LURASIDONE
WARNING
INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; AND SUICIDAL THOUGHTS AND BEHAVIORS
INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS TREATED WITH ANTIPSYCHOTIC DRUGS ARE AT AN INCREASED RISK OF DEATH. LATUDA IS NOT APPROVED FOR THE TREATMENT OF PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS [SEE WARNINGS AND PRECAUTIONS ].
SUICIDAL THOUGHTS AND BEHAVIORS
ANTIDEPRESSANTS INCREASED THE RISK OF SUICIDAL THOUGHTS AND BEHAVIOR IN PEDIATRIC AND YOUNG ADULTS IN SHORT-TERM STUDIES. CLOSELY MONITOR ALL ANTIDEPRESSANT-TREATED PATIENTS FROM CLINICAL WORSENING, AND FOR EMERGENCE OF SUICIDAL THOUGHTS AND BEHAVIORS. LATUDA IS NOT APPROVED FOR USE IN PEDIATRIC PATIENTS WITH DEPRESSION [SEE WARNINGS AND PRECAUTIONS ].
DESCRIPTION
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.
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.
INDICATIONS
INDICATIONS
LATUDA IS INDICATED FOR:
· TREATMENT OF ADULT AND ADOLESCENT PATIENTS AGE 13 TO 17 YEARS WITH SCHIZOPHRENIA [SEE CLINICAL STUDIES ].
· MONOTHERAPY TREATMENT OF ADULT PATIENTS WITH MAJOR DEPRESSIVE EPISODES ASSOCIATED WITH BIPOLAR I DISORDER (BIPOLAR DEPRESSION) [SEE CLINICAL STUDIES ].
· ADJUNCTIVE TREATMENT WITH LITHIUM OR VALPROATE IN ADULT PATIENTS WITH MAJOR DEPRESSIVE EPISODES ASSOCIATED WITH BIPOLAR I DISORDER (BIPOLAR DEPRESSION) [SEE CLINICAL STUDIES ].
DOSAGE
DOSAGE AND ADMINISTRATION
SCHIZOPHRENIA
ADULTS
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.
ADOLESCENTS
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 80 MG PER DAY [SEE CLINICAL STUDIES ]. THE MAXIMUM RECOMMENDED DOSE IS 80 MG PER DAY.
DEPRESSIVE EPISODES ASSOCIATED WITH BIPOLAR I DISORDER
THE RECOMMENDED STARTING DOSE OF LATUDA IN ADULTS 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 ].
THE EFFICACY OF LATUDA IN THE TREATMENT OF MANIA ASSOCIATED WITH BIPOLAR DISORDER HAS NOT BEEN ESTABLISHED.
ADMINISTRATION INFORMATION
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 ].
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 SCHIZOPHRENIA].
DOSE MODIFICATIONS FOR 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 ].
DOSE MODIFICATIONS FOR 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 OF CYP3A4 INHIBITORS AND CYP3A4 INDUCERS
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 33).
TABLE 33: 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. REVISED : JAN 2017
SIDE EFFECTS
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 BOX WARNING AND WARNINGS AND PRECAUTIONS ]
· SUICIDAL THOUGHTS AND BEHAVIORS [SEE BOX 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 [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 ]
· FALLS [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 ]
· 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.
ADULTS
THE INFORMATION BELOW IS DERIVED FROM AN INTEGRATED CLINICAL STUDY DATABASE FOR LATUDA CONSISTING OF 3799 ADULT 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 ADULT 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 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 ADULT SHORT-TERM SCHIZOPHRENIA STUDIES
PERCENTAGE OF PATIENTS REPORTING REACTION
LATUDA
BODY SYSTEM OR ORGAN CLASS PLACEBO (N=708) (%) 20MG/DAY (N=71) (%) 40MG/DAY (N=487) (%) 80 MG/DAY (N=538) (%) 120 MG/DAY (N=291) (%) 160 MG/DAY (N=121) (%) ALLLATUDA (N=1508) (%)
GASTROINTESTINAL DISORDERS
NAUSEA 5 11 10 9 13 7 10
VOMITING 6 7 6 9 9 7 8
DYSPEPSIA 51165866
SALIVARY HYPERSECRETION <1 1 1 2 4 2 2
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
BACK PAIN 2043403
NERVOUS SYSTEM DISORDERS
SOMNOLENCE* 7 15 16 15 26 8 17
AKATHISIA 3 6 11 12 22 7 13
EXTRAPYRAMIDAL DISORDER** 6 6 11 12 22 13 14
DIZZINESS 2 6 4 4 5 6 4
PSYCHIATRIC DISORDERS
INSOMNIA 8 8 10 11 9 7 10
AGITATION 4 10 7 3 6 5 5
ANXIETY 4 3 6 4 7 3 5
RESTLESSNESS 1 1 3 1 3 2 2
NOTE: FIGURES ROUNDED TO THE NEAREST INTEGER * SOMNOLENCE INCLUDES ADVERSE EVENT TERMS: HYPERSOMNIA, HYPERSOMNOLENCE, SEDATION, AND SOMNOLENCE ** EXTRAPYRAMIDAL SYMPTOMS INCLUDE ADVERSE EVENT TERMS: BRADYKINESIA , COGWHEEL RIGIDITY, DROOLING, DYSTONIA , EXTRAPYRAMIDAL DISORDER, HYPOKINESIA, MUSCLE RIGIDITY, OCULOGYRIC CRISIS, OROMANDIBULAR DYSTONIA , PARKINSONISM , PSYCHOMOTOR RETARDATION, TONGUE SPASM, TORTICOLLIS , TREMOR , AND TRISMUS
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 ADULT 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 18.
