Drugs Details

Drugs Info of Latuda
Drugs Details
  • Drugs Type  : FDA
  • Date : 12th Feb 2015 05:28 am
  • Brand Name : Latuda
  • Generic Name : lurasidone (Pronunciation: loo RAS i done)
Descriptions

LATUDA is an atypical antipsychotic belonging to the chemical class of benzisothiazol derivatives.

Its chemical name is (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1ylmethyl] 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:

 

LATUDA (lurasidone hydrochloride) Structural Formula Illustration

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 20 mg, 40 mg, 60 mg, 80 mg, or 120 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.

What are the possible side effects of lurasidone (Latuda)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop taking lurasidone and call your doctor at once if you have a serious side effect such as:

  • dizziness, fainting, fast or pounding heartbeats;
  • agitation, hostility, confusion, thoughts about hurting yourself;
  • seizure (convulsions);
  • fever, chills, body aches, flu symptoms, sores in your mouth and throat;
  • high blood sugar (increased thirst, increased urination, hunger, dry mouth,...

Read All Potential Side Effects and See Pictures of Latuda »

What are the precautions when taking lurasidone hcl tablets for oral administration (Latuda)?

See also Warning section.

Before taking lurasidone, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney problems, liver problems, stroke, breast cancer, diabetes (including family history), obesity, low blood pressure, seizures, low white blood cell count, dementia (such as Alzheimer's Disease), trouble swallowing.

This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities...

Read All Potential Precautions of Latuda »

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

Indications

Schizophrenia

LATUDA is indicated for the treatment of patients with schizophrenia.

The efficacy of LATUDA in schizophrenia was established in five 6-week controlled studies of adult patients with schizophrenia [see Clinical Studies].

The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use LATUDA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see DOSAGE AND ADMINISTRATION].

Depressive Episodes Associated with Bipolar I Disorder

Monotherapy

LATUDA is indicated as monotherapy for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). The efficacy of LATUDA was established in a 6-week monotherapy study in adult patients with bipolar depression [see Clinical Studies].

Adjunctive Therapy with Lithium or Valproate

LATUDA is indicated as adjunctive therapy with either lithium or valproate for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). The efficacy of LATUDA as adjunctive therapy was established in a 6-week study in adult patients with bipolar depression who were treated with lithium or valproate [see Clinical Studies].

The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use LATUDA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see DOSAGE AND ADMINISTRATION].

The efficacy of LATUDA in the treatment of mania associated with bipolar disorder has not been established.

Dosage Administration

Schizophrenia

The recommended starting dose of LATUDA is 40 mg once daily. Initial dose titration is not required. LATUDA has been shown to be effective in a dose range of 40 mg per day to 160 mg per day [see Clinical Studies]. The maximum recommended dose is 160 mg per day.

Depressive Episodes Associated with Bipolar I Disorder

The recommended starting dose of LATUDA is 20 mg given once daily as monotherapy or as adjunctive therapy with lithium or valproate. Initial dose titration is not required. LATUDA has been shown to be effective in a dose range of 20 mg per day to 120 mg per day as monotherapy or as adjunctive therapy with lithium or valproate [see Clinical Studies]. The maximum recommended dose, as monotherapy or as adjunctive therapy with lithium or valproate, is 120 mg per day. In the monotherapy study, the higher dose range (80 mg to 120 mg per day) did not provide additional efficacy, on average, compared to the lower dose range (20 to 60 mg per day) [see Clinical Studies].

Administration Instructions

LATUDA should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of LATUDA. Administration with food increases the AUC approximately 2-fold and increases the Cmax approximately 3-fold. In the clinical studies, LATUDA was administered with food [see CLINICAL PHARMACOLOGY].

Dose Modifications in Special Populations

Renal Impairment

Dose adjustment is recommended in moderate (creatinine clearance: 30 to < 50 mL/min) and severe renal impairment (creatinine clearance < 30 mL/min) patients. The recommended starting dose is 20 mg per day. The dose in these patients should not exceed 80 mg per day [see Use in Specific Populations].

Hepatic Impairment

Dose adjustment is recommended in moderate (Child-Pugh Score = 7 to 9) and severe hepatic impairment (Child-Pugh Score = 10 to 15) patients. The recommended starting dose is 20 mg per day. The dose in moderate hepatic impairment patients should not exceed 80 mg per day and the dose in severe hepatic impairment patients should not exceed 40 mg/day [see Use in Specific Populations].

Dose Modifications Due to Drug Interactions

Concomitant Use with CYP3A4 Inhibitors

LATUDA should not be used concomitantly with a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) [see CONTRAINDICATIONS].

If LATUDA is being prescribed and a moderate CYP3A4 inhibitor (e.g. diltiazem, atazanavir, erythromycin, fluconazole, verapamil etc.) is added to the therapy, the LATUDA dose should be reduced to half of the original dose level. Similarly, if a moderate CYP3A4 inhibitor is being prescribed and LATUDA is added to the therapy, the recommended starting dose of LATUDA is 20 mg per day, and the maximum recommended dose of LATUDA is 80 mg per day [see CONTRAINDICATIONS; DRUG INTERACTIONS].

Grapefruit and grapefruit juice should be avoided in patients taking LATUDA, since these may inhibit CYP3A4 and alter LATUDA concentrations [see DRUG INTERACTIONS].

Concomitant Use with CYP3A4 Inducers

LATUDA should not be used concomitantly with a strong CYP3A4 inducer (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.) [see CONTRAINDICATIONS; DRUG INTERACTIONS]. If LATUDA is used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the LATUDA dose after chronic treatment (7 days or more) with the CYP3A4 inducer.

How Supplied

Dosage Forms And Strengths

LATUDA tablets are available in the following shape and color (Table 1) with respective one-sided debossing:

Table 1: LATUDA Tablet Presentations

Tablet Strength Tablet Color/Shape Tablet Markings
20 mg white to off-white round L20
40 mg white to off-white round L40
60 mg white to off white oblong L60
80 mg pale green oval L80
120 mg white to off-white oval L120

Storage And Handling

LATUDA tablets are white to off-white, round (20 mg or 40 mg), white to off-white, oblong (60 mg), pale green, oval (80 mg) or white to off-white, oval (120 mg) and identified with strength-specific one-sided debossing, “L20” (20 mg), “L40” (40 mg), “L80” (80 mg) or “L120” (120 mg). Tablets are supplied in the following strengths and package configurations (Table 26):

Table 26: Package Configuration for LATUDA Tablets

Tablet Strength Package Configuration NDC Code
20 mg Bottles of 30 63402-302-30
Bottles of 90 63402-302-90
Bottles of 500 63402-302-50
Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-302-10 Carton 63402-302-01 Blister
40 mg Bottles of 30 63402-304-30
Bottles of 90 63402-304-90
Bottles of 500 63402-304-50
Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-304-10 Carton 63402-304-01 Blister
60 mg Bottles of 30 63402-306-30
Bottles of 90 63402-306-90
Bottles of 500 63402-306-50
Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-306-10 Carton 63402-306-01 Blister
80 mg Bottles of 30 63402-308-30
Bottles of 90 63402-308-90
Bottles of 500 63402-308-50
Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-308-10 Carton 63402-308-01 Blister
120 mg Bottles of 30 63402-312-30
Bottles of 90 63402-312-90
Bottles of 500 63402-312-50
Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-312-10 Carton 63402-312-01 Blister
Storage

Store LATUDA tablets at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [See USP Controlled Room Temperature].

