Special Warning : אזהרת שימוש

5 WARNINGS AND PRECAUTIONS
5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
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 the 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. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer’s disease [see Boxed Warning , Warnings and Precautions (5.3)].

5.2 Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and over 4400 pediatric patients, the incidence of suicidal thoughts and behaviors in patients 24 years of age and younger was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.

No suicides occurred in any of the pediatric studies. There were suicides in the 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 Patients with Suicidal Thoughts or Behaviors in the Pooled Placebo- Controlled Trials of Antidepressants in Pediatric* and Adult Patients 
Age            Drug-Placebo Difference in Number of Patients
Range          with Suicidal Thoughts or Behaviors per 1000
(years)        Patients Treated

Increases Compared to Placebo
<18                           14 additional patients
18 to 24                         5 additional patients
Decreases Compared to Placebo
25 to 64                            1 fewer patient
≥65                              6 fewer patients
*REXULTI is not approved in pediatric patients with MDD.
It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression.

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

5.3 Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis
In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer’s disease [see Boxed Warning , Warnings and Precautions (5.1)].

5.4 Neuroleptic Malignant Syndrome (NMS)
Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs, including REXULTI. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

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

5.5 Tardive Dyskinesia
Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. The risk appears to be highest among the elderly, especially elderly women, but it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drugs differ in their potential to cause tardive dyskinesia is unknown.

The risk of tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the cumulative dose increases. The syndrome can develop after relatively brief treatment periods, at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown.

Given these considerations, REXULTI should be prescribed in a manner most likely to reduce 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, use the lowest dose and the shortest duration of treatment needed to produce a satisfactory clinical response. The need for continued treatment should be reassessed periodically.

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

5.6 Metabolic Changes
Atypical antipsychotic drugs, including REXULTI, have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and body weight gain. Although all of the drugs in the class to date have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with diabetic ketoacidosis hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with REXULTI. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication and monitor periodically during long-term treatment.

Adjunctive Treatment of Major Depressive Disorder: In the 6-week placebo-controlled, fixed-dose clinical studies in adult patients with MDD, the proportions of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) and borderline (≥100 and <126 mg/dL) to high were similar in patients treated with REXULTI and placebo.

In the long-term, open-label depression studies, 5% of adult patients with normal baseline fasting glucose experienced a shift to high while taking REXULTI plus an antidepressant (ADT); 25% of patients with borderline fasting glucose experienced shifts to high. Combined, 9% of patients with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term depression studies.
Schizophrenia (Adults): In the 6-week placebo-controlled, fixed-dose clinical studies in patients with schizophrenia, the proportions of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) or borderline (≥100 and <126 mg/dL) to high were similar in patients treated with REXULTI and placebo. In the long-term, open-label schizophrenia studies, 8% of adult patients with normal baseline fasting glucose experienced a shift from normal to high while taking REXULTI; 17% of patients with borderline fasting glucose experienced shifts from borderline to high.
Combined, 10% of patients with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term schizophrenia studies.

Schizophrenia Pediatric Patients (13 to 17 years of age): In the long-term, open-label study in pediatric patients with schizophrenia, 2.7% of pediatric patients with normal baseline fasting glucose experienced a shift from normal (<100 mg/dL) to high (≥126 mg/dL) while taking REXULTI.


Agitation Associated with Dementia Due to Alzheimer’s Disease: In the 12-week placebo-controlled, fixed-dose studies in patients (51 to 90 years of age) with agitation associated with dementia due to Alzheimer’s disease, the proportions of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) or impaired (≥100 and <126 mg/dL) to high were similar in patients treated with REXULTI (14%) and patients treated with placebo (16%).
Of the patients who were previously treated with REXULTI for 12-weeks and continued into a 12-week, active-treatment extension study, 15% of patients with normal baseline fasting glucose experienced a shift from normal (<100 mg/dL) to high (≥126 mg/dL) fasting glucose while taking REXULTI; 30% of patients with impaired fasting glucose experienced shifts from impaired fasting glucose (≥100 and <126 mg/dL) to high fasting glucose. Combined, 20% of patients with normal or impaired fasting glucose experienced shifts to high fasting glucose.


