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 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.

In two of four placebo-controlled trials in elderly patients with dementia- related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus oral risperidone when compared to patients treated with oral risperidone alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed.

UZEDY is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)].

5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly

Patients with Dementia-Related Psychosis

Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73 to 97 years) in trials of oral risperidone in elderly patients with dementia- related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse reactions in patients treated with oral risperidone compared to patients treated with placebo. UZEDY is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

5.3 Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and 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.

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

5.4 Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may 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 predict, which patients will 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 with the duration of treatment and the cumulative dose. The syndrome can develop, after relatively brief treatment periods, even 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, however, 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 the syndrome is unknown.

Given these considerations, UZEDY 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: (1) who suffer from a chronic illness that 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 producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

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

5.5 Metabolic Changes

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

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including risperidone. 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. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including UZEDY, 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, including UZEDY, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including UZEDY, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including UZEDY, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of risperidone.

Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled studies in another indication with oral risperidone are presented in Table 2.

Table 2: Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adults with Schizophrenia or Another Indication with Oral Risperidone

	Oral Risperidone
	** Placebo**	1 mg to 8 mg per day	** >8 mg to 16mg per day**
	Mean change from baseline (mg/dL)
Serum Glucose	N=555 -1.4	N=748 0.8	N=164 0.6
	Proportion of Patients with Shifts
Serum Glucose (<140 mg/dL to ≥200 mg/dL)	0.6% (3/525)	0.4% (3/702)	0% (0/158)

In longer-term, controlled and uncontrolled studies in adults, oral risperidone was associated with a mean change in glucose of +2.8 mg/dL at Week 24 (N=151) and +4.1 mg/dL at Week 48 (N=50).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Before or soon after initiation of antipsychotic medications, obtain a fasting lipid profile at baseline and monitor periodically during treatment.

Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adults with schizophrenia or another indication with oral risperidone are presented in Table 3.

Table 3: Change in Random Lipids from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adults with Schizophrenia or Another Indication with Oral Risperidone

	Oral Risperidone****
	Placebo	1 mg to 8 mg per day	** >8 mg to 16mg per day**
	Mean change from baseline (mg/dL)
Cholesterol Change from baseline	N=559 0.6	N=742 6.9	N=156 1.8
Triglycerides Change from baseline	N=183 -17.4	N=307 -4.9	N=123 -8.3
	** Proportion of Patients with Shifts**
Cholesterol (<200 mg/dL to ≥240 mg/dL)	2.7% (10/368)	4.3% (22/156)	6.3% (6/96)
Triglycerides (<500 mg/dL to ≥500 mg/dL)	1.1% (2/180)	2.7% (8/301)	2.5% (3/121)

In longer-term, controlled and uncontrolled studies, oral risperidone was associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (N=231) and +5.5 mg/dL at Week 48 (N=86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (N=52).

Weight Gain

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

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo- controlled, 3- to 8- week, fixed- or flexible-dose studies in adults with schizophrenia or another indication with oral risperidone are presented in Table 4.

Table 4: Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥7% Gain in Body Weight From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adults With Schizophrenia or Another Indication with Oral Risperidone

	Oral Risperidone
	Placebo (n=597)	1 mg to 8 mg per day (n=769)	** >8 mg to 16mg per day** (n=158)
Weight (kg) Change from baseline	-0.3	0.7	2.2
Weight Gain ≥7% increase from baseline****	2.9%	8.7%	20.9%

In longer-term, controlled and uncontrolled studies, oral risperidone was associated with a mean change in weight of +4.3 kg at Week 24 (n=395) and +5.3 kg at Week 48 (n=203).

5.6 Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This in turn may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia may lead to decreased bone density in both female and male patients.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

5.7 Orthostatic Hypotension and Syncope

UZEDY may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, probably reflecting its alpha- adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of patients treated with oral risperidone in Phase 2 and 3 studies in adults with schizophrenia.