Manufactured for: Sunovion Pharmaceuticals Inc. Marlborough, MA 01752 USA. Issued: July/2013

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

Side Effects

The following adverse reactions are discussed in more detail in other sections of the labeling:

  • Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
  • Suicidal Thoughts and Behaviors [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
  • Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis [see WARNINGS AND PRECAUTIONS]
  • Neuroleptic Malignant Syndrome [see WARNINGS AND PRECAUTIONS]
  • Tardive Dyskinesia [see WARNINGS AND PRECAUTIONS]
  • Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see WARNINGS AND PRECAUTIONS]
  • Hyperprolactinemia [see WARNINGS AND PRECAUTIONS]
  • Leukopenia, Neutropenia, and Agranulocytosis [see WARNINGS AND PRECAUTIONS]
  • Orthostatic Hypotension and Syncope [see WARNINGS AND PRECAUTIONS]
  • Seizures [see WARNINGS AND PRECAUTIONS]
  • Potential for Cognitive and Motor Impairment [see WARNINGS AND PRECAUTIONS]
  • Body Temperature Dysregulation [see WARNINGS AND PRECAUTIONS]
  • Suicide [see WARNINGS AND PRECAUTIONS]
  • Activation of Mania/Hypomania [see WARNINGS AND PRECAUTIONS]
  • Dysphagia [see WARNINGS AND PRECAUTIONS]
  • Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The information below is derived from an integrated clinical study database for LATUDA consisting of 3799 patients exposed to one or more doses of LATUDA for the treatment of schizophrenia and bipolar depression in placebo-controlled studies. This experience corresponds with a total experience of 1250.9 patient-years. A total of 1106 LATUDA-treated patients had at least 24 weeks and 371 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.

Schizophrenia

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 160 mg (n=1508).

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, extrapyramidal symptoms, and nausea.

Adverse Reactions Associated with Discontinuation of Treatment

A total of 9.5% (143/1508) LATUDA-treated patients and 9.3% (66/708) 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 15.

Table 15: Adverse Reactions 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

View Enlarged Table
Dose-Related Adverse Reactions in the Schizophrenia Studies

Akathisia and extrapyramidal symptoms were dose-related. The frequency of akathisia increased with dose up to 120 mg/day (5.6% for LATUDA 20 mg, 10.7% for LATUDA 40 mg, 12.3% for LATUDA 80 mg, and 22.0% for LATUDA 120 mg). Akathisia was reported by 7.4% (9/121) of patients receiving 160 mg/day. Akathisia occurred in 3.0% of subjects receiving placebo. The frequency of extrapyramidal symptoms increased with dose up to 120 mg/day (5.6% for LATUDA 20 mg, 11.5% for LATUDA 40 mg, 11.9% for LATUDA 80 mg, and 22.0% for LATUDA 120 mg).

Bipolar Depression (Monotherapy)

The following findings are based on the short-term, placebo-controlled premarketing study for bipolar depression in which LATUDA was administered at daily doses ranging from 20 to 120 mg (n=331).

Commonly Observed Adverse Reactions

The most common adverse reactions (incidence ≥ 5%, in either dose group, and at least twice the rate of placebo) in patients treated with LATUDA were akathisia, extrapyramidal symptoms, somnolence, nausea, vomiting, diarrhea, and anxiety.

Adverse Reactions Associated with Discontinuation of Treatment

A total of 6.0% (20/331) LATUDA-treated patients and 5.4% (9/168) 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 bipolar depression) are shown in Table 16.

Table 16: Adverse Reactions in 2% or More of LATUDA-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in a Short-term Monotherapy Bipolar Depression Study

Body System or Organ Class Dictionary-derived Term Percentage of Patients Reporting Reaction
Placebo (N=168) (%) LATUDA 20-60 mg/day (N=164) (%) LATUDA 80-120 mg/day (N=167) (%) All LATUDA (N=331) (%)
Gastrointestinal Disorders
  Nausea   8 10 17 14
  Dry Mouth 4 6 4 5
  Vomiting 2 2 6 4
  Diarrhea 2 5 3 4
Infections and Infestations
  Nasopharyngitis 1 4 4 4
  Influenza 1 < 1 2 2
  Urinary Tract Infection < 1 2 1 2
Musculoskeletal and Connective TissueDisorders
  Back Pain < 1 3 < 1 2
Nervous System Disorders
  Extrapyramidal Symptoms* 2 5 9 7
  Akathisia 2 8 11 9
  Somnolence** 7 7 14 11
Psychiatric Disorders
  Anxiety 1 4 5 4
Note: Figures rounded to the nearest integer
*Extrapyramidal symptoms includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus
** Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence
Dose-Related Adverse Reactions in the Monotherapy Study

In the short-term, placebo-controlled study (involving lower and higher LATUDA dose ranges) [see Clinical Studies] the adverse reactions that occurred with a greater than 5% incidence in the patients treated with LATUDA in any dose group and greater than placebo in both groups were nausea (10.4%, 17.4%), somnolence (7.3%, 13.8%), akathisia (7.9%, 10.8%), and extrapyramidal symptoms (4.9%, 9.0%) for LATUDA 20 to 60 mg/day and LATUDA 80 to 120 mg/day, respectively.

Bipolar Depression

Adjunctive Therapy with Lithium or Valproate

The following findings are based on two short-term, placebo-controlled premarketing studies for bipolar depression in which LATUDA was administered at daily doses ranging from 20 to 120 mg as adjunctive therapy with lithium or valproate (n=360).

Commonly Observed Adverse Reactions

The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in subjects treated with LATUDA were akathisia and somnolence.

Adverse Reactions Associated with Discontinuation of Treatment

A total of 5.8% (21/360) LATUDA-treated patients and 4.8% (16/334) 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 bipolar depression) are shown in Table 17.

Table 17: Adverse Reactions in 2% or More of LATUDA-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Short-term Adjunctive Therapy Bipolar Depression Studies

Body System or Organ Class Dictionary-derived Term Percentage of Patients Reporting Reaction
Placebo
(N=334)
(%)
LATUDA20 to 120 mg/day
(N=360)
(%)
Gastrointestinal Disorders
  Nausea 10 14
  Vomiting 1 4
General Disorders
  Fatigue 1 3
Infections and Infestations 
  Nasopharyngitis 2 4
Investigations
  Weight Increased < 1 3
Metabolism and Nutrition Disorders
  Increased Appetite 1 3
Nervous System Disorders
  Extrapyramidal Symptoms* 9 14
  Somnolence** 5 11
  Akathisia 5 11
Psychiatric Disorders
  Restlessness < 1 4
Note: Figures rounded to the nearest integer
*Extrapyramidal symptoms includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus
** Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence

Extrapyramidal Symptoms

Schizophrenia

In the short-term, placebo-controlled schizophrenia studies, for LATUDA-treated patients, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 13.5% versus 5.8% for placebo-treated patients. The incidence of akathisia for LATUDA-treated patients was 12.9% versus 3.0% for placebo-treated patients. Incidence of EPS by dose is provided in Table 18.

Table 18: Incidence of EPS Compared to Placebo in Schizophrenia Studies

Adverse Event Term Placebo
(N=708)
(%)
LATUDA
20 mg/day
(N=71)
(%)
40 mg/day
(N=487)
(%)
80 mg/day
(N=538)
(%)
120 mg/day
(N=291)
(%)
160 mg/day
(N=121)
(%)
All EPS events 9 10 21 23 39 20
All EPS events, excluding Akathisia/ Restlessness 6 6 11 12 22 13
  Akathisia 3 6 11 12 22 7
  Dystonia* < 1 0 4 5 7 2
  Parkinsonism** 5 6 9 8 17 11
  Restlessness 1 1 3 1 3 2
Note: Figures rounded to the nearest integer
* Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus
** Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor
Bipolar Depression

Monotherapy

In the short-term, placebo-controlled monotherapy bipolar depression study, for LATUDA-treated patients, the incidence of reported events related to EPS, excluding akathisia and restlessness was 6.9% versus 2.4% for placebo-treated patients. The incidence of akathisia for LATUDA-treated patients was 9.4% versus 2.4% for placebo-treated patients. Incidence of EPS by dose groups is provided in Table 19.