TABLE 18: ADVERSE REACTIONS IN 2% OR MORE OF LATUDA-TREATED PATIENTS AND THAT OCCURRED AT GREATER INCIDENCE THAN IN THE PLACEBO-TREATED PATIENTS IN THE ADULT 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
VOMITING 2 2 6 4
DIARRHEA 2 5 3 4
DRY MOUTH 4645
INFECTIONS AND INFESTATIONS
NASOPHARYNGITIS 1 4 4 4
INFLUENZA 1<122
URINARY TRACT INFECTION <1212
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
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 INCLUDE 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 ADULT 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 ADULT 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 19.
TABLE 19: ADVERSE REACTIONS IN 2% OR MORE OF LATUDA-TREATED PATIENTS AND THAT OCCURRED AT GREATER INCIDENCE THAN IN THE PLACEBO-TREATED PATIENTS IN THE ADULT SHORT-TERM ADJUNCTIVE THERAPY BIPOLAR DEPRESSION STUDIES
BODY SYSTEM OR ORGAN CLASS DICTIONARY-DERIVED TERM PERCENTAGE OF PATIENTS REPORTING REACTION
PLACEBO (N=334) (%) LATUDA 20 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 INCLUDE 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
ADOLESCENTS
THE FOLLOWING FINDINGS ARE BASED ON THE SHORT-TERM, PLACEBO-CONTROLLED ADOLESCENT STUDY FOR SCHIZOPHRENIA IN WHICH LATUDA WAS ADMINISTERED AT DAILY DOSES RANGING FROM 40 (N=110) TO 80 MG (N=104).
COMMONLY OBSERVED ADVERSE REACTIONS:
THE MOST COMMON ADVERSE REACTIONS (INCIDENCE ?5% AND AT LEAST TWICE THE RATE OF PLACEBO) IN ADOLESCENT PATIENTS (13 TO 17 YEARS) TREATED WITH LATUDA WERE SOMNOLENCE, NAUSEA, AKATHISIA, EXTRAPYRAMIDAL SYMPTOMS (NON-AKATHISIA, 40MG ONLY), VOMITING, AND RHINORRHEA /RHINITIS (80MG ONLY).
ADVERSE REACTIONS ASSOCIATED WITH DISCONTINUATION OF TREATMENT:
THE INCIDENCE OF DISCONTINUATION DUE TO ADVERSE REACTIONS BETWEEN LATUDA-AND PLACEBO-TREATED ADOLESCENT PATIENTS (13 TO 17 YEARS) WAS 4% AND 8%, RESPECTIVELY.
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 ADOLESCENT PATIENTS WITH SCHIZOPHRENIA) ARE SHOWN IN TABLE 20.
TABLE 20: ADVERSE REACTIONS IN 2% OR MORE OF LATUDA-TREATED PATIENTS AND THAT OCCURRED AT GREATER INCIDENCE THAN IN THE PLACEBO-TREATED PATIENTS IN THE ADOLESCENT SHORT-TERM SCHIZOPHRENIA STUDY
BODY SYSTEM OR ORGAN CLASS DICTIONARY-DERIVED TERM PERCENTAGE OF PATIENTS REPORTING REACTION
PLACEBO (N=112) LATUDA 40 MG/DAY (N=110) LATUDA 80 MG/DAY (N=104) ALL LATUDA (N=214)
GASTROINTESTINAL DISORDERS
NAUSEA 3 13 14 14
VOMITING 2 8 6 8
DIARRHEA 1 3 5 4
DRY MOUTH 0 2 3 2
INFECTIONS AND INFESTATIONS
VIRAL INFECTION **6111010
RHINITIS*** 2 <1 8 4
OROPHARYNGEAL PAIN 0 <1 3 2
TACHYCARDIA 0031
NERVOUS SYSTEM DISORDERS
SOMNOLENCE* 7 15 13 15
AKATHISIA 2 9 9 9
DIZZINESS 1 5 5 5
NOTE: FIGURES ROUNDED TO THE NEAREST INTEGER * SOMNOLENCE INCLUDES ADVERSE EVENT TERMS: HYPERSOMNIA, SEDATION, AND SOMNOLENCE ** VIRAL INFECTION INCLUDES ADVERSE EVENT TERMS: NASOPHARYNGITIS, INFLUENZA, VIRAL INFECTION, UPPER RESPIRATORY TRACT INFECTION *** RHINITIS INCUDES ADVERSE EVENT TERMS: RHINITIS, ALLERGIC RHINITIS , RHINORRHEA, AND NASAL CONGESTION
EXTRAPYRAMIDAL SYMPTOMS
SCHIZOPHRENIA
ADULTS
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 21.