UZEDY should be used with particular caution in (1) patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia and (2) in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of oral risperidone and antihypertensive medication.

5.8 Falls

Antipsychotics, including UZEDY, may cause somnolence, postural hypotension, motor and sensory instability which may lead to falls and, consequently, fractures or other fall-related injuries. Somnolence, postural hypotension, motor and sensory instability have been reported with the use of risperidone. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.9 Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including risperidone. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and a history of drug-induced leukopenia/neutropenia. In patients with a pre-existing history of a clinically significant 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 UZEDY 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 treated promptly if such symptoms or signs occur. Discontinue UZEDY in patients with absolute neutrophil count <1000/mm3 and follow their WBC followed until recovery.

5.10 Potential for Cognitive and Motor Impairment

UZEDY, like other antipsychotics, may cause somnolence and has the potential to impair judgement, thinking, and motor skills. Somnolence was a commonly reported adverse reaction associated with oral risperidone treatment, especially when ascertained by direct questioning of patients. This adverse reaction is dose-related, and in a study utilizing a checklist to detect adverse reactions, 41% of the high-dose patients (oral risperidone 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for detecting adverse reactions than spontaneous reporting, by which 8% of oral risperidone 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse reaction.

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

5.11 Seizures

During premarketing studies of oral risperidone in adult patients with schizophrenia, seizures occurred in 0.3% of patients (9 out of 2,607 patients), two in association with hyponatremia. Use UZEDY cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

5.12 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia. Antipsychotic drugs, including UZEDY, should be used cautiously in patients at risk for aspiration.

5.13 Priapism

Priapism has been reported during postmarketing surveillance for other risperidone products. A case of priapism was reported in premarket studies of UZEDY. Severe priapism may require surgical intervention.

5.14 Body Temperature Regulation

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone use. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use UZEDY with caution in patients who may experience these conditions.

6 ADVERSE REACTIONS

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

• Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)]
• Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2)]
• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
• Tardive dyskinesia [see Warnings and Precautions (5.4)]
• Metabolic changes [see Warnings and Precautions (5.5)]
• Hyperprolactinemia [see Warnings and Precautions (5.6)]
• Orthostatic hypotension and syncope [see Warnings and Precautions (5.7)]
• Falls [see Warnings and Precautions (5.8)]
• Leukopenia, neutropenia and agranulocytosis [see Warnings and Precautions (5.9)]
• Potential for cognitive and motor impairment [see Warnings and Precautions (5.10)]
• Seizures [see Warnings and Precautions (5.11)]
• Dysphagia [see Warnings and Precautions (5.12)]
• Priapism [see Warnings and Precautions (5.13)]
• Body temperature regulation [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.

The safety of UZEDY for the treatment of schizophrenia in adults is based on adequate and well-controlled studies of oral risperidone in studies of patients with schizophrenia and other indications. The results of those adequate and well-controlled studies are presented below.

The data described in this section are derived from a clinical trial database consisting of 9,803 patients exposed to one or more doses of oral risperidone for the treatment of schizophrenia and other psychiatric disorders. Of these 9,803 patients, 2,687 were patients who received oral risperidone while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with oral risperidone varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 3 years) exposures. Safety was assessed by collecting adverse reactions and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs.

Injection site reactions for UZEDY presented in this section (see “Injection Site Reactions with UZEDY” below) are based on a randomized withdrawal study in patients with schizophrenia consisting of a 12-week open-label oral risperidone (2 mg to 5 mg) stabilization phase, followed by a placebo- controlled phase in which patients were randomized to UZEDY (once monthly or once every 2 months) or placebo for a variable time until impending relapse or study completion [see Clinical Studies (14)].

The safety of UZEDY was evaluated in a total of 740 adult patients with schizophrenia who received at least 1 dose of UZEDY during the clinical development program. A total of 351 patients were exposed to UZEDY for at least 6 months, of which 221 patients were exposed to UZEDY for at least 12 months, which included 112 patients exposed to once monthly and 109 patients to once every 2 months dosing regimens. In addition, 32 patients were exposed to UZEDY for at least 24 months.

