UZEDY

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 )] The most common adverse reactions with risperidone (≥5% and greater than 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. ( 6.1 ) The most common injection site reactions with UZEDY (≥5% and greater than placebo) were pruritus and nodule. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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.

4 CONTRAINDICATIONS UZEDY is contraindicated in patients with a known hypersensitivity to risperidone, its metabolite, paliperidone, or to any of its components. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone or paliperidone. Known hypersensitivity to risperidone, paliperidone, or to any of the components in UZEDY. ( 4 )

11 DESCRIPTION UZEDY contains risperidone, an atypical antipsychotic. Risperidone belongs to the chemical class of benzisoxazole derivatives. The chemical designation 3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl) piperidin-1yl] ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a] pyrimidin-4-one. Its molecular formula is C 23 H 27 FN 4 O 2 and its molecular weight is 410.5 g/mol. The structural formula is: Risperidone is a white to off-white powder. It is practically insoluble in water and soluble in methanol and 0.1 N HCl. It has the following pKa values: 8.28 (piperidine moiety) and 3.12 (pyrimidine moiety). UZEDY is a sterile, white to off-white opaque viscous extended-release injectable suspension, intended for subcutaneous administration in the following strengths of risperidone (and deliverable volumes from a single-dose prefilled syringe): 50 mg (0.14 mL), 75 mg (0.21 mL), 100 mg (0.28 mL), 125 mg (0.35 mL), 150 mg (0.42 mL), 200 mg (0.56 mL), and 250 mg (0.7 mL). The inactive ingredients include dimethyl sulfoxide (45% w/w), methoxy-poly(ethylene glycol)- co -poly(D,L-lactide) (15% w/w), and poly(D,L-lactide)- co -poly(ethylene glycol)- co -poly(D,L-lactide) (10% w/w). image

2 DOSAGE AND ADMINISTRATION Establish tolerability with oral risperidone prior to initiating UZEDY. ( 2.1 ) Administer UZEDY by subcutaneous injection in the abdomen or upper arm by a healthcare professional. Do not administer by any other route. ( 2.1 ) Initiate UZEDY at the clinically appropriate dose using the following table. ( 2.1 ) Prior Oral Risperidone 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 See Full Prescribing Information for important preparation and administration information. ( 2.4 ) 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. 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. 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. image image image image image image image image image image image image image image image image image image image image

1 INDICATIONS AND USAGE UZEDY is indicated for the treatment of schizophrenia in adults. UZEDY is an atypical antipsychotic indicated for the treatment of schizophrenia in adults. ( 1 )

10 OVERDOSAGE Human Experience No cases of overdose were reported in premarketing studies with UZEDY. In premarketing experience with oral risperidone, there were eight reports of acute risperidone overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure. Postmarketing experience with oral risperidone included reports of acute overdosage with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other postmarketing adverse reactions related to oral risperidone overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of oral risperidone and paroxetine. Management of Overdosage There is no specific antidote to risperidone. Provide supportive care including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Consider contacting the Poison Help Line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations.