TABLE 21: INCIDENCE OF EPS COMPARED TO PLACEBO IN ADULT SCHIZOPHRENIA STUDIES
ADVERSE EVENT TERM LATUDA
PLACEBO (N=708) (%) 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
ADOLESCENTS
IN THE SHORT-TERM, PLACEBO-CONTROLLED, STUDY OF SCHIZOPHRENIA IN ADOLESCENTS, THE INCIDENCE OF EPS, EXCLUDING EVENTS RELATED TO AKATHISIA, FOR LATUDA-TREATED PATIENTS WAS HIGHER IN THE 40 MG (10%) AND THE 80 MG (7.7%) TREATMENT GROUPS VS. PLACEBO (3.6%); AND THE INCIDENCE OF AKATHISIA-RELATED EVENTS FOR LATUDA-TREATED PATIENTS WAS 8.9% VS. 1.8% FOR PLACEBO-TREATED PATIENTS. INCIDENCE OF EPS BY DOSE IS PROVIDED IN TABLE 22.
TABLE 22: INCIDENCE OF EPS COMPARED TO PLACEBO IN THE ADOLESCENT SCHIZOPHRENIA STUDY
ADVERSE EVENT TERM LATUDA
PLACEBO (N=112) (%) 40 MG/DAY (N=110) (%) 80 MG/DAY (N=104) (%)
ALL EPS EVENTS 5 14 14
ALL EPS EVENTS, EXCLUDING AKATHISIA/RESTLESSNESS 4 7 7
AKATHISIA 2 9 9
PARKINSONISM** <1 4 0
DYSKINESIA <1<11
DYSTONIA* 0 <1 1
NOTE: FIGURES ROUNDED TO THE NEAREST INTEGER * DYSTONIA INCLUDES ADVERSE EVENT TERMS: DYSTONIA, TRISMUS, OCULOGYRIC CRISIS, OROMANDIBULAR DYSTONIA, TONGUE SPASM, AND TORTICOLLIS ** PARKINSONISM INCLUDES ADVERSE EVENT TERMS: BRADYKINESIA, DROOLING, EXTRAPYRAMIDAL DISORDER, GLABELLAR REFLEX ABNORMAL, HYPOKINESIA, PARKINSONISM, AND PSYCHOMOTOR RETARDATION
BIPOLAR DEPRESSION
MONOTHERAPY
IN THE ADULT 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 23.
TABLE 23: INCIDENCE OF EPS COMPARED TO PLACEBO IN THE ADULT 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 ADULT 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 24.
TABLE 24: INCIDENCE OF EPS COMPARED TO PLACEBO IN THE ADULT 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
ADULTS
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%).
ADOLESCENTS
THE MEAN CHANGE FROM BASELINE FOR LATUDA-TREATED PATIENTS WITH ADOLESCENT SCHIZOPHRENIA 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, 7.0%; PLACEBO, 1.8%), THE SAS (LATUDA, 8.3%; PLACEBO, 2.7%) AND THE AIMS (LATUDA, 2.8%; PLACEBO, 0.9%).
BIPOLAR DEPRESSION
ONOTHERAPY
THE MEAN CHANGE FROM BASELINE FOR LATUDA-TREATED ADULT 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 ADULT 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
ADULTS
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.
ADOLESCENTS
IN THE SHORT-TERM, PLACEBO-CONTROLLED, ADOLESCENT SCHIZOPHRENIA STUDY, DYSTONIA OCCURRED IN 1% OF LATUDA-TREATED PATIENTS (1% LATUDA 40 MG AND 1% LATUDA 80 MG) COMPARED TO 0% OF PATIENTS RECEIVING PLACEBO. NO PATIENTS DISCONTINUED THE CLINICAL STUDY DUE TO DYSTONIC EVENTS.
BIPOLAR DEPRESSION
MONOTHERAPY
IN THE ADULT 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 ADULT 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 ADULT 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 16 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
ADULTS
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 25).
TABLE 25: SERUM CREATININE SHIFTS FROM NORMAL AT BASELINE TO HIGH AT STUDY END-POINT IN ADULT SCHIZOPHRENIA STUDIES
LABORATORY PARAMETER PLACEBO (N=708) LATUDA 20 MG/DAY (N=71) LATUDA 40 MG/DAY (N=487) LATUDA 80 MG/DAY (N=538) LATUDA 120 MG/DAY (N=291) LATUDA 160 MG/DAY (N=121)
SERUM CREATININE ELEVATED 2% 1% 2% 2% 5% 7%
ADOLESCENTS
SERUM CREATININE: IN THE SHORT-TERM, PLACEBO-CONTROLLED, ADOLESCENT SCHIZOPHRENIA STUDY, THE MEAN CHANGE FROM BASELINE IN SERUM CREATININE WAS ?0.009 MG/DL FOR LATUDA-TREATED PATIENTS COMPARED TO +0.017 MG/DL FOR PLACEBO-TREATED PATIENTS. A CREATININE SHIFT FROM NORMAL TO HIGH (BASED ON THE CENTRALIZED LABORATORY DEFINITION) OCCURRED IN 7.2% (14/194) OF LATUDA-TREATED PATIENTS AND 2.9% (3/103) ON PLACEBO (TABLE 26).