Adverse Reactions in Studies with Oral Risperidone

The most common adverse reactions in clinical trials of oral risperidone (>5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain.

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Adult Patients with Schizophrenia Treated with Oral Risperidone

Table 5 lists the adverse reactions reported in 2% or more of oral risperidone-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.

Table 5: Adverse Reactions in ≥2% of Oral Risperidone-Treated Adult Patients (and greater than placebo) with Schizophrenia in Double-Blind, Placebo-Controlled Trials

	Percentage of Patients Reporting Reaction
	Oral Risperidone
** System/Organ Class** Adverse Reaction	2 mg to 8 mg per day ** (N=366)**	>8 mg to 16 mg per day ** (N=198)**	Placebo ** (N=225)**
Cardiac Disorders
Tachycardia	1	3	0
Eye Disorders
Vision blurred	3	1	1
** Gastrointestinal Disorders**
Nausea	9	4	4
Constipation	8	9	6
Dyspepsia	8	6	5
Dry mouth	4	0	1
Abdominal discomfort	3	1	1
Salivary hypersecretion	2	1	<1
Diarrhea	2	1	1
General Disorders
Fatigue	3	1	0
Chest pain	2	2	1
Asthenia	2	1	<1
** Infections and Infestations**
Nasopharyngitis	3	4	3
Upper respiratory tract infection	2	3	1
Sinusitis	1	2	1
Urinary tract infection	1	3	0
Investigations
Blood creatine phosphokinase increased	1	2	<1
Heart rate increased	<1	2	0
Musculoskeletal and Connective Tissue Disorders
Back pain	4	1	1
Arthralgia	2	3	<1
Pain in extremity	2	1	1
Nervous System Disorders
Parkinsonism*	14	17	8
Akathisia*	10	10	3
Sedation	10	5	2
Dizziness	7	4	2
Dystonia*	3	4	2
Tremor*	2	3	1
Dizziness postural	2	0	0
Psychiatric Disorders
Insomnia	32	25	27
Anxiety	16	11	11
Respiratory, Thoracic and Mediastinal Disorders
Nasal congestion	4	6	2
Dyspnea	1	2	0
Epistaxis	<1	2	0
** Skin and Subcutaneous Tissue Disorders**
Rash	1	4	1
Dry skin	1	3	0
Vascular Disorders
Orthostatic hypotension	2	1	0

• Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson’s disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor.

Other Adverse Reactions Observed During the Clinical Trial Evaluations of Oral Risperidone

The following is a list of additional adverse drug reactions that have been reported during the clinical trial evaluation of oral risperidone:

Blood and Lymphatic System Disorders**:**anemia, granulocytopenia, neutropenia

Cardiac Disorders**:******sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block

Ear and Labyrinth Disorders**:**ear pain, tinnitus

Endocrine Disorders**:******hyperprolactinemia

Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual acuity reduced

Gastrointestinal Disorders**:******dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, aptyalism

General Disorders**:******edema peripheral, thirst, gait disturbance, chest discomfort, chest pain, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness, feeling abnormal

Immune System Disorders**:******drug hypersensitivity

Infections and Infestations**:**pneumonia, influenza, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic

Investigations**:******body temperature increased, blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased

Metabolism and Nutrition Disorders**:******decreased appetite, polydipsia, anorexia

Musculoskeletal, Connective Tissue, and Bone Disorders**:******joint swelling, joint stiffness, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, muscle rigidity, rhabdomyolysis

Nervous System Disorders**:******balance disorder, disturbance in attention, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, syncope, loss of consciousness, hypoesthesia, tardive dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation

Psychiatric Disorders**:******agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness, libido decreased, anorgasmia

Renal and Urinary Disorders**:******enuresis, dysuria, pollakiuria, urinary incontinence

****Reproductive System and Breast Disorders:****menstruation irregular, amenorrhea, gynecomastia, galactorrhea, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement

****Respiratory, Thoracic, and Mediastinal Disorders:****wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema

Skin and Subcutaneous Tissue Disorders**:******erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, acne, hyperkeratosis, seborrheic dermatitis, rash generalized, rash maculopapular

****Vascular Disorders:****hypotension, flushing

Discontinuations Due to Adverse Drug Reactions with Oral Risperidone

Approximately 7% (39/564) of oral risperidone-treated patients in double- blind, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more oral risperidone- treated patients were:

Table 6: Adverse Reactions Associated with Discontinuation in ≥2% of Oral Risperidone-Treated Adult Patients in Schizophrenia Trials

	Oral Risperidone
** Adverse Reaction**	2 mg to 8 mg per day (N=366)	>8 mg to 16 mg per day (N=198)	Placebo (N=225)
Dizziness	1.4%	1%	0%
Nausea	1.4%	0%	0%
Vomiting	0.8%	0%	0%
Parkinsonism	0.8%	0%	0%
Somnolence	0.8%	0%	0%
Dystonia	0.5%	0%	0%
Agitation	0.5%	0%	0%
Abdominal pain	0.5%	0%	0%
Orthostatic hypotension	0.3%	0.5%	0%
Akathisia	0.3%	2%	0%

Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated patients in a double-blind, placebo- and active-controlled trial.

Dose Dependency of Adverse Reactions in Clinical Trials of Oral Risperidone

Extrapyramidal Symptoms

Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with oral risperidone treatment. Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of oral risperidone (2, 6, 10, and 16 mg/day), including (1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS:

Table 7: Extrapyramidal Symptoms Associated with Oral Risperidone- Treated Adult Patients in an 8-Week Fixed Dose Schizophrenia Trial

Dose Groups	Placebo	Oral Risperidone 2 mg	Oral Risperidone 6 mg	Oral Risperidone 10 mg	Oral Risperidone 16 mg
Parkinsonism	1.2	0.9	1.8	2.4	2.6
EPS Incidence	13%	17%	21%	21%	35%

Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of oral risperidone (1, 4, 8, 12, and 16 mg/day):

Table 8: Extrapyramidal Symptoms Associated with Oral Risperidone- Treated Adult Patients in an 8-Week Fixed Dose Schizophrenia Trial

Dose Groups	Oral Risperidone 1 mg	Oral Risperidone 4 mg	Oral Risperidone 8 mg	Oral Risperidone 12 mg	Oral Risperidone 16 mg
Parkinsonism	0.6	1.7	2.4	2.9	4.1
EPS Incidence	7%	12%	17%	18%	20%

Changes in Body Weight

Weight gain was observed in short-term, controlled trials and longer-term uncontrolled studies in adults [see Warnings and Precautions (5.5) and Adverse Reactions (6)].

Dystonia

****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.

Other Adverse Reactions

Adverse reaction data elicited by a checklist for side effects from a large study comparing 5 fixed doses of oral risperidone (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness, palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function abnormal, fatigue, and skin discoloration.

Changes in ECG

Between-group comparisons for pooled placebo-controlled trials of oral risperidone in adults revealed no statistically significant differences between oral risperidone and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all oral risperidone doses were pooled from randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of oral risperidone were associated with a higher mean increase in heart rate compared to placebo (4 to 6 beats per minute).

Injection Site Reactions with UZEDY

Local tolerability assessments were administered to patients who reported injection site adverse reactions in a randomized withdrawal study with UZEDY in adult patients with schizophrenia. The injection site was assessed by appropriately trained personnel throughout the clinical development program.

All injection site reactions (nodule, pruritus, erythema, mass, and swelling) were mild to moderate in severity with the exception of 1 case of severe pruritus which resolved after 6 days. Injection site reactions were reported in 22 patients (13%) in the placebo group, 36 patients (20%) in the UZEDY once monthly group, and 37 patients (21%) in the UZEDY once every 2 months group. The most common injection site reactions were: nodule (7% in each UZEDY- treated group and 3% in the placebo group) and pruritus (5% and 3% in the UZEDY-treated once monthly and once every 2 months groups, respectively, and 2% in the placebo group).