Table 19: Incidence of EPS Compared to Placebo in the Monotherapy Bipolar Depression Study

Adverse Event Term Placebo
(N=168)
(%)
LATUDA
20 to 60 mg/day
(N=164)
(%)
80 to 120 mg/day
(N=167)
(%)
All EPS events 5 12 20
All EPS events, excluding Akathisia/Restlessness 2 5 9
  Akathisia 2 8 11
  Dystonia* 0 0 2
  Parkinsonism** 2 5 8
  Restlessness <1 0 3
Note: Figures rounded to the nearest integer
* Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus
** Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor

Adjunctive Therapy with Lithium or Valproate

In the short-term, placebo-controlled adjunctive therapy bipolar depression studies, for LATUDA-treated patients, the incidence of EPS, excluding akathisia and restlessness, was 13.9% versus 8.7% for placebo. The incidence of akathisia for LATUDA-treated patients was 10.8% versus 4.8% for placebo-treated patients. Incidence of EPS is provided in Table 20.

Table 20: Incidence of EPS Compared to Placebo in the Adjunctive Therapy Bipolar Depression Studies

Adverse Event Term Placebo
(N=334)
(%)
LATUDA 20 to 120 mg/day
(N=360)
(%)
All EPS events 13 24
All EPS events, excluding Akathisia/Restlessness 9 14
  Akathisia 5 11
  Dystonia* < 1 1
  Parkinsonism** 8 13
  Restlessness < 1 4
Note: Figures rounded to the nearest integer
* Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus
** Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor

In the short-term, placebo-controlled schizophrenia and bipolar depression studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (BAS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesias.

Schizophrenia

The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients, with the exception of the Barnes Akathisia Scale global score (LATUDA, 0.1; placebo, 0.0). The percentage of patients who shifted from normal to abnormal was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA, 14.4%; placebo, 7.1%), the SAS (LATUDA, 5.0%; placebo, 2.3%) and the AIMS (LATUDA, 7.4%; placebo, 5.8%).

Bipolar Depression

Monotherapy

The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA, 8.4%; placebo, 5.6%), the SAS (LATUDA, 3.7%; placebo, 1.9%) and the AIMS (LATUDA, 3.4%; placebo, 1.2%).

Adjunctive Therapy with Lithium or Valproate

The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA, 8.7%; placebo, 2.1%), the SAS (LATUDA, 2.8%; placebo, 2.1%) and the AIMS (LATUDA, 2.8%; placebo, 0.6%).

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.

Schizophrenia

In the short-term, placebo-controlled schizophrenia clinical studies, dystonia occurred in 4.2% of LATUDA-treated subjects (0.0% LATUDA 20 mg, 3.5% LATUDA 40 mg, 4.5% LATUDA 80 mg, 6.5% LATUDA 120 mg and 2.5% LATUDA 160 mg) compared to 0.8% of subjects receiving placebo. Seven subjects (0.5%, 7/1508) discontinued clinical trials due to dystonic events – four were receiving LATUDA 80 mg/day and three were receiving LATUDA 120 mg/day.

Bipolar Depression

Monotherapy

In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, dystonia occurred in 0.9% of LATUDA-treated subjects (0.0% and 1.8% for LATUDA 20 to 60 mg/day and LATUDA 80 to 120 mg/day, respectively) compared to 0.0% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events.

Adjunctive Therapy with Lithium or Valproate

In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, dystonia occurred in 1.1% of LATUDA-treated subjects (20 to 120 mg) compared to 0.6% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events.

Other Adverse Reactions Observed During the Premarketing Evaluation of LATUDA

Following is a list of adverse reactions reported by patients treated with LATUDA at multiple doses of ≥ 20 mg once daily within the premarketing database of 2905 patients with schizophrenia. 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 15 or those that appear elsewhere in the LATUDA label are not included. Although the reactions reported occurred during treatment with LATUDA, they were not necessarily caused by it.

Reactions are further categorized by 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

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

General Disorders and Administrative Site Conditions: Rare: sudden death

Investigations: Frequent: CPK increased

Metabolism and Nutritional System Disorders: Frequent: decreased appetite

Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis

Nervous System Disorders: Infrequent: cerebrovascular accident, dysarthria

Psychiatric Disorders: Infrequent: abnormal dreams, panic attack, sleep disorder

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: Frequent: hypertension

Clinical Laboratory Changes

Schizophrenia

Serum Creatinine: In short-term, placebo-controlled trials, the mean change from Baseline in serum creatinine was +0.05 mg/dL for LATUDA-treated patients compared to +0.02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 3.0% (43/1453) of LATUDA-treated patients and 1.6% (11/681) on placebo. The threshold for high creatinine value varied from > 0.79 to > 1.3 mg/dL based on the centralized laboratory definition for each study (Table 21).

Table 21: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in Schizophrenia Studies

View Enlarged Table
Bipolar Depression

Monotherapy

Serum Creatinine: In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, the mean change from Baseline in serum creatinine was +0.01 mg/dL for LATUDA-treated patients compared to -0.02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 2.8% (9/322) of LATUDA-treated patients and 0.6% (1/162) on placebo (Table 22).

Table 22: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in a Monotherapy Bipolar Depression Study

Laboratory Parameter Placebo
(N=168)
LATUDA 20 to 60 mg/day
(N=164)
LATUDA 80 to 120 mg/day
(N=167)
Serum Creatinine Elevated < 1% 2% 4%

Adjunctive Therapy with Lithium or Valproate

Serum Creatinine: In short-term, placebo-controlled premarketing adjunctive studies for bipolar depression, the mean change from Baseline in serum creatinine was +0.04 mg/dL for LATUDA-treated patients compared to -0.01 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 4.3% (15/360) of LATUDA-treated patients and 1.6% (5/334) on placebo (Table 23).

Table 23: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in the Adjunctive Therapy Bipolar Depression Studies

Laboratory Parameter Placebo
(N=334)
LATUDA 20 to 120 mg/day
(N=360)
Serum Creatinine Elevated 2% 4%

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Interactions

Potential for Other Drugs to Affect LATUDA

LATUDA is predominantly metabolized by CYP3A4. LATUDA should not be used concomitantly with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) or strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.) [see CONTRAINDICATIONS]. The LATUDA dose should be reduced to half of the original level when used concomitantly with moderate inhibitors of CYP3A4 (e.g., diltiazem, atazanavir, erythromycin, fluconazole, verapamil, etc.). If LATUDA is used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the LATUDA dose [see DOSAGE AND ADMINISTRATION].

Lithium: It is not necessary to adjust the LATUDA dose when used concomitantly with lithium (Figure 1).

Valproate: It is not necessary to adjust the LATUDA dose when used concomitantly with valproate. A dedicated drug-drug interaction study has not been conducted with valproate and LATUDA. Based on pharmacokinetic data from the bipolar depression studies valproate levels were not affected by lurasidone, and lurasidone concentrations were not affected by valproate.

Grapefruit: Grapefruit and grapefruit juice should be avoided in patients taking LATUDA, since these may inhibit CYP3A4 and alter LATUDA concentrations [see DOSAGE AND ADMINISTRATION].

Figure 1: Impact of Other Drugs on LATUDA Pharmacokinetics

View Enlarged Table

Potential for LATUDA to Affect Other Drugs

No dose adjustment is needed for lithium, substrates of P-gp, CYP3A4 (Figure 2) or valproate when coadministered with LATUDA. ).

Figure 2: Impact of LATUDA on Other Drugs

View Enlarged Table

Drug Abuse And Dependence

Controlled Substance

LATUDA is not a controlled substance.

