATUDA 20 mg/day and 60 mg/day for the treatment of pediatric patients 6 to 17 years of age with irritability associated with autistic disorder diagnosed by Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., Text Revision [DSM-IV-TR] criteria. The primary objective of the study   as measured by improvement from Baseline in the irritability subscale of the Aberrant Behavior Checklist (ABC) at Endpoint (Week 6) was not met. A total of 149 patients were randomized to LATUDA or placebo. Vomiting occurred at a higher rate than reported in other LATUDA studies (4/49 or 8% for 20mg, 14/51 or 27% for 60mg, and 2/49 or 4% for placebo), particularly in children ages 6 to 12 (13 out of 18 patients on LATUDA with vomiting).

 

Juvenile animal studies

Adverse effects were seen on growth, physical and neurobehavioral development at doses as low as 0.2 times the MRHD based on mg/m2.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Pregnancy

Advise patients that LATUDA may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy.

MEDICATION GUIDE

(Additions and/or revisions are underlined)

What is the most important information I should know about LATUDA? LATUDA may cause serious side effects, including:

  1. Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). Medicines like LATUDA can increase the risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). LATUDA should not be used to treat people with dementia-related psychosis.

  2. Increased risk of suicidal thoughts or actions (antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions).

  • Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) depression, bipolar illness (also called manic-depressive illness), or a history of suicidal thoughts or actions.

What is LATUDA?

LATUDA is a prescription medicine used to treat:

  • schizophrenia in people 13 years of age or older

  • depressive episodes associated with bipolar I disorder, alone or with lithium or valproate in adults

It is not known if LATUDA is safe and effective in people under 13 years of age.

Do not take LATUDA if you are:

  • taking certain other medicines called CYP3A4 inhibitors or inducers including ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, rifampin, avasimibe, St. John’s wort, phenytoin, or carbamazepine. Ask your healthcare provider if you are not sure if you are taking any of these medicines.

Before taking LATUDA, tell your healthcare provider about all of your medical conditions, including if you:

  • are pregnant or plan to become pregnant. It is not known if LATUDA will harm your unborn baby. Using LATUDA in the last trimester of pregnancy may cause muscle movement problems, medicine withdrawal symptoms, or both in your newborn.

  • If you become pregnant while taking LATUDA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/.

  • are breastfeeding or plan to breastfeed. It is not known if LATUDA passes into your breast milk.

Especially tell your healthcare provider if you take or plan to take medicines for:

  • depression

  • high blood pressure

  • Parkinson’s disease

  • Trouble sleeping

  • Abnormal heart beats or rhythm

  • Epilepsy

  • Inflammation

  • psychosis

Know the medicines you take. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.

What should I avoid while taking LATUDA?

  • Avoid eating grapefruit or drinking grapefruit juice while you take LATUDA since these can affect the amount of LATUDA in the blood.

The most common side effects of LATUDA in adults include:

  • sleepiness or drowsiness

  • restlessness and feeling like you need to move around (akathisia)

  • nausea

The most common side effects of LATUDA in adolescents (13 to 17 years old) include:

  • sleepiness or drowsiness

  • restlessness and feeling like you need to move around (akathisia)

How should I store LATUDA?

  • Store LATUDA tablets at room temperature between 68°F to 77°F (20°C to 25°C).

01/27/2017 (SUPPL-27)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA?RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS

Suicidal Thoughts and Behaviors

LATUDA is not approved for use in pediatric patients with depression.

5 Warnings and Precautions

5.10 Seizures

(Additions and/or revisions are underlined)

Schizophrenia

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

 

Bipolar Depression

Monotherapy

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

Adjunctive Therapy with Lithium or Valproate

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

5.11 Potential for Cognitive and Motor Impairment

(Additions and/or revisions are underlined)

Schizophrenia

Adolescents

In the short-term, placebo-controlled adolescent schizophrenia study, somnolence was reported by 14.5% (31/214) of patients treated with LATUDA (15.5% LATUDA 40 mg and 13.5% LATUDA 80 mg,/day) compared to 7.1% (8/112) of placebo patients.

 

Bipolar Depression

Monotherapy

In the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, somnolence was reported by 7.3% (12/164) and 13.8% (23/167) with LATUDA 20 to 60 mg and

80 to120 mg, respectively compared to 6.5% (11/168) of placebo patients.