Dyslipidemia

Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment.

Adjunctive Treatment of Major Depressive Disorder: In the 6-week placebo-controlled, fixed-dose clinical studies in patients with MDD, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in REXULTI- and placebo-treated patients. Table 3 shows the proportions of patients with changes in fasting triglycerides.

Table 3: Change in Fasting Triglycerides in the 6-Week, Placebo-Controlled, Fixed-Dose MDD Studies Proportion of Patients with Shifts Baseline to Post-Baseline

Triglycerides                              Placebo                   1 mg/day                      2 mg/day                 3 mg/day 

Normal to High                                6%                         5%                          13%                      9% (<150 mg/dL to ≥200 and
(15/257)*                  (7/145)*                     (15/115)*                (13/150)* <500 mg/dL)
Normal/Borderline                             0%                         0%                          0.7%                     0% to Very High                                          *
(0/309)                   (0/177)*                      (1/143)*                (0/179)* (<200 mg/dL to ≥500 mg/dL)
* denotes n/N where N=the total number of patients who had a measurement at baseline and at least one post-baseline result.
n=the number of patients with shift.

In the long-term, open-label depression studies, shifts in baseline fasting cholesterol from normal to high were reported in 9% (total cholesterol), 3% (LDL cholesterol), and shifts in baseline from normal to low were reported in 14% (HDL cholesterol) of patients taking REXULTI. Of patients with normal baseline triglycerides, 17% experienced shifts to high, and 0.2% experienced shifts to very high. Combined, 0.6% of patients with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term depression studies.

Schizophrenia (Adults): In the 6-week placebo-controlled, fixed-dose clinical studies in adult patients with schizophrenia, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in REXULTI- and placebo-treated patients. Table 4 shows the proportions of patients with changes in fasting triglycerides.

Table 4: Change in Fasting Triglycerides in the 6-Week Placebo-Controlled, Fixed-Dose Schizophrenia Studies in Adult Patients

Proportion of Patients with Shifts Baseline to Post-Baseline
Triglycerides
Placebo                  1 mg/day                   2 mg/day                4 mg/day 
Normal to High                                    6%                        10%                        8%                     10% (<150 mg/dL to ≥200 and <500
(15/253)*                   (7/72)*                  (19/232)*               (22/226)* mg/dL)
Normal/Borderline to                               0%                         0%                        0%                    0.4% Very High                                                  *                         *                          * (0/303)                    (0/94)                    (0/283)                (1/283)* (<200 mg/dL to ≥500 mg/dL)
* denotes n/N where N=the total number of patients who had a measurement at baseline and at least one post-baseline result.
n=the number of patients with shift.

In the long-term, open-label schizophrenia studies in adult patients, shifts in baseline fasting cholesterol from normal to high were reported in 6% (total cholesterol), 2% (LDL cholesterol), and shifts in baseline from normal to low were reported in 17% (HDL cholesterol) of patients taking REXULTI. Of patients with normal baseline triglycerides, 13% experienced shifts to high, and 0.4% experienced shifts to very high triglycerides. Combined, 0.6% of patients with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term schizophrenia studies.

Schizophrenia [ Pediatric Patients (13 to 17 years of age)]: In the long-term, open-label study in pediatric patients with schizophrenia, shifts in baseline fasting total cholesterol from normal to high (<170 to ≥200 mg/dL) were reported in 7% of patients taking REXULTI, and shifts in baseline HDL cholesterol from normal to low (≥40 to <40 mg/dL) were reported in 12.9% of patients taking REXULTI. Of patients with normal baseline triglycerides, 8.5% experienced shifts from normal to high (<150 to ≥200 mg/dL).


Agitation Associated with Dementia Due to Alzheimer’s Disease: In the 12-week placebo-controlled, fixed-dose clinical studies in patients (55 to 90 years of age) with agitation associated with dementia due to Alzheimer’s disease, changes in total cholesterol, LDL cholesterol, and HDL cholesterol were similar in REXULTI- and placebo-treated patients.