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. Strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine): Increase risperidone plasma concentration. ( 2.3 , 7.1 ) Strong CYP3A4 inducers (e.g., carbamazepine): Decrease plasma concentrations of risperidone. ( 2.3 , 7.1 ) 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 )] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of risperidone, in schizophrenia, is unclear. The drug’s therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D 2 ) and serotonin Type 2 (5HT 2 ) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone (paliperidone) [see Clinical Pharmacology ( 12.3 )] . Antagonism at receptors other than D 2 and 5HT 2 may explain some of the other effects of risperidone. 12.2 Pharmacodynamics Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT 2 ), dopamine Type 2 (D 2 ), α 1 and α 2 adrenergic, and H 1 histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT 1C , 5HT 1D , and 5HT 1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D 1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10 -5 M) for cholinergic muscarinic or β 1 and β 2 adrenergic receptors. 12.3 Pharmacokinetics The pharmacokinetics of the risperidone and 9-hydroxyrisperidone combined and the individual components (risperidone and 9-hydroxyrisperidone), following subcutaneous injection of UZEDY, were evaluated in both healthy subjects (n = 53) and in patients with clinically stable schizophrenia and schizoaffective disorder after single doses (12.5 to 225 mg, n = 195) and 3 repeated monthly doses (75 mg and 150 mg, n=24). For all doses, steady-state levels of risperidone and 9-hydroxyrisperidone were approached within 2 months of UZEDY initiation. Steady-state plasma exposure values of risperidone, 9-hydroxyrisperidone, and risperidone and 9-hydroxyrisperidone combined following once monthly administration of UZEDY are approximately 2- to 2.5-fold higher than single dose exposure, while the values for UZEDY administered once every 2 months are about 1.5-fold higher than the respective single dose exposure. After administration of UZEDY, plasma levels of risperidone, 9-hydroxyrisperidone, and risperidone and 9-hydroxyrisperidone combined (AUC 0-tau and C max ) increase in a dose-proportional manner. The average exposure values (C avg,ss ) over the dosing period are comparable for UZEDY administered once monthly and once every 2 months at corresponding doses. Following both once monthly (50 mg to 125 mg) and once every 2 months dosing (100 mg to 250 mg), the mean exposure of risperidone and 9-hydroxyrisperidone combined (AUC 0-tau ) of UZEDY corresponds to that of oral risperidone (2 mg to 5 mg/day) administered over an equivalent dosing period (see Table 1 ). Absorption UZEDY contains risperidone in a liquid delivery system. Following subcutaneous injection, a depot forms which provides a sustained plasma levels of risperidone and 9-hydroxyrisperidone combined over one month or two months. All UZEDY doses, administered once monthly or once every 2 months, showed two absorption peaks for risperidone in plasma. After subcutaneous administration, median t max for the risperidone and 9-hydroxyrisperidone combined ranges from 8 to 14 days. Therapeutic concentrations in plasma are within 6 to 24 hours following the first subcutaneous injection. UZEDY administered in the abdomen and upper arm results in similar pharmacokinetic profiles for all UZEDY doses, permitting either injection site to be used interchangeably. Distribution Once absorbed, risperidone is rapidly distributed. The volume of distribution is 1 to 2 L/kg. Risperidone is bound to albumin and α 1 -acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displace each other from plasma binding sites. Elimination The combined clearance of the risperidone and 9-hydroxyrisperidone following UZEDY administration is 14.3 L/h at steady state. The mean apparent half-life (t½) of UZEDY ranges between 14 to 22 days for risperidone, 9-hydroxyrisperidone, and risperidone and 9-hydroxyrisperidone combined. Metabolism Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme cytochrome CYP2D6 with minor contribution by CYP3A4. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone). CYP2D6 is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP2D6 is subject to genetic polymorphism (about 6 to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone; whereas, poor CYP2D6 metabolizers convert it much more slowly. Population PK analysis demonstrates that plasma exposure to risperidone and 9-hydroxyrisperidone combined was similar in CYP2D6 extensive, intermediate, poor and non-poor metabolizers following subcutaneous injection with UZEDY. Excretion Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14 C-risperidone administered as a solution to three healthy male volunteers, total recovery of radioactivity at 1-week was 84%, including 70% in the urine and 14% in the feces. Specific Populations Based on population pharmacokinetic analyses, age, sex, race and weight do not have a clinically meaningful effect on the pharmacokinetics of UZEDY. Patients with Renal Impairment UZEDY was not studied in patients with renal impairment; however, such effect has been investigated with oral risperidone. In patients with moderate to severe renal disease treated with oral risperidone, the apparent clearance (CL/F) of risperidone and 9-hydroxyrisperidone combined was decreased by 60% in patients with moderate to severe renal disease compared with young healthy subjects [see Use in Specific Populations ( 8.6 )] . Patients with Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of UZEDY has not been studied. The effect of hepatic impairment on the pharmacokinetics of oral risperidone has been evaluated in a phase I study. While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein [see Use in Specific Populations ( 8.7 )] . Drug Interaction Studies No specific drug interaction studies have been performed with UZEDY. The drug interaction data provided in this section is based on studies with oral risperidone. Effects of other drugs on the exposures of risperidone, 9-hydroxyrisperidone, and risperidone and 9-hydroxyrisperidone combined as well as the effects of risperidone on the exposures of other drugs is summarized below. Effects of Other Drugs on Risperidone, 9-hydroxyrisperidone, and Risperidone and 9-hydroxyrisperidone Combined Pharmacokinetics Strong CYP2D6 Inhibitors (Fluoxetine and Paroxetine) Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), potent CYP2D6 inhibitors, have been shown to increase the plasma concentration of risperidone by 2.5- to 2.8-fold and 3- to 9-fold, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied. Moderate CYP3A4 Inhibitor (Erythromycin) There were no significant interactions between oral risperidone and erythromycin, a moderate CYP3A4 inhibitor. Strong CYP3A4 Inducer (Carbamazepine) Carbamazepine co-administration with oral risperidone decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. Co-administration of other known CYP3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of UZEDY treatment. Amitriptyline, Cimetidine, Ranitidine, Clozapine Clinically meaningful pharmacokinetic interaction between UZEDY and other drugs, such as amitriptyline, cimetidine, ranitidine, and clozapine, is not expected. Amitriptyline did not affect the pharmacokinetics of risperidone or of risperidone and 9-hydroxyrisperidone combined following concomitant administration with oral risperidone. Cimetidine and ranitidine increased the bioavailability of oral risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of risperidone and 9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9-hydroxyrisperidone combined by 20%. Chronic administration of clozapine with oral risperidone have shown to affect the clearance of risperidone; however, clinical relevance is unknown. There was no clinically relevant effect of oral risperidone (1 to 6 mg/day) on the pharmacokinetics of topiramate 400 mg/day. Effects of Oral Risperidone on Pharmacokinetics of Other Drugs Lithium Repeated doses of oral risperidone (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C max ) of lithium (n = 13). Valproate Repeated doses of oral risperidone (4 mg once daily) did not affect the predose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n = 21). However, there was a 20% increase in valproate peak plasma concentration (C max ) after concomitant administration of oral risperidone. Topiramate Oral risperidone administered at doses from 1 to 6 mg/day concomitantly with topiramate 400 mg/day resulted in a 23% decrease in risperidone C max and a 33% decrease in risperidone AUC 0‑12 hour at steady state. Minimal reductions in the exposure to risperidone and 9-hydroxyrisperidone combined, and no change for 9-hydroxyrisperidone were observed. This interaction is unlikely to be of clinical significance. There was no clinically relevant effect of oral risperidone on the pharmacokinetics of topiramate. Digoxin Oral risperidone (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. CYP2D6 Substrates In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP2D6. Therefore, UZEDY is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, oral risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP2D6.