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).

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

Warnings

Included as part of the PRECAUTIONS section.

Precautions

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

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

Suicidal Thoughts and Behaviors in Adolescents and Young Adults

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

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

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

Table 2

Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
Increases Compared to Placebo
< 18 14 additional cases
18-24 5 additional cases
Decreases Compared to Placebo
25-64 1 fewer case
≥ 65 6 fewer cases

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

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

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

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

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

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

Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis

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

Neuroleptic Malignant Syndrome

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

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

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

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

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

Tardive Dyskinesia

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

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

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

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

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

Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because LATUDA was not marketed at the time these studies were performed, it is not known if LATUDA is associated with this increased risk.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Schizophrenia

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

Table 3: Change in Fasting Glucose in Schizophrenia Studies

  LATUDA
Placebo 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day
  Mean Change from Baseline (mg/dL)
  n=680 n=71 n=478 n=508 n=283 n=113
Serum Glucose -0.0 -0.6 2.6 -0.4 2.5 2.5
  Proportion of Patients with Shifts to ≥ 126 mg/dL
Serum Glucose ( ≥ 126 mg/dL) 8.30% (52/628) 11.70% (7/60) 12.70% (57/449) 6.80% (32/472) 10.00% (26/260) 5.60% (6/108)

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

Bipolar Depression

Monotherapy

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

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

  LATUDA
Placebo 20 to 60 mg/day 80 to 120 mg/day
Mean Change from Baseline (mg/dL)
  n=148 n=140 n=143
Serum Glucose 1.8 -0.8 1.8
Proportion of Patients with Shifts to ≥ 126 mg/dL
Serum Glucose ( ≥ 126 mg/dL) 4.30% (6/141) 2.20% (3/138) 6.40% (9/141)

Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.2 mg/dL at week 24 (n=129).

Adjunctive Therapy with Lithium or Valproate

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

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

  Placebo LATUDA 20 to 120 mg/day
Mean Change from Baseline (mg/dL)
  n=302 n=319
Serum Glucose -0.9 1.2
Proportion of Patients with Shifts to ≥ 126 mg/dL
Serum Glucose 1.0% ( ≥ 126 mg/dL) 1% (3/290) 1.3% (4/316)

Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.7 mg/dL at week 24 (n=88).

Dyslipidemia

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

Schizophrenia

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

Table 6: Change in Fasting Lipids in Schizophrenia Studies

  LATUDA
Placebo 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day
Mean Change from Baseline (mg/dL)
  n=660 n=71 n=466 n=499 n=268 n=115
Total Cholesterol -5.8 -12.3 -5.7 -6.2 -3.8 -6.9
Triglycerides -13.4 -29.1 -5.1 -13 -3.1 -10.6
Proportion of Patients with Shifts
Total Cholesterol ( ≥ 240 mg/dL) 5.3% (30/571) 13.8% (8/58) 6.2% (25/402) 5.3% (23/434) 3.8% (9/238) 4.0% (4/101)
Triglycerides ( ≥ 200 mg/dL) 10.1% (53/526) 14.3% (7/49) 10.8% (41/379) 6.3% (25/400) 10.5% (22/209) 7.0% (7/100)

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

Bipolar Depression

Monotherapy

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

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

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

Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term and continued in the longer-term study had a mean change in total cholesterol and triglycerides of -0.5 (n=130) and -1.0 (n=130) mg/dL at week 24, respectively.

Adjunctive Therapy with Lithium or Valproate

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

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

  Placebo LATUDA 20 to 120 mg/day
Mean Change from Baseline (mg/dL)
  n=303 n=321
Total cholesterol -2.9 -3.1
Triglycerides -4.6 +4.6
Proportion of Patients with Shifts
Total cholesterol ( ≥ 240 mg/dL) 5.7% (15/263) 5.4% (15/276)
Triglycerides ( ≥ 200 mg/dL) 8.6% (21/243) 10.8% (28/260)

Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA, as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in total cholesterol and triglycerides of -0.9 (n=88) and +5.3 (n=88) mg/dL at week 24, respectively.

Weight Gain

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

Schizophrenia

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

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

  LATUDA
Placebo
(n=696)
20 mg/day
(n=71)
40 mg/day
(n=484)
80 mg/day
(n=526)
120 mg/day
(n=291)
160 mg/day
(n=114)
All Patients -0.02 -0.15 +0.22 +0.54 +0.68 +0.6

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

Bipolar Depression

Monotherapy

Data from the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 10. The mean weight gain was +0.29 kg for LATUDA-treated patients compared to -0.04 kg for placebo-treated patients. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 2.4% for LATUDA-treated patients versus 0.7% for placebo-treated patients.

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

  LATUDA
Placebo
(n=151)
20 to 60 mg/day
(n=143)
80 to 120 mg/day
(n=147)
All Patients -0.04 +0.56 +0.02

Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term and continued in the longer-term study had a mean change in weight of -0.02 kg at week 24 (n=130).

Adjunctive Therapy with Lithium or Valproate

Data from the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 11. The mean weight gain was +0.11 kg for LATUDA-treated patients compared to +0.16 kg for placebo-treated patients. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 3.1% for LATUDA-treated patients versus 0.3% for placebo-treated patients.

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

  Placebo
(n=307)
LATUDA 20 to 120 mg/day
(n=327)
All Patients +0.16 +0.11

Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA, as adjunctive therapy with either lithium or valproate in the short-term and continued in the longer-term study, had a mean change in weight of +1.28 kg at week 24 (n=86).

Hyperprolactinemia

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

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

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

Schizophrenia

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

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

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

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

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

Bipolar Depression

Monotherapy

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

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

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

Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo

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

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

Adjunctive Therapy with Lithium or Valproate

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

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

  LATUDA
Placebo 20 to 120 mg/day
All Patients 0.0 (n=301) +2.8 (n=321)
Females +0.4 (n=156) +3.2 (n=162)
Males -0.1 (n=145) +2.4 (n=159)

Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

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

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

Leukopenia, Neutropenia and Agranulocytosis

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

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

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

Orthostatic Hypotension and Syncope

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

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

Schizophrenia

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

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

Bipolar Depression

Monotherapy

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

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

Adjunctive Therapy with Lithium or Valproate

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

Seizures

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

Schizophrenia

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

Bipolar Depression

Monotherapy

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

Adjunctive Therapy with Lithium or Valproate

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

Potential for Cognitive and Motor Impairment

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

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

Schizophrenia

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

Bipolar Depression

Monotherapy

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

Adjunctive Therapy with Lithium or Valproate

In the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar 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.

Body Temperature Dysregulation

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

Suicide

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

Schizophrenia

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

Bipolar Depression

Monotherapy

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

Adjunctive Therapy with Lithium or Valproate

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

Activation of Mania/Hypomania

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

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

Dysphagia

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

Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies

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

Patient Counseling Information

Physicians are advised to discuss with patients for whom they prescribe LATUDA all relevant safety information including, but not limited to, the following:

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Advise patients and caregivers that elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs are at increased risk of death compared with placebo. LATUDA is not approved for elderly patients with dementia-related psychosis [see BOXED WARNING; WARNINGS AND PRECAUTIONS].

Suicidal Thoughts and Behaviors; and Activation of Mania or Hypomania

Educate patients, families, and caregivers about the risk of suicidal thoughts and behaviors with antidepressant treatment, as well as the risk of mania and hypomania. Advise them about monitoring for the emergence of suicidal thoughts and behavior, manic/hypomanic symptoms, irritability, agitation, or unusual changes in behavior. Instruct patients, families, and caregivers to report such symptoms to the healthcare provider [see WARNINGS AND PRECAUTIONS].

Neuroleptic Malignant Syndrome

Advise patients and caregivers that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see WARNINGS AND PRECAUTIONS].

Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain)

Educate patients and caregivers about the risk of metabolic changes and the need for specific monitoring. The risks include hyperglycemia and diabetes mellitus, dyslipidemia, weight gain, and cardiovascular reactions. Educate patients and caregivers about the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus (e.g., polydipsia, polyuria, polyphagia, and weakness). Monitor all patients for these symptoms. Patients who are diagnosed with diabetes or have risk factors for diabetes (obesity, family history of diabetes) should have their fasting blood glucose monitored before beginning treatment and periodically during treatment. Patients who develop symptoms of hyperglycemia should have assessments of fasting glucose. Clinical monitoring of weight is recommended [see WARNINGS AND PRECAUTIONS].

Orthostatic Hypotension

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

Leukopenia/Neutropenia

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

Interference with Cognitive and Motor Performance

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

Pregnancy and Nursing

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

Concomitant Medication and Alcohol

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

Heat Exposure and Dehydration

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

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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

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

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

Mutagenesis

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

Impairment of Fertility

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

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

Use In Specific Populations

Pregnancy - Pregnancy Category B

Risk Summary

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

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

Human Data

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

Animal Data

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

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

Nursing Mothers

LATUDA was excreted in milk of rats during lactation. It is not known whether LATUDA or its metabolites are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision sho

OverDose

Human Experience

In premarketing clinical studies, 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.

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. Consider the possibility of multiple-drug overdose.

Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of 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.

ContrainDications

  • Known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has been observed with lurasidone [see ADVERSE REACTIONS].
  • Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) [see DRUG INTERACTIONS].
  • Strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.) [see DRUG INTERACTIONS].

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

Clinical Pharamacology

Mechanism of Action

The mechanism of action of LATUDA in the treatment of schizophrenia and bipolar depression is unknown. However, its efficacy in schizophrenia and bipolar depression could be mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.

Pharmacodynamics

LATUDA is an antagonist with high affinity binding at the dopamine D2 receptors (Ki=1 nM) and the 5-hydroxytryptamine (5-HT, serotonin) receptors 5-HT2A (Ki=0.5 nM) and 5-HT7 (Ki=0.5 nM) receptors. It also binds with moderate affinity to the human α2C adrenergic receptors (Ki=11 nM), is a partial agonist at serotonin 5-HT1A (Ki=6.4 nM) receptors, and is an antagonist at the α2A adrenergic receptors (Ki=41 nM). LATUDA exhibits little or no affinity for histamine H1 and muscarinic M1 receptors (IC50 > 1,000 nM).

ECG Changes

The effects of LATUDA on the QTc interval were evaluated in a randomized, double-blind, multiple-dose, parallel-dedicated thorough QT study in 43 patients with schizophrenia or schizoaffective disorder, who were treated with LATUDA doses of 120 mg daily, 600 mg daily and completed the study. The maximum mean (upper 1-sided, 95% CI) increase in baseline-adjusted QTc intervals based on individual correction method (QTcI) was 7.5 (11.7) ms and 4.6 (9.5) ms, for the 120 mg and 600 mg dose groups respectively, observed at 2 to 4 hours after dosing. In this study, there was no apparent dose (exposure)-response relationship.

In short-term, placebo-controlled studies in schizophrenia and bipolar depression, no post-baseline QT prolongations exceeding 500 msec were reported in patients treated with LATUDA or placebo.

Pharmacokinetics

The activity of LATUDA is primarily due to the parent drug. The pharmacokinetics of LATUDA is dose-proportional within a total daily dose range of 20 mg to 160 mg. Steady-state concentrations of LATUDA 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

LATUDA 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. LATUDA is highly bound (~99%) to serum proteins.

In a food effect study, LATUDA mean Cmax and AUC were about 3-times and 2-times, respectively, when administered with food compared to the levels observed under fasting conditions. LATUDA 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].

In clinical studies, establishing the safety and efficacy of LATUDA, patients were instructed to take their daily dose with food [see DOSAGE AND ADMINISTRATION].

Metabolism and Elimination

LATUDA is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation. LATUDA is metabolized into two active metabolites (ID-14283 and ID-14326) and two major non-active metabolites (ID-20219 and ID-20220). Based on in vitro studies, LATUDA is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes. Because LATUDA is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of LATUDA.

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 LATUDA.

Following administration of 40 mg of LATUDA, the mean (%CV) apparent clearance was 3902 (18.0) mL/min.

Clinical Studies

Schizophrenia

The efficacy of LATUDA for the treatment of schizophrenia was established in five short-term (6-week), placebo-controlled studies in adult patients (mean age of 38.4 years, range 18-72) who met DSM-IV criteria for schizophrenia. An active-control arm (olanzapine or quetiapine extended-release) was included in two studies 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. The BPRSd consists of 18 items rated on a scale of 1 (not present) to 7 (severe). BPRSd scores may range from 18 to 126.
  3. The Clinical Global Impression severity scale (CGI-S) is a clinician-rated scale that measures the subject's current illness state on a 1- to 7-point scale.
  4. 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. Study 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. Study 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. Study 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. Study 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.
  5. Study 5: In a 6-week, placebo- and active-controlled trial (N=482) involving two fixed doses of LATUDA (80 or 160 mg/day) and an active control (quetiapine extended-release), both LATUDA doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S.

Thus, the efficacy of LATUDA at doses of 40, 80, 120 and 160 mg/day has been established (Table 24).

Table 24: Primary Efficacy Results for Studies in Schizophrenia (BPRSd or PANSS Scores)

Study Treatment Group Mean Baseline Score LS Mean Change (SD) Primary Efficacy Measure: BPRSd from Baseline (SE) Placebo-subtracted Differencea (95% CI)
1 LATUDA (40 mg/day)* 54.2 (8.8) -9.4 (1.6) -5.6 (-9.8, -1.4)
LATUDA (120 mg/day)* 52.7 (7.6) -11.0 (1.6) -6.7 (-11.0, -2.5)
Placebo 54.7 (8.1) -3.8 (1.6) --
2 LATUDA (80 mg/day)* 55.1 (6.0) -8.9 (1.3) -4.7 (-8.3,-1.1)
Placebo 56.1 (6.8) -4.2 (1.4) --
  Primary Efficacy Measure: PANSS
3 LATUDA (40 mg/day)* 96.6 (10.7) -25.7 (2.0) -9.7 (-15.3, -4.1)
LATUDA (120 mg/day)* 97.9 (11.3) -23.6 (2.1) -7.5 (-13.4, -1.7)
Olanzapine (15 mg/day )*b 96.3 (12.2) -28.7 (1.9) -12.6 (-18.2, -7.9)
Placebo 95.8 (10.8) -16.0 (2.1) --
4 LATUDA (40 mg/day) 96.5 (11.5) -19.2 (1.7) -2.1 (-7.0, 2.8)
LATUDA (80 mg/day)* 96.0 (10.8) -23.4 (1.8) -6.4 (-11.3, -1.5)
LATUDA (120 mg/day) 96.0 (9.7) -20.5 (1.8) -3.5 (-8.4, 1.4)
Placebo 96.8 (11.1) -17.0 (1.8) --
5 LATUDA (80 mg/day)* 97.7 (9.7) -22.2 (1.8) -11.9 (-16.9, -6.9)
LATUDA (160 mg/day)* 97.5 (11.8) -26.5 (1.8) -16.2 (-21.2, -11.2)
Quetiapine Extended-release (600 mg/day)*b 97.7 (10.2) -27.8 (1.8) -17.5 (-22.5, -12.4)
Placebo 96.6 (10.2) -10.3 (1.8) --
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, unadjusted for multiple comparisons.
aDifference (drug minus placebo) in least-squares mean change from baseline.
bIncluded for assay sensitivity.
* Doses statistically significantly superior to placebo.