Adjunctive Therapy with Lithium or Valproate

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

5.2. Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

(Additions and/or revisions are underlined)

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000  adult patients, and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. 

LATUDA is not approved for use in pediatric patients with depression.

5.6 Metabolic Changes

(Additions and/or revisions are underlined)

Schizophrenia

Adults

Table 3: Change in Fasting Glucose in Adult Schizophrenia Studies

 

Adolescents

In studies of adolescents and adults with schizophrenia, changes in fasting glucose were similar. In the short-term, placebo-controlled study of adolescents, fasting serum glucose mean values were -+1.3 for placebo (n=95), +0.1 for 40mg (n=90), and +1.8 for 80mg (n=92).

 

Bipolar Depression

Monotherapy

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

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

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 5.

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

 

Dyslipidemia

Schizophrenia

Adults

Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 6: Change in Fasting Lipids in Adult Schizophrenia Studies

Table 6: Change in Fasting Lipids in Adult Schizophrenia Studies

Adolescents

In the adolescent short-term, placebo-controlled study, fasting serum cholesterol mean values were -9.6 for placebo (n=95), -4.4 for 40mg (n=89), and +1.6 for 80mg (n=92), and fasting serum triglyceride mean values were +0.1 for placebo (n=95), -0.6 for 40mg (n=89), and +8.5 for 80mg (n=92).

 

Bipolar Depression

Monotherapy

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

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

Adjunctive Therapy with Lithium or Valproate

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

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

 

Weight Gain

Schizophrenia

Adults

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

Adolescents

Data from the short-term, placebo-controlled adolescent schizophrenia study are presented in Table 10. The mean weight gain was +0.5 kg for LATUDA-treated patients compared to +0.2 kg for placebo-treated patients. The proportion of patients with a greater than or equal to 7% increase in body weight (at Endpoint) was 3.3% for LATUDA-treated patients versus 4.5% for placebo-treated patients.

Table 10: Mean Change in Weight (kg) from Baseline in the Adolescent Schizophrenia Study  (Table revised; please refer to label)

 

Bipolar Depression

Monotherapy

Data from the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 11.

Table 11: Mean Change in Weight (kg) from Baseline in the Adult Monotherapy Bipolar Depression Study

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 12.

Table 12: Mean Change in Weight (kg) from Baseline in the Adult Adjunctive Therapy Bipolar Depression Studies

5.7 Hyperprolactinemia

(Additions and/or revisions are underlined)

Schizophrenia

Adults

…Median changes for prolactin by dose are shown in Table 13.

Table 13: Median Change in Prolactin (ng/mL) from Baseline in Adult Schizophrenia Studies

Adolescents

In the short-term, placebo-controlled adolescent schizophrenia study, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was +1.1 ng/mL and was +0.1 ng/mL for placebo-treated patients. For LATUDA-treated patients, the median change from baseline to endpoint for males was +1.0 ng/mL and for females was +2.6 ng/mL. Median changes for prolactin by dose are shown in Table 14.

Table 14: Median Change in Prolactin (ng/mL) from Baseline in the Adolescent Schizophrenia Study

(New table added; please refer to label)

The proportion of patients with prolactin elevations ?5x ULN was 0.5% for LATUDA-treated patients  versus 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 1.3% for LATUDA-treated patients versus 0% for placebo- treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% versus 1.6% for placebo-treated male patients.

 

Bipolar Depression

Monotherapy

The median change from baseline to endpoint in prolactin levels, in the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study… 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 15.

Table 15: Median Change in Prolactin (ng/mL) from Baseline in the Adult Monotherapy Bipolar Depression Study

Adjunctive Therapy with Lithium or Valproate

The median change from baseline to endpoint in prolactin levels, in the  adult  short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/mL with LATUDA 20 to 120 mg/day compared to 0.0 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +2.4 ng/mL and for females was +3.2 ng/mL. Median changes for prolactin across the dose range are shown in Table 16.

Table 16: Median Change in Prolactin (ng/mL) from Baseline in the Adult Adjunctive Therapy Bipolar Depression Studies

5.9 Orthostatic Hypotension and Syncope

(Additions and/or revisions are underlined)

Schizophrenia

Adolescents

The incidence of orthostatic hypotension reported as adverse events from the short-term, placebo-controlled adolescent schizophrenia study was 0.5% (1/214) in LATUDA-treated patients and 0% (0/112) in placebo-treated patients. No syncope event was reported.

Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0% with LATUDA 40 mg and 2.9% with LATUDA 80 mg, compared to 1.8% with placebo.

 

Bipolar Depression

Monotherapy

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

Adjunctive Therapy with Lithium or Valproate

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

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive revisions; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LATUDA during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and- researchprograms/pregnancyregistry/.

 

Risk Summary

There are no studies of LATUDA use in pregnant women. The limited available data are not sufficient to inform a drug-associated risk of birth defects or miscarriage. In animal reproduction studies, no teratogenic effects were seen in pregnant rats and rabbits given lurasidone during the period of organogenesis at doses approximately 1.5- and 6-times, the maximum recommended human dose (MRHD) of 160 mg/day, respectively based on mg/m2 body surface area.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.


Clinical Considerations

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.

 

Data

Animal Data

Pregnant rats were treated with oral lurasidone at doses of 3, 10, and 25 mg/kg/day during the period of organogenesis. These doses are 0.2, 0.6, and 1.5 times the MRHD of 160 mg/day based on mg/m2 body surface area. No teratogenic or embryo-fetal effects were observed up to 1.5 times the MHRD of 160 mg/day, based on mg/m2.

Pregnant rabbits were treated with oral lurasidone at doses of 2, 10, and 50 mg/kg/day during the period of organogenesis. These doses are 0.2, 1.2 and 6 times the MRHD of 160 mg/day based on mg/m2 No teratogenic or embryo-fetal effects were observed up to 6 times the MHRD of 160 mg/day based on mg/m2.

Pregnant rats were treated with oral lurasidone at doses of 0.4, 2, and 10 mg/kg/day during the periods of organogenesis and lactation. These doses are 0.02, 0.1 and 0.6 times the MRHD of 160 mg/day based on mg/m2. No pre- and postnatal developmental effects were observed up to 0.6 times the MRHD of 160 mg/day, based on mg/m2.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

Lactation studies have not been conducted to assess the presence of lurasidone in human milk, the effects on the breastfed infant, or the effects on milk production. Lurasidone is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for LATUDA and any potential adverse effects on the breastfed infant from LATUDA or from the underlying maternal condition.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

Schizophrenia

The safety and effectiveness of LATUDA 40-mg/day and 80-mg/day for the treatment of schizophrenia in adolescents (13 to 17 years) was established in a 6-week, placebo-controlled clinical study in 326 adolescent  patients.

 

Depression

The safety and effectiveness of LATUDA have not been established with depression.

 

Irritability Associated with Autistic Disorder

The effectiveness of LATUDA in pediatric patients for the treatment of irritability associated with autistic disorder has not been established.

Efficacy was not demonstrated in a 6-week study   evaluating LATUDA 20 mg/day and 60 mg/day for the treatment of pediatric patients 6 to 17 years of age with irritability associated with autistic disorder diagnosed by Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., Text Revision [DSM-IV-TR] criteria. The primary objective of the study   as measured by improvement from Baseline in the irritability subscale of the Aberrant Behavior Checklist (ABC) at Endpoint (Week 6) was not met. A total of 149 patients were randomized to LATUDA or placebo. Vomiting occurred at a higher rate than reported in other LATUDA studies (4/49 or 8% for 20mg, 14/51 or 27% for 60mg, and 2/49 or 4% for placebo), particularly in children ages 6 to 12 (13 out of 18 patients on LATUDA with vomiting).

 

Juvenile animal studies

Adverse effects were seen on growth, physical and neurobehavioral development at doses as low as 0.2 times the MRHD based on mg/m2.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Pregnancy

Advise patients that LATUDA may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy.

MEDICATION GUIDE

(Additions and/or revisions are underlined)

What is the most important information I should know about LATUDA? LATUDA may cause serious side effects, including:

  1. Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). Medicines like LATUDA can increase the risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). LATUDA should not be used to treat people with dementia-related psychosis.

  2. Increased risk of suicidal thoughts or actions (antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions).

  • Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) depression, bipolar illness (also called manic-depressive illness), or a history of suicidal thoughts or actions.

What is LATUDA?