Table 5 shows the proportions of patients with changes in fasting triglycerides in REXULTI- and placebo-treated patients.

Table 5         Change in Fasting Triglycerides in the 12-Week Placebo-Controlled, Fixed-Dose Agitation Associated with Dementia Due to Alzheimer’s Disease Studies
Proportion of Patients with Shifts Baseline to Post-Baseline
Triglycerides                                                    Placebo                 1 mg/day           2 mg/day          3 mg/day Normal to High                                                     6%                       9%               13%                 6% (<150 and 200 to <500 mg/dL)                                    (10/157)*                 (9/99)*          (17/133)*           (6/94)* Borderline to High
12%                     33%                28%               26%
(150 and <200mg/dL to 200 and <500
(3/26)*                 (2/6)*             (7/25)*           (6/23)* mg/dL)
Table 5         Change in Fasting Triglycerides in the 12-Week Placebo-Controlled, Fixed-Dose Agitation Associated with Dementia Due to Alzheimer’s Disease Studies
Proportion of Patients with Shifts Baseline to Post-Baseline
Triglycerides                                                      Placebo             1 mg/day            2 mg/day       3 mg/day Normal/Borderline to High                                           7%                   11%                 15%            10% (<200 mg/dL to 200 and <500 mg/dL)                               (13/183)*             (11/105)*           (24/158)*      (12/117)* *denotes n/N where N=the total number of patients who had a measurement at baseline and at least one post-baseline result n=the number of patients with shift

Of the patients who were previously treated with REXULTI for 12 weeks and continued into a 12-week, active-treatment extension study, 9% of patients taking REXULTI showed shifts in baseline fasting total cholesterol from normal (<200 mg/dL) to high (≥240 mg/dL), and 16% of patients taking REXULTI showed shifts in baseline HDL cholesterol from normal to low (≥40 to <40 mg/dL). Of the patients with normal baseline triglycerides, 18% experienced shifts from normal (<150 mg/dL) to high (200 to <500 mg/dL).


Weight Gain

Weight gain has been observed in patients treated with atypical antipsychotics, including REXULTI. Monitor weight at baseline and frequently thereafter.

Adjunctive Treatment of Major Depressive Disorder:

Table 6 shows weight gain data at last visit and percentage of adult patients with ≥7% increase in body weight at endpoint from the 6-week placebo-controlled, fixed-dose clinical studies in patients with MDD.

Table 6: Increases in Body Weight in the 6-Week Placebo-Controlled, Fixed-Dose MDD Studies 
Placebo                 1 mg/day                  2 mg/day                         3 mg/day n=407                   n=225                     n=187                            n=228 Mean Change from Baseline (kg) at Last Visit
All Patients                    +0.3                        +1.3                          +1.6                     +1.6 Proportion of Patients with a ≥7% Increase in Body Weight (kg) at Any Visit (*n/N) 2%                       5%                      5%                         2% (8/407)*                 (11/225)*               (9/187)*                   (5/228)* * N=the total number of patients who had a measurement at baseline and at least one post-baseline result.
n=the number of subjects with a shift ≥7%.

In the long-term, open-label depression studies, 4% of patients discontinued due to weight increase. REXULTI was associated with mean change from baseline in weight of 2.9 kg at Week 26 and 3.1 kg at Week 52. In the long-term, open label depression studies, 30% of patients demonstrated a ≥7% increase in body weight and 4% demonstrated a ≥7% decrease in body weight.

Schizophrenia (Adults): Table 7 shows weight gain data at last visit and percentage of adult patients with ≥7% increase in body weight at endpoint from the 6-week placebo-controlled, fixed-dose clinical studies in patients with schizophrenia.