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of oral risperidone. 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.

These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia, diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication.

Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.

7 DRUG INTERACTIONS

The interactions of UZEDY with co-administration of other drugs have not been studied. The drug interaction data provided in this section is based on studies with oral risperidone.

7.1 Drugs Having Clinically Important Interactions with UZEDY

Table 9 includes clinically significant drug interactions with UZEDY.

Table 9: Clinically Important Drug Interactions with UZEDY

Strong CYP2D6 Inhibitors
Clinical Impact:	Concomitant use of UZEDY with strong CYP2D6 inhibitors may increase the plasma exposure of risperidone and lower the plasma exposure of a major active metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)].
Intervention:	When initiation of strong CYP2D6 inhibitors is considered, patients may be placed on the lowest dose (50 mg once monthly or 100 mg once every 2 months) of UZEDY prior to the planned start of strong CYP2D6 inhibitors to adjust for the expected increase in plasma concentrations of risperidone. When strong CYP2D6 inhibitors are initiated in patients receiving UZEDY 50 mg once monthly or 100 mg once every 2 months, it is recommended to continue treatment with the same dose unless clinical judgment necessitates interruption of UZEDY treatment. The effects of discontinuation of strong CYP2D6 inhibitors on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied [see Clinical Pharmacology (12.3)].
Strong CYP3A4 Inducers
Clinical Impact:	Concomitant use of UZEDY and a strong CYP3A4 inducer may cause decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone which could lead to decreased efficacy of UZEDY [see Clinical Pharmacology (12.3)].
Intervention:	Changes in efficacy and safety should be carefully monitored with any dose adjustment of UZEDY. At the initiation of therapy with a strong CYP3A4 inducer, patients should be closely monitored during the first 4 to 8 weeks. In patients receiving UZEDY at a specific dose, consider increasing the dose to the next highest dose. In patients receiving UZEDY 125 mg once monthly or 250 mg once every 2 months, additional oral risperidone therapy may need to be considered. On discontinuation of a strong CYP3A4 inducer, the dosage of UZEDY or any additional oral risperidone therapy should be reevaluated and, if necessary, decreased to adjust for the expected increase in plasma concentration of risperidone and 9-hydroxyrisperidone. For patients treated with UZEDY 50 mg once monthly or UZEDY 100 mg once every 2 months discontinuing from a strong CYP3A4 inducer, it is recommended to continue treatment with the same dose unless clinical judgment necessitates interruption of UZEDY treatment [see Dosage and Administration (2.3)].
Centrally-Acting Drugs and Alcohol
Clinical Impact:	Due to additive pharmacologic effects, the concomitant use of centrally-acting drugs, including alcohol, may increase nervous system disorders.
Intervention:	Caution should be used when UZEDY is administered in combination with other centrally-acting drugs or alcohol.
Hypotensive Agents
Clinical Impact:	Because of its potential for inducing hypotension, UZEDY may enhance the hypotensive effects of other therapeutic agents with this potential.
Intervention:	Caution should be used when UZEDY is administered with other therapeutic effects of other therapeutic agents with this potential.
Dopamine Agonists
Clinical Impact:	Agents with central antidopaminergic activity such as UZEDY may antagonize the pharmacologic effects of dopamine agonists.
Intervention:	Caution should be used when UZEDY is administered in combination with levodopa and dopamine agonists.
Methylphenidate
Clinical Impact:	Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS) [see Adverse Reactions (6.2)].
Intervention:	Monitor for symptoms of EPS with concomitant use of UZEDY and methylphenidate.