LATUDA is a prescription medicine used to treat:

  • schizophrenia in people 13 years of age or older

  • depressive episodes associated with bipolar I disorder, alone or with lithium or valproate in adults

It is not known if LATUDA is safe and effective in people under 13 years of age.

Do not take LATUDA if you are:

  • taking certain other medicines called CYP3A4 inhibitors or inducers including ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, rifampin, avasimibe, St. John’s wort, phenytoin, or carbamazepine. Ask your healthcare provider if you are not sure if you are taking any of these medicines.

Before taking LATUDA, tell your healthcare provider about all of your medical conditions, including if you:

  • are pregnant or plan to become pregnant. It is not known if LATUDA will harm your unborn baby. Using LATUDA in the last trimester of pregnancy may cause muscle movement problems, medicine withdrawal symptoms, or both in your newborn.

  • If you become pregnant while taking LATUDA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/.

  • are breastfeeding or plan to breastfeed. It is not known if LATUDA passes into your breast milk.

Especially tell your healthcare provider if you take or plan to take medicines for:

  • depression

  • high blood pressure

  • Parkinson’s disease

  • Trouble sleeping

  • Abnormal heart beats or rhythm

  • Epilepsy

  • Inflammation

  • psychosis

Know the medicines you take. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.

 

What should I avoid while taking LATUDA?

  • Avoid eating grapefruit or drinking grapefruit juice while you take LATUDA since these can affect the amount of LATUDA in the blood.

The most common side effects of LATUDA in adults include:

  • sleepiness or drowsiness

  • restlessness and feeling like you need to move around (akathisia)

  • nausea

The most common side effects of LATUDA in adolescents (13 to 17 years old) include:

  • sleepiness or drowsiness

  • restlessness and feeling like you need to move around (akathisia)

How should I store LATUDA?

  • Store LATUDA tablets at room temperature between 68°F to 77°F (20°C to 25°C).

01/11/2017 (SUPPL-21)

Approved Drug Label (PDF)

Boxed Warning

(section revised, additions underlined)

WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; AND SUICIDAL THOUGHTS AND BEHAVIORS

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 use in patients with dementia-related psychosis.

Suicidal Thoughts and Behaviors

Antidepressants increased the risk of suicidal thoughts and behavior in patients aged 24 years and younger in short-term studies. Monitor closely for clinical worsening and for emergence of suicidal thoughts and behaviors. The safety and efficacy of LATUDA have not been established in pediatric patients.

5 Warnings and Precautions

5.2 Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults

(section revised, additions underlined)

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

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

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

(please refer to label for Table 2)

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

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

6 Adverse Reactions

6.2 Postmarketing Experience

(New subsection added)

Hypersensitivity has been identified as an adverse drug reaction with LATUDA during postapproval use. Hypersensitivity may include symptoms such as angioedema, pruritus, rash, throat swelling, tongue swelling, urticaria and cutaneous reactions such as dermatitis bullous, rash maculopapular, rash pustular, skin eruption and skin exfoliation. As this reaction is reported voluntarily from a population of uncertain size, the incidence rates of this adverse reaction (hypersensitivity) and its symptoms cannot be estimated.

7 Drug Interactions

7.1 Drugs Having Clinically Important Interactions with Latuda

(Extensive additions, please refer to Table 24 in label)

7.2 Drugs Having No Clinically Important Interactions With LATUDA

(New subsection added)

Based on pharmacokinetic studies, no dosage adjustment of LATUDA is required when administered concomitantly with lithium, substrates of P-gp, CYP3A4 or valproate.

8 Use in Specific Populations

8.4 Pediatric Use

(subsection revised, additions underlined)

The safety and effectiveness of LATUDA in pediatric patients have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients.

Juvenile animal studies

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

8.6 Renal Impairment

(New subsection added)

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

8.7 Hepatic Impairment

(New subsection added)

Reduce the maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score greater than or equal to7). Patients with moderate to severe hepatic impairment (Child-Pugh score greater than or equal to 7 ) generally had higher exposure to lurasidone than patients with normal hepatic function. Greater exposure may increase the risk of LATUDA-associated adverse reactions.

8.8 Other Specific Populations

(New subsection added)

No dosage adjustment for LATUDA is required on the basis of a patient’s sex, race, or smoking status.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Extensive revisions, please refer to label)

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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