Table 7: Increases in Body Weight in the 6-Week Placebo-Controlled, Fixed-Dose Schizophrenia Studies in Adult Patients

Placebo                 1 mg/day                  2 mg/day                         4 mg/day n=362                   n=120                     n=362                            n=362 Mean Change from Baseline (kg) at Last Visit
All Patients                    +0.2                       +1.0                          +1.2                          +1.2 Proportion of Patients with a ≥7% Increase in Body Weight (kg) at Any Visit (*n/N) 4%                       10%                     11%                        10% (15/362)*                (12/120)*               (38/362)*                  (37/362)* * denotes n/N where N=the total number of patients who had a measurement at baseline and at least one post-baseline result.
n=the number of patients with a shift ≥7%.

In the long-term, open-label schizophrenia studies in adult patients, 0.6% of patients discontinued due to weight increase.
REXULTI was associated with mean change from baseline in weight of 1.3 kg at Week 26 and 2.0 kg at Week 52. In the long-term, open label schizophrenia studies, 20% of patients demonstrated a ≥7% increase in body weight and 10% demonstrated a ≥7% decrease in body weight.

Schizophrenia [Pediatric Patients (13 to 17 years of age)]: In the long-term, open label study in pediatric patients with schizophrenia, 0.5% of patients discontinued due to weight increase. The mean increase in weight from the open-label study baseline to last visit was 3.8 kg. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for natural growth of children and adolescents by comparisons to age- and gender- matched population standards. A z-score change <0.5 SD is considered not clinically significant. In this study, the mean change in z-score from open-label baseline to last visit was 0.10 SD for body weight, while 20% of patients had an increase in age- and-gender-adjusted body weight z-score of at least 0.5 SD from baseline. When treating pediatric, weight gain should be monitored and assessed against that expected for normal growth.


Agitation Associated with Dementia Due to Alzheimer’s Disease: In the 12-week placebo-controlled, fixed-dose clinical studies in patients (51 to 90 years of age) with agitation associated with dementia due to Alzheimer’s disease, the proportion of the patients with a ≥7% increase in body weight (kg) at any visit were 2% in REXULTI compared to 0% in placebo group.

In patients who were previously treated with REXULTI for 12 weeks and who continued into a 12-week, active-treatment extension study, there was no mean change in weight (kg) from baseline to last visit in association with REXULTI. In this extension study, 4% of patients demonstrated ≥7% increase in body weight, and 5% demonstrated a ≥7% decrease in body weight from baseline to last visit.



5.7 Pathological Gambling and Other Compulsive Behaviors
Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking REXULTI. Other compulsive urges, reported less frequently, include sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with REXULTI. In some cases, although not all, urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.

5.8 Leukopenia, Neutropenia, and Agranulocytosis
Leukopenia and neutropenia have been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in this class.
Possible risk factors for leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of REXULTI at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue REXULTI in patients with absolute neutrophil count <1000/mm3 and follow their WBC until recovery.

5.9 Orthostatic Hypotension and Syncope
Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. In the short-term, placebo-controlled clinical studies of REXULTI plus ADT in adult patients with MDD, the incidence of orthostatic hypotension-related adverse reactions in REXULTI plus ADT- treated patients compared to placebo plus ADT-treated patients included: dizziness (2% versus 2%) and orthostatic hypotension (0.1% versus 0%). In the short-term, placebo-controlled clinical studies of REXULTI in adult patients with schizophrenia, the incidence of orthostatic hypotension-related adverse reactions in REXULTI-treated patients compared to placebo patients included: dizziness (2% versus 2%), orthostatic hypotension (0.4% versus 0.2%), and syncope (0.1% versus 0%). In 12-week, placebo-controlled clinical studies of REXULTI in patients with agitation associated with dementia due to Alzheimer’s disease, the incidence of orthostatic hypotension-related adverse reactions in patients treated with REXULTI compared to patients treated with placebo included: dizziness (3% versus 3%), orthostatic hypotension (1% versus 1%), and syncope (0.2% versus 0.8%).

Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia, concomitant treatment with antihypertensive medication), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. REXULTI has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from the premarketing clinical studies.

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

5.11 Seizures
Like other antipsychotic drugs, REXULTI may cause seizures. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients.