7.2 Drugs Having No Clinically Important Interactions with UZEDY

Based on pharmacokinetic studies with oral risperidone, no dosage adjustment of UZEDY is required when administered concomitantly with amitriptyline, cimetidine, ranitidine, clozapine, topiramate, and moderate CYP3A4 inhibitors (erythromycin). Additionally, no dosage adjustment is necessary for lithium, valproate, topiramate, digoxin, and CYP2D6 substrates (donepezil and galantamine) when co-administered with UZEDY [see Clinical Pharmacology (12.3)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

For patients who have never taken risperidone, establish tolerability with oral risperidone prior to initiating UZEDY.

UZEDY must be administered by a healthcare professional as an abdominal or upper arm subcutaneous injection. Do not administer UZEDY by any other route.

For detailed preparation and administration instructions, see Dosage and Administration (2.4).

To start UZEDY, switch from oral daily risperidone. Initiate UZEDY, as either a once monthly injection or a once every 2 month injection, the day after the last dose of oral therapy. See Table 1 to determine how to switch from oral risperidone to UZEDY once monthly (50 mg, 75 mg, 100 mg, or 125 mg) or once every 2 months (100 mg, 150 mg, 200 mg, or 250 mg) given via abdominal or upper arm subcutaneous injection. Neither a loading dose nor supplemental oral risperidone doses are recommended when switching.

Table 1: Dosage Recommendations for Switching from Daily Oral Risperidone to UZEDY

Prior Therapy	UZEDY Dosage Once Monthly	UZEDY Dosage Once Every 2 Months
2 mg of oral risperidone per day	50 mg	100 mg
3 mg of oral risperidone per day	75 mg	150 mg
4 mg of oral risperidone per day	100 mg	200 mg
5 mg of oral risperidone per day	125 mg	250 mg

Patients can switch between doses of UZEDY once monthly and once every 2 months by administering the first dose of the new dosing regimen on the next scheduled date of administration in the original dosing regimen. Revise the dose administration schedule to reflect the change.

When a dose of UZEDY is missed, administer the next UZEDY injection as soon as possible. Do not administer more frequently than recommended.

2.2 Dosage Modifications in Patients with Renal Impairment or Hepatic

Impairment

Prior to initiating UZEDY in patients with renal or hepatic impairment, titrate with oral risperidone to at least 2 mg once daily. Following oral titration, and based on clinical response and tolerability, the recommended dosage of UZEDY is 50 mg once monthly [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].

2.3 Dosage Modifications for Concomitant Use with Strong CYP2D6 Inhibitors

and Strong CYP3A4 Inducers

Concomitant Use with Strong CYP2D6 Inhibitors

When initiation of fluoxetine or paroxetine is considered, place patients on a lower dose of UZEDY prior to the planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma concentrations of risperidone.

When fluoxetine or paroxetine is initiated in patients receiving the recommended dose of 50 mg once monthly or 100 mg once every 2 months of UZEDY, continue treatment with these doses unless clinical judgment necessitates interruption of UZEDY [see Drug Interactions (7.1)].

Concomitant Use with Strong CYP3A4 Inducers

At the initiation of therapy with strong CYP3A4 inducers (such as carbamazepine), patients should be closely monitored during the first 4 to 8 weeks since the dose of UZEDY may need to be adjusted. A dose increase, or additional oral risperidone, may be considered.

On discontinuation of a strong CYP3A4 inducer, re-evaluated the dosage of UZEDY or any additional oral risperidone therapy and, if necessary, decrease to adjust for the expected increase in plasma concentration of risperidone.

On discontinuation of a strong CYP3A4 inducer in a patient treated with UZEDY 50 mg once monthly or 100 mg once every 2 months, continue treatment with these doses unless clinical judgment necessitates interruption of UZEDY [see Drug Interactions (7.1)].

2.4 Preparation and Administration Instructions

• Read the instructions for preparation and administration below before administering UZEDY.
• For subcutaneous injection only. Do not inject by any other route.
• To be administered by a healthcare professional only.
• Allow UZEDY to come to room temperature for at least 30 minutes prior to administration.
• As a universal precaution, always wear gloves.