TABLE 26: SERUM CREATININE SHIFTS FROM NORMAL AT BASELINE TO HIGH AT STUDY END-POINT IN THE ADOLESCENT SCHIZOPHRENIA STUDY
LABORATORY PARAMETER PLACEBO (N=103) LATUDA 40 MG/DAY (N=97) LATUDA 80 MG/DAY (N=97)
SERUM CREATININE ELEVATED 2.9% 7.2% 7.2%
BIPOLAR DEPRESSION
MONOTHERAPY
SERUM CREATININE: IN THE ADULT 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 27).
TABLE 27: SERUM CREATININE SHIFTS FROM NORMAL AT BASELINE TO HIGH AT STUDY END-POINT IN THE ADULT 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 ADULT 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 28).
TABLE 28: SERUM CREATININE SHIFTS FROM NORMAL AT BASELINE TO HIGH AT STUDY END-POINT IN THE ADULT ADJUNCTIVE THERAPY BIPOLAR DEPRESSION STUDIES
LABORATORY PARAMETER PLACEBO (N=334) LATUDA 20 TO 120 MG/DAY (N=360)
SERUM CREATININE ELEVATED 2% 4%
POSTMARKETING EXPERIENCE
THE FOLLOWING ADVERSE REACTIONS HAVE BEEN IDENTIFIED DURING POSTAPPROVAL USE OF LATUDA. BECAUSE THESE REACTIONS ARE REPORTED VOLUNTARILY FROM A POPULATION OF UNCERTAIN SIZE, IT IS NOT ALWAYS POSSIBLE TO RELIABLY ESTIMATE THEIR FREQUENCY OR ESTABLISH A CAUSAL RELATIONSHIP TO DRUG EXPOSURE.
HYPERSENSITIVITY REACTIONS: URTICARIA , THROAT SWELLING, TONGUE SWELLING, AND DYSPNEA .
HYPONATREMIA
DRUG INTERACTIONS
DRUGS HAVING CLINICALLY IMPORTANT INTERACTIONS WITH LATUDA
TABLE 29: CLINICALLY IMPORTANT DRUG INTERACTIONS WITH LATUDA
STRONG CYP3A4 INHIBITORS
CLINICAL IMPACT: CONCOMITANT USE OF LATUDA WITH STRONG CYP3A4 INHIBITORS INCREASED THE EXPOSURE OF LURASIDONE COMPARED TO THE USE OF LATUDA ALONE [SEE CLINICAL PHARMACOLOGY ].
INTERVENTION: LATUDA SHOULD NOT BE USED CONCOMITANTLY WITH STRONG CYP3A4 INHIBITORS [SEE CONTRAINDICATIONS ].
EXAMPLES: KETOCONAZOLE , CLARITHROMYCIN , RITONAVIR, VORICONAZOLE, MIBEFRADIL
MODERATE CYP3A4 INHIBITORS
CLINICAL IMPACT: CONCOMITANT USE OF LATUDA WITH MODERATE CYP3A4 INHIBITORS INCREASED THE EXPOSURE OF LURASIDONE COMPARED TO THE USE OF LATUDA ALONE [SEE CLINICAL PHARMACOLOGY ].
INTERVENTION: LATUDA DOSE SHOULD BE REDUCED TO HALF OF THE ORIGINAL LEVEL WHEN USED CONCOMITANTLY WITH MODERATE INHIBITORS OF CYP3A4 [SEE DOSAGE AND ADMINISTRATION ].
EXAMPLES: DILTIAZEM, ATAZANAVIR, ERYTHROMYCIN , FLUCONAZOLE , VERAPAMIL
STRONG CYP3A4 INDUCERS
CLINICAL IMPACT: CONCOMITANT USE OF LATUDA WITH STRONG CYP3A4 INDUCERS DECREASED THE EXPOSURE OF LURASIDONE COMPARED TO THE USE OF LATUDA ALONE [SEE CLINICAL PHARMACOLOGY ].
INTERVENTION: LATUDA SHOULD NOT BE USED CONCOMITANTLY WITH STRONG CYP3A4 INHIBITORS [SEE CONTRAINDICATIONS ].
EXAMPLES: RIFAMPIN , AVASIMIBE, ST. JOHN'S WORT, PHENYTOIN, CARBAMAZEPINE
MODERATE CYP3A4 INDUCERS
CLINICAL IMPACT: CONCOMITANT USE OF LATUDA WITH STRONG CYP3A4 INDUCERS DECREASED THE EXPOSURE OF LURASIDONE COMPARED TO THE USE OF LATUDA ALONE [SEE CLINICAL PHARMACOLOGY ].
INTERVENTION: LATUDA DOSE SHOULD BE INCREASED WHEN USED CONCOMITANTLY WITH MODERATE INDUCERS OF CYP3A4 [SEE DOSAGE AND ADMINISTRATION ] .