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. 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.

Depressive Episodes Associated with Bipolar I Disorder

Monotherapy

The efficacy of LATUDA, as monotherapy, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adult patients (mean age of 41.5 years, range 18 to 74) who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=485). Patients were randomized to one of two flexible-dose ranges of LATUDA (20 to 60 mg/day, or 80 to 120 mg/day) or placebo.

The primary rating instrument used to assess depressive symptoms in this study was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with total scores ranging from 0 (no depressive features) to 60 (maximum score). The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the Clinical Global Impression-Bipolar-Severity of Illness scale (CGI-BP-S), a clinician-rated scale that measures the subject's current illness state on a 7-point scale, where a higher score is associated with greater illness severity.

For both dose groups, LATUDA was superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6. The primary efficacy results are provided in Table 25. The high dose range (80 to 120 mg per day) did not provide additional efficacy on average, compared to the low dose range (20 to 60 mg per day).

Adjunctive Therapy with Lithium or Valproate

The efficacy of LATUDA, as an adjunctive therapy with lithium or valproate, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adult patients (mean age of 41.7 years, range 18 to 72) who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=340). Patients who remained symptomatic after treatment with lithium or valproate were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo.

The primary rating instrument used to assess depressive symptoms in this study was the MADRS. The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the CGI-BP-S scale.

LATUDA was superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6, as an adjunctive therapy with lithium or valproate (Table 25).

Table 25: Primary Efficacy Results for Studies in Depressive Episodes Associated with Bipolar I Disorder (MADRS Scores)

Study Treatment Group Primary Efficacy Measure: MADRS
Mean Baseline Score(SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differencea (95% CI)
Monotherapy study LATUDA (20-60 mg/day)* 30.3 (5.0) -15.4 (0.8) -4.6 (-6.9, -2.3)
LATUDA (80-120 mg/day)* 30.6 (4.9) -15.4 (0.8) -4.6 (-6.9, -2.3)
Placebo 30.5 (5.0) -10.7 (0.8) --
Adjunctive Therapy study LATUDA (20-120 mg/day)* + lithium or valproate 30.6 (5.3) -17.1 (0.9) -3.6 (-6.0, -1.1)
Placebo + lithium or valproate 30.8 (4.8) -13.5 (0.9) --
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, unadjusted for multiple comparisons.
aDifference (drug minus placebo) in least-squares mean change from baseline.
* Treatment group statistically significantly superior to placebo.

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

Patient Information

LATUDA
(luh-TOO-duh)
(lurasidone hydrochloride) Tablets

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).

  • Talk to your, or your family member's, healthcare provider about:
    • all risks and benefits of treatment with antidepressant medicines.
    • all treatment choices for depression or other serious mental illness.
  • Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
  • 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.
  • How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
    • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
    • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
    • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

  • thoughts about suicide or dying
  • attempts to commit suicide
  • new or worse depression
  • new or worse anxiety
  • feeling very agitated or restless
  • panic attacks
  • trouble sleeping (insomnia)
  • new or worse irritability
  • acting aggressive, being angry, or violent
  • acting on dangerous impulses
  • an extreme increase in activity and talking (mania)
  • other unusual changes in behavior or mood

What else do I need to know about antidepressant medicines?

  • Never stop an antidepressant medicine without first talking to your healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
  • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
  • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
  • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
  • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child's healthcare provider for more information.

What is LATUDA?

LATUDA is a prescription medicine used to treat adults with:

  • schizophrenia
  • depressive episodes associated with bipolar I disorder, alone or with lithium or valproate It is not known if LATUDA is safe and effective in children.

Who should not take LATUDA?

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.
  • 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.

What should I tell my healthcare provider before taking LATUDA?

Before you take LATUDA, tell your healthcare provider if you:

  • have or have had diabetes or high blood sugar in you or your family. Your healthcare provider should check your blood sugar before you start LATUDA and also during therapy.
  • have or have had high levels of total cholesterol, triglycerides or LDL-cholesterol or low levels of HDL-cholesterol
  • have or have had low or high blood pressure
  • have or have had low white blood cell count
  • have or have had seizures
  • have or have had abnormal thyroid tests
  • have or have had high prolactin levels
  • have or have had heart problems
  • have or have had liver problems
  • have or have had any other medical conditions
  • are pregnant or plan to become pregnant. It is not known if LATUDA will harm your unborn baby.
  • are breastfeeding or plan to breastfeed. It is not known if LATUDA passes into your breast milk. You and your healthcare provider should decide if you will take LATUDA or breastfeed. You should not do both.

Tell the healthcare provider about all the medicines that you take or recently have taken including prescription medicines, over-the-counter medicines, herbal supplements and vitamins.

LATUDA and other medicines may affect each other causing serious side effects. LATUDA may affect the way other medicines work, and other medicines may affect how LATUDA works.

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.

How should I take LATUDA?

  • Take LATUDA exactly as your healthcare provider tells you to take it. Do not change the dose yourself.
  • Take LATUDA by mouth, with food (at least 350 calories).
  • If you take too much LATUDA, call your healthcare provider or poison control center at 1-800-222-1222 right away, or go to the nearest hospital emergency room.

What should I avoid while taking LATUDA?

  • Avoid eating grapefruit or drinking grapefruit juice while you take LATUDAsince these can affect the amount of LATUDA in the blood. Do not drive, operate machinery, or do other dangerous activities until you know how LATUDA affects you. LATUDA may make you drowsy.
  • Avoid getting overheated or dehydrated.
    • Do not over-exercise.
    • In hot weather, stay inside in a cool place if possible.
    • Stay out of the sun. Do not wear too much or heavy clothing.
    • Drink plenty of water.
  • Do not drink alcohol while taking LATUDA. It may make some side effects of LATUDA worse.

What are possible side effects of LATUDA?

LATUDA can cause serious side effects, including:

  • See “What is the most important information I should know about LATUDA?”
  • stroke that can lead to death can happen in elderly people with dementia who take medicines like LATUDA
  • neuroleptic malignant syndrome (NMS). NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including LATUDA. NMS can cause death and must be treated in a hospital. Call your healthcare provider right away if you become severely ill and have some or all of these symptoms:
    • high fever
    • excessive sweating
    • rigid muscles
    • confusion
    • changes in your breathing, heartbeat, and blood pressure
  • movements you cannot control in your face, tongue, or other body parts (tardive dyskinesia). These may be signs of a serious condition. Tardive dyskinesia may not go away, even if you stop taking LATUDA. Tardive dyskinesia may also start after you stop taking LATUDA.
  • high blood sugar (hyperglycemia). High blood sugar can happen if you have diabetes already or if you have never had diabetes. High blood sugar could lead to:
    • build-up of acid in your blood due to ketones (ketoacidosis)
    • coma
    • death
      Increases in blood sugar can happen in some people who take LATUDA. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or a family history of diabetes) your healthcare provider should check your blood sugar before you start LATUDA and during therapy.
      Call your healthcare provider if you have any of these symptoms of high blood sugar (hyperglycemia) while taking LATUDA:
      • feel very thirsty
      • need to urinate more than usual
      • feel very hungry
      • feel weak or tired
      • feel sick to your stomach
      • feel confused, or your breath smells fruity
  • high fat levels in your blood (increased cholesterol and triglycerides). High fat levels may happen in people treated with LATUDA. You may not have any symptoms, so your healthcare provider may decide to check your cholesterol and triglycerides during your treatment with LATUDA.
  • increase in weight (weight gain). Weight gain has been reported in patients taking medicines like LATUDA. You and your healthcare provider should check your weight regularly. Talk to your healthcare provider about ways to control weight gain, such as eating a healthy, balanced diet, and exercising.
  • increases in prolactin levels. Your healthcare provider may do blood tests to check your prolactin levels.
  • low white blood cell count
  • decreased blood pressure (orthostatic hypotension), including lightheadedness or fainting caused by a sudden change in heart rate and blood pressure when rising too quickly from a sitting or lying position.
  • seizures
  • difficulty swallowing

The most common side effects of LATUDA include:

  • sleepiness or drowsiness
  • restlessness and feeling like you need to move around (akathisia)
  • difficulty moving, slow movements, muscle stiffness, or tremor
  • nausea

These are not all the possible side effects of LATUDA. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store LATUDA?