STEP 1

Check to make sure UZEDY kit contains:

• One sterile single-dose, prefilled glass syringe
• One sterile 21G x 5/8” needle

Do not substitute any components of the kit for administration.

 

STEP 2

Remove the kit from refrigerated storage and allow the package to sit at room temperature (20°C to 25°C [68°F to 77°F]) for at least 30 minutes.

Note: UZEDY is a solid at refrigerated temperatures and must reach room temperature prior to administration. Do not warm any other way and keep protected from light.

****

****STEP 3

Check that the drug in the syringe is white to off-white, opaque in color, and free from non-white particulate matter. Check that the pouch label states the needle size is 21G x 5/8”.

Do not use if any component of the kit is damaged or if the expiration date has passed.

****

****STEP 4

Expose the safety needle hub by peeling back the paper tab of the needle pouch. Set aside for use in Step 7.

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STEP 5

IMPORTANT: This step must be performed to ensure complete dosing. UZEDY is viscous and forceful downward flicks are required to move the bubble to the cap of the syringe. Failure to move the bubble to the cap of the syringe could result in incomplete dosage.

Firmly hold the syringe by the white collar.


Flick Syringe Forcefully Three Times to Move the Bubble to the Cap

• Flick with a forceful downward whipping motion of your full arm to move the bubble to the cap of the syringe.
• Repeat this action 3 times to ensure that the bubble is at the cap of the syringe.

Note: Standing while you do this may help achieve required force.

Check that the Bubble is at the Cap of the Syringe

• The bubble will appear partially opaque.
• Holding the syringe up to light or against a dark backdrop may improve visibility.
• If the bubble is not at the cap, repeat Step 5 until it is.

 

STEP 6

Hold the syringe vertically by the white collar. Bend and snap off the cap.

Do not touch the syringe tip to avoid contamination.


STEP 7

Attach the Needle to the Syringe

• Hold the syringe vertically with the white collar at the top.
• Push the green hub of safety needle inside the white collar of syringe and rotate the safety needle while holding the white collar until secure and tight.

Inspect the needle connection to check that the hub is not damaged.

****

STEP 8

Select Injection Site from the Following Areas:

• Stomach area (abdomen) around the belly button
• Back and outer area of the upper arms

Do not inject UZEDY anywhere except in the areas specified above.

Do not inject UZEDY into an area that is tender, red, bruised, callused, tattooed, hard, or has scars or stretch marks.


****STEP 9

Clean the Injection Site with an alcohol wipe.

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STEP 10

Remove the needle sheath by pulling the needle sheath away from the green hub to expose the needle.

Do not expel any visible air bubble.


****STEP 11

Pinch at least 1 inch of the area of cleaned skin with your free hand.


****STEP 12

Insert the needle into subcutaneous tissue (actual angle of injection will depend on the amount of subcutaneous tissue). Do not apply pressure to the plunger.


****STEP 13

Release the pinched skin once the needle is in the subcutaneous tissue.


****STEP 14

Inject the Medication

• Push on the plunger using a slow, firm, and steady push until the entire dose is delivered.
• Inject the entire dose at one time, without interruption.
• Check that the plunger stopper is at the White Collar.

IMPORTANT: UZEDY is viscous. Resistance will be experienced during dose delivery. Do not use excessive force in an attempt to deliver UZEDY faster.

****

STEP 15

Wait 2-3 seconds after the entire dose is delivered before removing the needle. Slowly pull the needle out from the injection site at the same angle as insertion.


****STEP 16

Activate (lock) the safety needle shield using one of the following methods:

***Surface Activation:**Place the needle shield on a flat surface and pull the syringe backward until the needle shield covers the needle tip.


***Finger/Thumb Activation:**Press either your thumb or finger on the needle shield and push it forward until the needle shield covers the needle tip.


There will be an audible click when the needle safety shield is locked.

Dispose of all syringe components in a suitable sharps container.