EXAMPLES: BOSENTAN, EFAVIRENZ, ETRAVIRINE, MODAFINIL , NAFCILLIN
DRUGS HAVING NO CLINICALLY IMPORTANT INTERACTIONS WITH LATUDA
BASED ON PHARMACOKINETIC STUDIES, NO DOSAGE ADJUSTMENT OF LATUDA IS REQUIRED WHEN ADMINISTERED CONCOMITANTLY WITH LITHIUM, VALPROATE, OR SUBSTRATES OF P-GP OR CYP3A4 [SEE CLINICAL PHARMACOLOGY ].
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).
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 BOX WARNING ].
SUICIDAL THOUGHTS AND BEHAVIORS IN PEDIATRIC AND YOUNG ADULT PATIENTS
IN POOLED ANALYSES OF PLACEBO-CONTROLLED TRIALS OF ANTIDEPRESSANT DRUGS (SSRIS AND OTHER ANTIDEPRESSANT CLASSES) THAT INCLUDED APPROXIMATELY 77,000 ADULT PATIENTS, AND OVER 4,400 PEDIATRIC PATIENTS, THE INCIDENCE OF SUICIDAL THOUGHTS AND BEHAVIORS IN PEDIATRIC AND YOUNG ADULT PATIENTS WAS GREATER IN ANTIDEPRESSANT-TREATED PATIENTS THAN IN PLACEBO-TREATED PATIENTS. THE DRUG-PLACEBO DIFFERENCES IN THE NUMBER OF CASES OF SUICIDAL THOUGHTS AND BEHAVIORS PER 1000 PATIENTS TREATED ARE PROVIDED IN TABLE 2.
NO SUICIDES OCCURRED IN ANY OF THE PEDIATRIC STUDIES. THERE WERE SUICIDES IN THE ADULT STUDIES, BUT THE NUMBER WAS NOT SUFFICIENT TO REACH ANY CONCLUSION ABOUT ANTIDEPRESSANT DRUG EFFECT ON SUICIDE.
TABLE 2: RISK DIFFERENCES OF THE NUMBER OF CASES OF SUICIDAL THOUGHTS OR BEHAVIORS IN THE
AGE RANGE DRUG-PLACEBO DIFFERENCE IN NUMBER OF PATIENTS OF SUICIDAL THOUGHTS OR BEHAVIORS PER 1000 PATIENTS TREATED
INCREASES COMPARED TO PLACEBO
<18 14 ADDITIONAL PATIENTS
18-24 5 ADDITIONAL PATIENTS
DECREASES COMPARED TO PLACEBO
25-64 1 FEWER PATIENT
?65 6 FEWER PATIENTS
LATUDA IS NOT APPROVED FOR USE IN PEDIATRIC PATIENTS WITH DEPRESSION.
IT IS UNKNOWN WHETHER THE RISK OF SUICIDAL THOUGHTS AND BEHAVIORS IN PEDIATRIC AND YOUNG ADULT PATIENTS EXTENDS TO LONGER-TERM USE, I.E., BEYOND FOUR MONTHS. HOWEVER, THERE IS SUBSTANTIAL EVIDENCE FROM PLACEBO-CONTROLLED MAINTENANCE STUDIES IN ADULTS WITH MDD THAT ANTIDEPRESSANTS DELAY THE RECURRENCE OF DEPRESSION.
MONITOR ALL ANTIDEPRESSANT-TREATED PATIENTS FOR CLINICAL WORSENING AND EMERGENCE OF SUICIDAL THOUGHTS AND BEHAVIORS, ESPECIALLY DURING THE INITIAL FEW MONTHS OF DRUG THERAPY AND AT TIMES OF DOSAGE CHANGES. COUNSEL FAMILY MEMBERS OR CAREGIVERS OF PATIENTS TO MONITOR FOR CHANGES IN BEHAVIOR AND TO ALERT THE HEALTHCARE PROVIDER. CONSIDER CHANGING THE THERAPEUTIC REGIMEN, INCLUDING POSSIBLY DISCONTINUING LATUDA, IN PATIENTS WHOSE DEPRESSION IS PERSISTENTLY WORSE, OR WHO ARE EXPERIENCING EMERGENT SUICIDAL THOUGHTS OR BEHAVIORS.
CEREBROVASCULAR ADVERSE REACTIONS, INCLUDING STROKE IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
IN PLACEBO-CONTROLLED TRIALS WITH RISPERIDONE, ARIPIPRAZOLE , AND OLANZAPINE IN ELDERLY SUBJECTS WITH DEMENTIA, THERE WAS A HIGHER INCIDENCE OF CEREBROVASCULAR ADVERSE REACTIONS (CEREBROVASCULAR ACCIDENTS AND TRANSIENT ISCHEMIC ATTACKS), INCLUDING FATALITIES, COMPARED TO PLACEBO-TREATED SUBJECTS. LATUDA IS NOT APPROVED FOR THE TREATMENT OF PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS [SEE BOX WARNING , INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS].
NEUROLEPTIC MALIGNANT SYNDROME
A POTENTIALLY FATAL SYMPTOM COMPLEX SOMETIMES REFERRED TO AS NEUROLEPTIC MALIGNANT SYNDROME (NMS) HAS BEEN REPORTED IN ASSOCIATION WITH ADMINISTRATION OF ANTIPSYCHOTIC DRUGS, INCLUDING LATUDA.