  • Store LATUDA tablets at room temperature between 68°F to 77°F (20°C to 25°C).
  • Keep LATUDA and all medicines out of the reach of children.

General information about the safe and effective use of LATUDA.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use LATUDA for a condition for which it was not prescribed. Do not give LATUDA to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about LATUDA. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about LATUDA that is written for health professionals.

For more information, go to www.LATUDA.com or call 1-888-394-7377.

What are the ingredients in LATUDA?

Active ingredient: lurasidone hydrochloride

Inactive ingredients: 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

This Medication Guide has been approved by the U.S. Food and Drug Administration.

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

Consumer Overview Uses

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

 

LURASIDONE - ORAL

 

(loo-RAS-i-done)

 

COMMON BRAND NAME(S): Latuda

 

WARNING: There may be a slightly increased risk of serious, possibly fatal side effects (such as stroke, heart failure, fast/irregular heartbeat, pneumonia) when this medication is used by older adults with dementia. This medication is not approved for the treatment of dementia-related behavior problems. Discuss the risks and benefits of this medication, as well as other effective and possibly safer treatments for dementia-related behavior problems, with the doctor.

Lurasidone is used to treat certain mental/mood disorders (such as schizophrenia, depression associated with bipolar disorder). Drugs used to treat depression can help prevent suicidal thoughts/attempts and provide other important benefits. However, studies have shown that a small number of people (especially people younger than 25) who take drugs to treat depression may experience worsening depression, other mental/mood symptoms, or suicidal thoughts/attempts. Therefore, it is very important to talk with the doctor about the risks and benefits of drugs used to treat depression (especially for people younger than 25), even if treatment is not for a mental/mood condition.

Tell the doctor immediately if you notice worsening depression/other psychiatric conditions, unusual behavior changes (including possible suicidal thoughts/attempts), or other mental/mood changes (including new/worsening anxiety, panic attacks, trouble sleeping, irritability, hostile/angry feelings, impulsive actions, severe restlessness, very rapid speech). Be especially watchful for these symptoms when a new drug to treat depression is started or when the dose is changed.

 

USES: This medication is used to treat certain mental/mood disorders (such as schizophrenia, depression associated with bipolar disorder). Lurasidone helps you to think more clearly, feel less nervous, and take part in everyday life. It may also help to decrease hallucinations (hearing/seeing things that are not there). In addition, this medication may improve your mood, sleep, appetite, and energy level. Lurasidone is a psychiatric medication that belongs to the class of drugs called atypical antipsychotics. It works by helping to restore the balance of certain natural substances in the brain.

 

HOW TO USE: Read the Medication Guide provided by your pharmacist before you start taking lurasidone and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth with food as directed by your doctor, usually once daily. Dosage is based on your medical condition, kidney/liver function, other drugs you are taking, and your response to treatment.

Take this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day.

Continue taking this medication exactly as prescribed, even if you are feeling better and thinking more clearly. Do not increase your dose or take this drug more often than prescribed. Your symptoms will not improve any faster, and your risk of side effects will increase. Do not stop taking this medication without consulting your doctor.

Avoid eating grapefruit or drinking grapefruit juice while using this medication unless your doctor or pharmacist says you may do so safely. Grapefruit can increase the chance of side effects with this medicine. Ask your doctor or pharmacist for more details.

Tell your doctor if your condition does not improve or if it worsens. It may take several weeks before you feel the full benefit of this medication.

Consumer Overview Side Effect

SIDE EFFECTS: See also Warning section.

Drowsiness, dizziness, nausea, shaking, weight gain, mask-like facial expression, inability to keep still, and agitation may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly. Your doctor may order another medication to lessen these effects.

This medication may cause a serious drop in blood pressure, especially when starting this medication. To reduce your risk of side effects from low blood pressure (such as dizziness), get up slowly when rising from a sitting or lying position.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if any of these serious side effects occur: drooling/trouble swallowing, fainting, signs of infection (such as persistent cough, fever).

Infrequently, this medication may cause face/muscle twitching and uncontrollable movements (tardive dyskinesia). In some cases, this condition may be permanent. Tell your doctor immediately if you develop any uncontrollable movements such as lip smacking, mouth puckering, tongue thrusting, chewing, or unusual arm/leg movements.

This drug may rarely make your blood sugar level rise, which can cause or worsen diabetes. Weight gain from this drug may increase the risk of this side effect. Tell your doctor immediately if you develop symptoms of high blood sugar such as increased thirst and urination. If you already have diabetes, be sure to check your blood sugar level regularly.

This medication may also cause a rise in your blood fat levels (cholesterol and triglycerides). These increases, along with diabetes and weight gain, may increase your risk for developing heart disease. Discuss the risks and benefits of treatment with your doctor.

In rare cases, lurasidone may increase your level of a certain substance made by the body (prolactin). For females, this increase in prolactin may result in unwanted breast milk, missed/stopped periods, or difficulty becoming pregnant. For males, it may result in decreased sexual ability, inability to produce sperm, or enlarged breasts. If you develop any of these symptoms, tell your doctor immediately.

Rarely, males may have a painful or prolonged erection lasting 4 or more hours. If this occurs, stop using this drug and get medical help right away, or permanent problems could occur.

Get medical help right away if this serious side effect occurs: seizure.

This medication may rarely cause a very serious condition called neuroleptic malignant syndrome (NMS). Get medical help right away if you have any of the following symptoms: fever, muscle stiffness/pain/tenderness/weakness, severe tiredness, severe confusion, sweating, fast/irregular heartbeat, dark urine, change in the amount of urine.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

 

Read the Latuda (lurasidone hcl tablets for oral administration) Side Effects Center for a complete guide to possible side effects

Learn More »

PRECAUTIONS: See also Warning section.

Before taking lurasidone, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney problems, liver problems, stroke, breast cancer, diabetes (including family history), obesity, low blood pressure, seizures, low white blood cell count, dementia (such as Alzheimer's Disease), trouble swallowing.

This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Avoid alcoholic beverages.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

This medication may decrease your ability to sweat, making you more likely to get heat stroke. Avoid activities that may cause you to overheat (such as doing strenuous work/exercise in hot weather, using hot tubs). When the weather is hot, drink plenty of fluids and dress lightly. If you become overheated, promptly seek cooler shelter and stop exercising. Get medical help right away if you develop a fever, mental/mood changes, headache, or dizziness.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor. Do not stop taking this medication unless directed by your doctor. Babies born to mothers who have used this drug during the last 3 months of pregnancy may infrequently develop symptoms including muscle stiffness or shakiness, drowsiness, feeding/breathing difficulties, or constant crying. If you notice any of these symptoms in your newborn anytime during their first month, tell the doctor right away.

It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding.

Consumer Overview Missed Dose

DRUG INTERACTIONS: See also How To Use section.

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Other medications can affect the removal of lurasidone from your body, which may affect how lurasidone works. Examples include diltiazem, azole antifungals (such as ketoconazole, itraconazole), certain HIV/hepatitis C virus protease inhibitors (such as atazanavir, boceprevir, ritonavir), macrolide antibiotics (such as clarithromycin), rifamycins (such as rifampin, rifabutin), telithromycin, antidepressants (such as fluoxetine, paroxetine, nefazodone), among others.