5.12 Body Temperature Dysregulation
Atypical antipsychotics may disrupt the body’s ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use REXULTI with caution in patients who may experience these conditions.

5.13 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Antipsychotic drugs, including REXULTI, should be used cautiously in patients at risk for aspiration.
5.14 Potential for Cognitive and Motor Impairment
REXULTI, like other antipsychotics, has the potential to impair judgment, thinking, or motor skills. In the 6-week placebo-controlled clinical studies in patients with MDD, somnolence (including sedation and hypersomnia) was reported in 4% for REXULTI plus ADT-treated patients compared to 1% of placebo plus ADT-treated patients.

In the 6-week placebo-controlled clinical studies in adult patients with schizophrenia, somnolence (including sedation and hypersomnia) was reported in 5% of REXULTI-treated patients compared to 3% of placebo-treated patients.

In the 12-week placebo-controlled, fixed-dose clinical studies in patients (51 to 90 years of age) with agitation associated with dementia due to Alzheimer’s disease, somnolence (including sedation) was reported in 3% of patients treated with REXULTI compared to 1% of patients treated with placebo.

Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that REXULTI therapy does not affect them adversely.

6 ADVERSE REACTIONS

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, Warnings and Precautions (5.1)]
•       Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Boxed Warning, Warnings and Precautions (5.2)]
•       Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.3)]
•       Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.4)]
•       Tardive Dyskinesia [see Warnings and Precautions (5.5)]
•       Metabolic Changes [see Warnings and Precautions (5.6)]
•       Pathological Gambling and Other Compulsive Behaviors [see Warnings and Precautions (5.7)]
•       Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.8)]
•       Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.9)]
•       Falls [see Warnings and Precautions (5.10)]
•       Seizures [see Warnings and Precautions (5.11)]
•       Body Temperature Dysregulation [see Warnings and Precautions (5.12)]
•       Dysphagia [see Warnings and Precautions (5.13)]
•       Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.14)] 
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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.

Adjunctive Treatment in Major Depressive Disorder (MDD)

The safety of REXULTI was evaluated in 1054 adult patients (18 to 65 years of age) diagnosed with MDD who participated in two 6-week, placebo-controlled, fixed-dose clinical studies in patients with major depressive disorder in which REXULTI was administered at doses of 1 mg to 3 mg daily as adjunctive treatment to continued antidepressant therapy; patients in the placebo group continued to receive antidepressant therapy [see Clinical Studies (14.1)].

Adverse Reactions Reported as Reasons for Discontinuation of Treatment A total of 3% (17/643) of REXULTI-treated patients and 1% (3/411) of placebo-treated patients discontinued due to adverse reactions.

Adverse Reactions in REXULTI Studies for Adjunctive MDD in Adults

Adverse reactions associated with the adjunctive use of REXULTI (incidence of 2% or greater and adjunctive REXULTI incidence greater than adjunctive placebo) that occurred during acute therapy (up to 6-weeks in patients with MDD) are shown in Table 8.

Table 8: Adverse Reactions in ≥2% of REXULTI-Treated Patients and Greater than Placebo in Pooled 6-Week Placebo-Controlled, Fixed-Dose Adjunctive MDD Studies in Adults (Study 1 and Study 2) 
REXULTI
Placebo                                                        All
1 mg/day        2 mg/day       3 mg/day
(N=411)                                                     REXULTI
%
(N=226)         (N=188)        (N=229)
%                %             %
(N=643)
%
Gastrointestinal Disorders
Constipation              1           3                2             1              2 General Disorders and Administration Site Conditions
Fatigue                   2           3                2             5              3 Infections and Infestations
Nasopharyngitis           2           7                1             3              4 Investigations
Weight Increased          2           7                8             6              7 Blood Cortisol                                                                      2 Decreased                 1           4                0             3 Metabolism and Nutrition
Increased Appetite        2           3                3             2              3 Nervous System Disorders
Akathisia                 2           4                7             14             9 Headache                  6           9                4             6              7 Somnolence               0.5          4                4             6              5 Tremor                    2           4                2             5              4 Dizziness                 1           1                5             2              3 Psychiatric Disorders
Anxiety                   1           2                4             4              3 Restlessness              0           2                3             4              3 

Dose-Related Adverse Reactions in the Adjunctive MDD Studies
In Studies 1 and 2, among the adverse reactions that occurred at ≥2% incidence in the patients treated with REXULTI plus ADT, the incidences of akathisia and restlessness increased with increases in dose.