CLINICAL MANIFESTATIONS OF NMS ARE HYPERPYREXIA, MUSCLE RIGIDITY, ALTERED MENTAL STATUS, AND EVIDENCE OF AUTONOMIC INSTABILITY (IRREGULAR PULSE OR BLOOD PRESSURE, TACHYCARDIA , DIAPHORESIS, AND CARDIAC DYSRHYTHMIA). ADDITIONAL SIGNS MAY INCLUDE ELEVATED CREATINE PHOSPHOKINASE, MYOGLOBINURIA (RHABDOMYOLYSIS ), AND ACUTE RENAL FAILURE .
THE DIAGNOSTIC EVALUATION OF PATIENTS WITH THIS SYNDROME IS COMPLICATED. IT IS IMPORTANT TO EXCLUDE CASES WHERE THE CLINICAL PRESENTATION INCLUDES BOTH SERIOUS MEDICAL ILLNESS (E.G., PNEUMONIA, SYSTEMIC INFECTION) AND UNTREATED OR INADEQUATELY TREATED EXTRAPYRAMIDAL SIGNS AND SYMPTOMS (EPS ). OTHER IMPORTANT CONSIDERATIONS IN THE DIFFERENTIAL DIAGNOSIS INCLUDE CENTRAL ANTICHOLINERGIC TOXICITY, HEAT STROKE , DRUG FEVER, AND PRIMARY CENTRAL NERVOUS SYSTEM PATHOLOGY .
THE MANAGEMENT OF NMS SHOULD INCLUDE: 1) IMMEDIATE DISCONTINUATION OF ANTIPSYCHOTIC DRUGS AND OTHER DRUGS NOT ESSENTIAL TO CONCURRENT THERAPY; 2) INTENSIVE SYMPTOMATIC TREATMENT AND MEDICAL MONITORING; AND 3) TREATMENT OF ANY CONCOMITANT SERIOUS MEDICAL PROBLEMS FOR WHICH SPECIFIC TREATMENTS ARE AVAILABLE. THERE IS NO GENERAL AGREEMENT ABOUT SPECIFIC PHARMACOLOGICAL TREATMENT REGIMENS FOR NMS.
IF A PATIENT REQUIRES ANTIPSYCHOTIC DRUG TREATMENT AFTER RECOVERY FROM NMS, THE POTENTIAL REINTRODUCTION OF DRUG THERAPY SHOULD BE CAREFULLY CONSIDERED. IF REINTRODUCED, THE PATIENT SHOULD BE CAREFULLY MONITORED, SINCE RECURRENCES OF NMS HAVE BEEN REPORTED.
TARDIVE DYSKINESIA
TARDIVE DYSKINESIA IS A SYNDROME CONSISTING OF POTENTIALLY IRREVERSIBLE, INVOLUNTARY , DYSKINETIC MOVEMENTS THAT CAN DEVELOP IN PATIENTS TREATED WITH ANTIPSYCHOTIC DRUGS. ALTHOUGH THE PREVALENCE OF THE SYNDROME APPEARS TO BE HIGHEST AMONG THE ELDERLY, ESPECIALLY ELDERLY WOMEN, IT IS IMPOSSIBLE TO RELY UPON PREVALENCE ESTIMATES TO PREDICT, AT THE INCEPTION OF ANTIPSYCHOTIC TREATMENT, WHICH PATIENTS ARE LIKELY TO DEVELOP THE SYNDROME. WHETHER ANTIPSYCHOTIC DRUG PRODUCTS DIFFER IN THEIR POTENTIAL TO CAUSE TARDIVE DYSKINESIA IS UNKNOWN.
THE RISK OF DEVELOPING TARDIVE DYSKINESIA AND THE LIKELIHOOD THAT IT WILL BECOME IRREVERSIBLE ARE BELIEVED TO INCREASE AS THE DURATION OF TREATMENT AND THE TOTAL CUMULATIVE DOSE OF ANTIPSYCHOTIC DRUGS ADMINISTERED TO THE PATIENT INCREASE. HOWEVER, THE SYNDROME CAN DEVELOP, ALTHOUGH MUCH LESS COMMONLY, AFTER RELATIVELY BRIEF TREATMENT PERIODS AT LOW DOSES.
THERE IS NO KNOWN TREATMENT FOR ESTABLISHED CASES OF TARDIVE DYSKINESIA, ALTHOUGH THE SYNDROME MAY REMIT, PARTIALLY OR COMPLETELY, IF ANTIPSYCHOTIC TREATMENT IS WITHDRAWN. ANTIPSYCHOTIC TREATMENT, ITSELF, HOWEVER, MAY SUPPRESS (OR PARTIALLY SUPPRESS) THE SIGNS AND SYMPTOMS OF THE SYNDROME AND THEREBY MAY POSSIBLY MASK THE UNDERLYING PROCESS. THE EFFECT THAT SYMPTOMATIC SUPPRESSION HAS UPON THE LONG-TERM COURSE OF THE SYNDROME IS UNKNOWN.