Tell your doctor or pharmacist if you are taking other products that cause dizziness or drowsiness, including alcohol, antihistamines (such as cetirizine, diphenhydramine), drugs for sleep or anxiety (such as alprazolam, diazepam, zolpidem), muscle relaxants, and narcotic pain relievers (such as codeine).

Check the labels on all your medicines (such as allergy or cough-and-cold products) because they may contain ingredients that cause dizziness or drowsiness. Ask your pharmacist about using those products safely.

 

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

 

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (such as blood sugar level, complete blood count, blood pressure, weight, cholesterol/triglyceride levels) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

 

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

 

STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

 

Information last revised July 2013 Copyright(c) 2013 First DataBank, Inc.

Patient Detailed Side Effect

Brand Names: Latuda

Generic Name: lurasidone (Pronunciation: loo RAS i done)

  • What is lurasidone (Latuda)?
  • What are the possible side effects of lurasidone (Latuda)?
  • What is the most important information I should know about lurasidone (Latuda)?
  • What should I discuss with my healthcare provider before taking lurasidone (Latuda)?
  • How should I take lurasidone (Latuda)?
  • What happens if I miss a dose (Latuda)?
  • What happens if I overdose (Latuda)?
  • What should I avoid while taking lurasidone (Latuda)?
  • What other drugs will affect lurasidone (Latuda)?
  • Where can I get more information?

What is lurasidone (Latuda)?

Lurasidone is an antipsychotic medication. It works by changing the effects of chemicals in the brain.

Lurasidone is used to treat schizophrenia in adults.

Lurasidone may also be used for purposes not listed in this medication guide.

What are the possible side effects of lurasidone (Latuda)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop taking lurasidone and call your doctor at once if you have a serious side effect such as:

  • dizziness, fainting, fast or pounding heartbeats;
  • agitation, hostility, confusion, thoughts about hurting yourself;
  • seizure (convulsions);
  • fever, chills, body aches, flu symptoms, sores in your mouth and throat;
  • high blood sugar (increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, weight loss);
  • very stiff (rigid) muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, feeling like you might pass out;
  • trouble swallowing; or
  • twitching or uncontrollable movements of your eyes, lips, tongue, face, arms, or legs.

Less serious side effects may include:

  • drowsiness;
  • feeling restless;
  • nausea, diarrhea, stomach pain, loss of appetite;
  • blurred vision;
  • weight gain;
  • breast swelling or discharge;
  • missed menstrual periods; or
  • decreased sex drive, impotence, or difficulty having an orgasm.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Latuda (lurasidone hcl tablets for oral administration) Side Effects Center for a complete guide to possible side effects

Learn More »

What is the most important information I should know about lurasidone (Latuda)?

Lurasidone is not for use in psychotic conditions related to dementia. Lurasidone may cause heart failure, sudden death, or pneumonia in older adults with dementia-related conditions.

You should not use this medication if you are allergic to lurasidone, or if you are also using ketoconazole (Extina, Ketozole, Nizoral, Xolegal) or rifampin (Rifater, Rifadin, Rifamate).

Before you take lurasidone, tell your doctor if you have liver disease, kidney disease, heart disease, high blood pressure, heart rhythm problems, a history of heart attack or stroke, high cholesterol or triglycerides, low white blood cell (WBC) counts, seizures, diabetes, Parkinson's disease, trouble swallowing, or a history of breast cancer or suicidal thoughts.

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

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

Drinking alcohol can increase certain side effects of lurasidone.

Stop using lurasidone and call your doctor at once if you have very stiff (rigid) muscles, high fever, sweating, confusion, fast or pounding heartbeats, feeling like you might pass out, tremors, or twitching or uncontrollable movements of your eyes, lips, tongue, face, arms, or legs.

There are many other drugs that can interact with lurasidone. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

Side Effects Centers
  • Latuda

Patient Detailed How Take

What should I discuss with my healthcare provider before taking lurasidone (Latuda)?

Lurasidone is not for use in psychotic conditions related to dementia. Lurasidone may cause heart failure, sudden death, or pneumonia in older adults with dementia-related conditions.

You should not use this medication if you are allergic to lurasidone, or if you are also using ketoconazole (Extina, Ketozole, Nizoral, Xolegal) or rifampin (Rifater, Rifadin, Rifamate).

To make sure you can safely take lurasidone, tell your doctor if you have any of these other conditions:

  • liver disease;
  • kidney disease;
  • heart disease, high blood pressure, heart rhythm problems;
  • a history of heart attack or stroke;
  • high cholesterol or triglycerides (a type of fat in the blood);
  • low white blood cell (WBC) counts;
  • a history of breast cancer;
  • seizures or epilepsy;
  • personal or family history of diabetes (lurasidone may raise your blood sugar);
  • a history of suicidal thoughts or actions;
  • Parkinson's disease; or
  • trouble swallowing.

Lurasidone may cause you to have high blood sugar (hyperglycemia). Talk to your doctor if you have any signs of hyperglycemia such as increased thirst or urination, excessive hunger, or weakness. If you are diabetic, check your blood sugar levels on a regular basis while you are taking lurasidone.

FDA pregnancy category B. Lurasidone is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether lurasidone passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using lurasidone.

Do not give this medication to a child without medical advice.

How should I take lurasidone (Latuda)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Lurasidone should be taken with food (at least 350 calories).

Use lurasidone regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

It may take several weeks before your symptoms improve. Keep using the medication as directed and tell your doctor if your symptoms do not improve.

Store at room temperature away from moisture and heat.

Side Effects Centers
  • Latuda

Patient Detailed Avoid Taking

What happens if I miss a dose (Latuda)?

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

What happens if I overdose (Latuda)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include some of the serious side effects listed in this medication guide.

What should I avoid while taking lurasidone (Latuda)?

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

Lurasidone may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Drinking alcohol can increase certain side effects of lurasidone.

What other drugs will affect lurasidone (Latuda)?

Before you take lurasidone, tell your doctor if you regularly use other medicines that make you sleepy (such as cold or allergy medicine, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by lurasidone.

Many drugs can interact with lurasidone. Below is just a partial list. Tell your doctor if you are using:

  • bosentan (Tracleer);
  • conivaptan (Vaprisol);
  • dexamethasone (Decadron, Hexadrol);
  • imatinib (Gleevec);
  • isoniazid (for treating tuberculosis);
  • St. John's wort;
  • an antibiotic such as clarithromycin (Biaxin), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin), rifapentine (Priftin), or telithromycin (Ketek);
  • antifungal medication such as fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Extina, Ketozole, Nizoral, Xolegal), or voriconazole (Vfend);
  • an antidepressant such as nefazodone;
  • heart or blood pressure medication such as diltiazem (Cartia, Cardizem), nicardipine (Cardene), quinidine (Quin-G), verapamil (Calan, Covera, Isoptin, Verelan), and others;
  • HIV/AIDS medicine such as atazanavir (Reyataz), delavirdine (Rescriptor), efavirenz (Sustiva, Atripla), etravirine (Intelence), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), nevirapine (Viramune), saquinavir (Invirase), or ritonavir (Norvir, Kaletra);
  • medicines to treat narcolepsy, such as armodafinil (Nuvigil) or modafinil (Progivil); or
  • seizure medication such as carbamazepine (Carbatrol, Tegretol), felbamate (Felbatol), oxcarbazepine (Trileptal), phenobarbital (Solfoton), phenytoin (Dilantin), or primidone (Mysoline).

This list is not complete and other drugs may interact with lurasidone. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about lurasidone.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 3.03. Revision date: 6/15/2012.

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