Schizophrenia

Adults
The safety of REXULTI was evaluated in 852 adult patients (18 to 65 years of age) diagnosed with schizophrenia who participated in two 6-week placebo-controlled, fixed-dose clinical studies in which REXULTI was administered at daily doses of 1 mg, 2 mg and 4 mg [see Clinical Studies (14.2)].

Adverse Reactions Occurring at an Incidence of 2% or More in Patients Treated with REXULTI for Schizophrenia Adverse reactions associated with REXULTI (incidence of 2% or greater and REXULTI incidence greater than placebo) during short-term (up to 6-weeks) studies in adult patients with schizophrenia are shown in Table 9.
Table 9: Adverse Reactions in ≥2% of REXULTI-Treated Patients and Greater than Placebo in Pooled 6-Week Placebo-Controlled, Fixed-Dose Schizophrenia Studies in Adult Patients (Study 3 and Study 4) 
REXULTI
Placebo                                                             ALL (N=368)         1 mg/day         2 mg/day         4 mg/day
REXULTI
%            (N=120)          (N=368)          (N=364)
%                %                 %
(N=852)
%
Gastrointestinal Disorders
Dyspepsia              2                  6                2                 3              3 Diarrhea               2                  1                3                 3              3 Investigations
Weight                 2                  3                4                 4              4 Increased
Blood                  1                  4                2                 2              2 Creatinine
Phosphokinase
Increased
Nervous System Disorders
Akathisia              5                  4                5                 7              6 Tremor                 1                  2                2                 3              3 Sedation               1                  2                2                 3              2 

Agitation Associated with Dementia Due to Alzheimer’s Disease
The safety of REXULTI was evaluated in 503 patients (51 to 90 years of age), with a probable diagnosis of agitation associated with dementia due to Alzheimer’s disease, who participated in two 12-week placebo-controlled, fixed-dose clinical studies in which REXULTI was administered at daily doses of 2 mg to 3 mg [see Clinical Studies (14.3)].
Discontinuation of Treatment Due to Adverse Reactions
In two 12-week placebo-controlled, fixed-dose, clinical studies, a total of 5.6% (28/503) of patients treated with REXULTI and 4.8% (12/251) of patients treated with placebo discontinued due to adverse reactions.
Adverse Reactions Occurring at an Incidence of 2% or More in Patients Treated with REXULTI for Agitation Associated with Dementia Due to Alzheimer’s Disease
Adverse reactions associated with REXULTI (incidence ≥2% and greater than placebo) during the 12-week fixed-dose clinical studies in geriatric patients for treatment of agitation associated with dementia due to Alzheimer’s disease are shown in Table 10.

Table 10     Adverse Reactions in ≥2% of REXULTI-Treated Patients and Greater than Placebo in Pooled 12-Week Placebo-Controlled, Fixed-Dose Agitation Associated with Dementia due to Alzheimer’s Disease Studies (Study 6 and Study 7)
REXULTI
ALL
Placebo      1 mg/day*       2 mg/day       3 mg/day        REXULTI
(N=251)       (N=137)         (N=213)        (N=153)        (N=503)
%             %               %              %              %
Infections and Infestations
Nasopharyngitis                      2            4             2              3                3 Urinary Tract Infection              1            2             3              3                3 Nervous System Disorders
Dizziness†                           2            1             5              3                3 Headache                                 8                 9             9                7                 8 ‡
Somnolence                               1                 2             3                4                 3 Psychiatric Disorders
Insomnia§                                3                 5             5                2                 4 *1 mg once day REXULTI dosage is not a recommended dosage for the treatment of agitation associated with dementia due to Alzheimer’s disease [see Dosage and Administration (2.4)].
†Dizziness   and Vertigo are grouped to Dizziness
‡Sedation and somnolence are group to somnolence.