GIVEN THESE CONSIDERATIONS, LATUDA SHOULD BE PRESCRIBED IN A MANNER THAT IS MOST LIKELY TO MINIMIZE THE OCCURRENCE OF TARDIVE DYSKINESIA. CHRONIC ANTIPSYCHOTIC TREATMENT SHOULD GENERALLY BE RESERVED FOR PATIENTS WHO SUFFER FROM A CHRONIC ILLNESS THAT (1) IS KNOWN TO RESPOND TO ANTIPSYCHOTIC DRUGS, AND (2) FOR WHOM ALTERNATIVE, EQUALLY EFFECTIVE, BUT POTENTIALLY LESS HARMFUL TREATMENTS ARE NOT AVAILABLE OR APPROPRIATE. IN PATIENTS WHO DO REQUIRE CHRONIC TREATMENT, THE SMALLEST DOSE AND THE SHORTEST DURATION OF TREATMENT PRODUCING A SATISFACTORY CLINICAL RESPONSE SHOULD BE SOUGHT. THE NEED FOR CONTINUED TREATMENT SHOULD BE REASSESSED PERIODICALLY.
IF SIGNS AND SYMPTOMS OF TARDIVE DYSKINESIA APPEAR IN A PATIENT ON LATUDA, DRUG DISCONTINUATION SHOULD BE CONSIDERED. HOWEVER, SOME PATIENTS MAY REQUIRE TREATMENT WITH LATUDA DESPITE THE PRESENCE OF THE SYNDROME.
METABOLIC CHANGES
ATYPICAL ANTIPSYCHOTIC DRUGS HAVE BEEN ASSOCIATED WITH METABOLIC CHANGES THAT MAY INCREASE CARDIOVASCULAR/CEREBROVASCULAR RISK. THESE METABOLIC CHANGES INCLUDE HYPERGLYCEMIA , DYSLIPIDEMIA , AND BODY WEIGHT GAIN. WHILE ALL OF THE DRUGS IN THE CLASS HAVE BEEN SHOWN TO PRODUCE SOME METABOLIC CHANGES, EACH DRUG HAS ITS OWN SPECIFIC RISK PROFILE.
HYPERGLYCEMIA AND DIABETES MELLITUS
HYPERGLYCEMIA, IN SOME CASES EXTREME AND ASSOCIATED WITH KETOACIDOSIS OR HYPEROSMOLAR COMA OR DEATH, HAS BEEN REPORTED IN PATIENTS TREATED WITH ATYPICAL ANTIPSYCHOTICS. ASSESSMENT OF THE RELATIONSHIP BETWEEN ATYPICAL ANTIPSYCHOTIC USE AND GLUCOSE ABNORMALITIES IS COMPLICATED BY THE POSSIBILITY OF AN INCREASED BACKGROUND RISK OF DIABETES MELLITUS IN PATIENTS WITH SCHIZOPHRENIA AND THE INCREASING INCIDENCE OF DIABETES MELLITUS IN THE GENERAL POPULATION. GIVEN THESE CONFOUNDERS, THE RELATIONSHIP BETWEEN ATYPICAL ANTIPSYCHOTIC USE AND HYPERGLYCEMIA-RELATED ADVERSE EVENTS IS NOT COMPLETELY UNDERSTOOD. HOWEVER, EPIDEMIOLOGICAL STUDIES SUGGEST AN INCREASED RISK OF TREATMENT-EMERGENT HYPERGLYCEMIA-RELATED ADVERSE EVENTS IN PATIENTS TREATED WITH THE ATYPICAL ANTIPSYCHOTICS. BECAUSE LATUDA WAS NOT MARKETED AT THE TIME THESE STUDIES WERE PERFORMED, IT IS NOT KNOWN IF LATUDA IS ASSOCIATED WITH THIS INCREASED RISK.
PATIENTS WITH AN ESTABLISHED DIAGNOSIS OF DIABETES MELLITUS WHO ARE STARTED ON ATYPICAL ANTIPSYCHOTICS SHOULD BE MONITORED REGULARLY FOR WORSENING OF GLUCOSE CONTROL. PATIENTS WITH RISK FACTORS FOR DIABETES MELLITUS (E.G., OBESITY , FAMILY HISTORY OF DIABETES) WHO ARE STARTING TREATMENT WITH ATYPICAL ANTIPSYCHOTICS SHOULD UNDERGO FASTING BLOOD GLUCOSE TESTING AT THE BEGINNING OF TREATMENT AND PERIODICALLY DURING TREATMENT. ANY PATIENT TREATED WITH ATYPICAL ANTIPSYCHOTICS SHOULD BE MONITORED FOR SYMPTOMS OF HYPERGLYCEMIA INCLUDING POLYDIPSIA , POLYURIA , POLYPHAGIA, AND WEAKNESS. PATIENTS WHO DEVELOP SYMPTOMS OF HYPERGLYCEMIA DURING TREATMENT WITH ATYPICAL ANTIPSYCHOTICS SHOULD UNDERGO FASTING BLOOD GLUCOSE TESTING. IN SOME CASES, HYPERGLYCEMIA HAS RESOLVED WHEN THE ATYPICAL ANTIPSYCHOTIC WAS DISCONTINUED; HOWEVER, SOME PATIENTS REQUIRED CONTINUATION OF ANTI-DIABETIC TREATMENT DESPITE DISCONTINUATION OF THE SUSPECT DRUG.