§Initial insomnia and insomnia are grouped to insomnia



Extrapyramidal Symptoms
Adjunctive Treatment of Major Depressive Disorder

The incidence of reported extrapyramidal symptoms (EPS)-related adverse reactions, excluding akathisia, was 6% for REXULTI plus ADT-treated patients versus 3% for placebo plus ADT-treated patients. The incidence of akathisia events for REXULTI plus ADT-treated patients was 9% versus 2% for placebo plus ADT-treated patients.

In the 6-week placebo-controlled MDD studies, data was objectively collected on the Simpson - Angus Rating Scale (SAS) for EPS, the Barnes Akathisia Rating Scale (BARS) for akathisia and the Abnormal Involuntary Movement Score (AIMS) for dyskinesia. The mean change from baseline at last visit for REXULTI plus ADT-treated patients for the SAS, BARS and AIMS was comparable to placebo - treated patients. The percentage of patients who shifted from normal to abnormal was greater in REXULTI plus ADT-treated patients versus placebo plus ADT-treated patients for the BARS (4% versus 0.6%) and the SAS (4% versus 3%).

Schizophrenia

The incidence of reported EPS-related adverse reactions, excluding akathisia, was 5% for REXULTI-treated patients versus 4% for placebo-treated patients. The incidence of akathisia events for REXULTI-treated patients was 6% versus 5% for placebo-treated patients.

In the 6-week placebo-controlled, fixed-dose schizophrenia studies in adults, data was objectively collected on the Simpson - Angus Rating Scale (SAS) for EPS, the Barnes Akathisia Rating Scale (BARS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia. The mean change from baseline at last visit for REXULTI-treated patients for the SAS, BARS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in REXULTI-treated patients versus placebo for the BARS (2% versus 1%) and the SAS (7% versus 5%).

Agitation Associated with Dementia Due to Alzheimer’s Disease

The incidence of reported EPS-related adverse reactions, excluding akathisia, was 3% for REXULTI-treated patients versus 2% for placebo-treated patients. The incidence of akathisia events for REXULTI-treated patients was 1% versus 0% for placebo-treated patients.

In the 12-week placebo-controlled, fixed-dose studies in agitation associated with dementia due to Alzheimer’s disease, data was objectively collected on the Simpson-Angus Rating Scale (SAS) for EPS, the Barnes Akathisia Rating Scale (BARS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia. The mean change from baseline at last visit for REXULTI-treated patients for the SAS, BARS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in REXULTI-treated patients versus placebo for the SAS (6% versus 2%).
Dystonia

Symptoms of dystonia 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.

Other Adverse Reactions Observed during Clinical TrialEvaluation of REXULTI 
Other adverse reactions (≥1% frequency and greater than placebo) within the short-term, placebo-controlled trials in adult patients with MDD and schizophrenia are shown below. The following listing does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have clinically significant implications, or 5) which occurred at a rate equal to or less than placebo.

Eye Disorders: Vision Blurred

Gastrointestinal Disorders: Nausea, Dry Mouth, Salivary Hypersecretion, Abdominal Pain, Flatulence 
Investigations: Blood Prolactin Increased

Musculoskeletal and Connective Tissue Disorders: Myalgia
Psychiatric Disorders: Abnormal Dreams

Skin and Subcutaneous Tissue Disorders: Hyperhidrosis

Pediatric Patients (13 to 17 years of age)
In an on-going, 2 year, open-label study in pediatric patients 13 to 17 years of age with schizophrenia, in which safety was assessed in 194 patients of which 140 received REXULTI for at least 6 months. Adverse reactions reported in clinical studies for this age group were generally similar to those observed in adult patients.


Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/


6.2 Postmarketing Experience
The following adverse reaction has been identified during post-approval use of REXULTI. 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.

Nervous System disorders: Neuroleptic Malignant Syndrome

Effects on Driving