SCHIZOPHRENIA
ADULTS
POOLED DATA FROM SHORT-TERM, PLACEBO-CONTROLLED SCHIZOPHRENIA STUDIES ARE PRESENTED IN TABLE 3.
TABLE 3: CHANGE IN FASTING GLUCOSE IN ADULT SCHIZOPHRENIA STUDIES
LATUDA
PLACEBO 20 MG/DAY 40 MG/DAY 80 MG/DAY 120 MG/DAY 160 MG/DAY
MEAN CHANGE FROM BASELINE (MG/DL)
N=680 N=71 N=478 N=508 N=283 N=113
SERUM GLUCOSE -0.0 -0.6 +2.6 -0.4 +2.5 +2.5
PROPORTION OF PATIENTS WITH SHIFTS TO ? 126 MG/DL
SERUM GLUCOSE (? 126 MG/DL) 8.3% (52/628) 11.7% (7/60) 12.7% ( 57/449) 6.8% (32/472) 10.0% (26/260) 5.6% (6/108)
IN THE UNCONTROLLED, LONGER-TERM SCHIZOPHRENIA STUDIES (PRIMARILY OPEN-LABEL EXTENSION STUDIES), LATUDA WAS ASSOCIATED WITH A MEAN CHANGE IN GLUCOSE OF +1.8 MG/DL AT WEEK 24 (N=355), +0.8 MG/DL AT WEEK 36 (N=299) AND +2.3 MG/DL AT WEEK 52 (N=307).
ADOLESCENTS
IN STUDIES OF ADOLESCENTS AND ADULTS WITH SCHIZOPHRENIA, CHANGES IN FASTING GLUCOSE WERE SIMILAR. IN THE SHORT-TERM, PLACEBO-CONTROLLED STUDY OF ADOLESCENTS, FASTING SERUM GLUCOSE MEAN VALUES WERE -1.3 FOR PLACEBO (N=95), +0.1 FOR 40MG (N=90), AND +1.8 FOR 80MG (N=92).
BIPOLAR DEPRESSION
MONOTHERAPY
DATA FROM THE ADULT SHORT-TERM, FLEXIBLE-DOSE, PLACEBO-CONTROLLED MONOTHERAPY BIPOLAR DEPRESSION STUDY ARE PRESENTED IN TABLE 4.
TABLE 4: CHANGE IN FASTING GLUCOSE IN THE ADULT MONOTHERAPY BIPOLAR DEPRESSION STUDY
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) 4.3% (6/141) 2.2% (3/138) 6.4% (9/141)
PATIENTS WERE RANDOMIZED TO FLEXIBLY DOSED LATUDA 20 TO 60 MG/DAY, LATUDA 80 TO 120 MG/DAY, OR PLACEBO
IN THE UNCONTROLLED, OPEN-LABEL, LONGER-TERM BIPOLAR DEPRESSION STUDY, PATIENTS WHO RECEIVED LATUDA AS MONOTHERAPY IN THE SHORT-TERM STUDY AND CONTINUED IN THE LONGER-TERM STUDY, HAD A MEAN CHANGE IN GLUCOSE OF +1.2 MG/DL AT WEEK 24 (N=129).
ADJUNCTIVE THERAPY WITH LITHIUM OR VALPROATE
DATA FROM THE ADULT SHORT-TERM, FLEXIBLE-DOSED, PLACEBO-CONTROLLED ADJUNCTIVE THERAPY BIPOLAR DEPRESSION STUDIES ARE PRESENTED IN TABLE 5.
TABLE 5: CHANGE IN FASTING GLUCOSE IN THE ADULT ADJUNCTIVE THERAPY BIPOLAR DEPRESSION STUDIES
PLACEBO LATUDA 20 TO 120 MG/DAY
MEAN CHANGE FROM BASELINE (MG/DL)
N=302 N=319
SERUM GLUCOSE -0.9 +1.2
PROPORTION OF PATIENTS WITH SHIFTS TO ? 126 MG/DL
SERUM GLUCOSE (? 126 MG/DL) 1.0% (3/290) 1.3% (4/316)
PATIENTS WERE RANDOMIZED TO FLEXIBLY DOSED LATUDA 20 TO 120 MG/DAY OR PLACEBO AS ADJUNCTIVE THERAPY WITH LITHIUM OR VALPROATE.
IN THE UNCONTROLLED, OPEN-LABEL, LONGER-TERM BIPOLAR DEPRESSION STUDY, PATIENTS WHO RECEIVED LATUDA AS ADJUNCTIVE THERAPY WITH EITHER LITHIUM OR VALPROATE IN THE SHORT-TERM STUDY AND CONTINUED IN THE LONGER-TERM STUDY, HAD A MEAN CHANGE IN GLUCOSE OF +1.7 MG/DL AT WEEK 24 (N=88).