12.1 Mechanism of Action The mechanism of action of risperidone, in schizophrenia, is unclear. The drug’s therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D 2 ) and serotonin Type 2 (5HT 2 ) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone (paliperidone) [see Clinical Pharmacology ( 12.3 )] . Antagonism at receptors other than D 2 and 5HT 2 may explain some of the other effects of risperidone.

12.2 Pharmacodynamics Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT 2 ), dopamine Type 2 (D 2 ), α 1 and α 2 adrenergic, and H 1 histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT 1C , 5HT 1D , and 5HT 1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D 1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10 -5 M) for cholinergic muscarinic or β 1 and β 2 adrenergic receptors.

12.3 Pharmacokinetics The pharmacokinetics of the risperidone and 9-hydroxyrisperidone combined and the individual components (risperidone and 9-hydroxyrisperidone), following subcutaneous injection of UZEDY, were evaluated in both healthy subjects (n = 53) and in patients with clinically stable schizophrenia and schizoaffective disorder after single doses (12.5 to 225 mg, n = 195) and 3 repeated monthly doses (75 mg and 150 mg, n=24). For all doses, steady-state levels of risperidone and 9-hydroxyrisperidone were approached within 2 months of UZEDY initiation. Steady-state plasma exposure values of risperidone, 9-hydroxyrisperidone, and risperidone and 9-hydroxyrisperidone combined following once monthly administration of UZEDY are approximately 2- to 2.5-fold higher than single dose exposure, while the values for UZEDY administered once every 2 months are about 1.5-fold higher than the respective single dose exposure. After administration of UZEDY, plasma levels of risperidone, 9-hydroxyrisperidone, and risperidone and 9-hydroxyrisperidone combined (AUC 0-tau and C max ) increase in a dose-proportional manner. The average exposure values (C avg,ss ) over the dosing period are comparable for UZEDY administered once monthly and once every 2 months at corresponding doses. Following both once monthly (50 mg to 125 mg) and once every 2 months dosing (100 mg to 250 mg), the mean exposure of risperidone and 9-hydroxyrisperidone combined (AUC 0-tau ) of UZEDY corresponds to that of oral risperidone (2 mg to 5 mg/day) administered over an equivalent dosing period (see Table 1 ). Absorption UZEDY contains risperidone in a liquid delivery system. Following subcutaneous injection, a depot forms which provides a sustained plasma levels of risperidone and 9-hydroxyrisperidone combined over one month or two months. All UZEDY doses, administered once monthly or once every 2 months, showed two absorption peaks for risperidone in plasma. After subcutaneous administration, median t max for the risperidone and 9-hydroxyrisperidone combined ranges from 8 to 14 days. Therapeutic concentrations in plasma are within 6 to 24 hours following the first subcutaneous injection. UZEDY administered in the abdomen and upper arm results in similar pharmacokinetic profiles for all UZEDY doses, permitting either injection site to be used interchangeably. Distribution Once absorbed, risperidone is rapidly distributed. The volume of distribution is 1 to 2 L/kg. Risperidone is bound to albumin and α 1 -acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displace each other from plasma binding sites. Elimination The combined clearance of the risperidone and 9-hydroxyrisperidone following UZEDY administration is 14.3 L/h at steady state. The mean apparent half-life (t½) of UZEDY ranges between 14 to 22 days for risperidone, 9-hydroxyrisperidone, and risperidone and 9-hydroxyrisperidone combined. Metabolism Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme cytochrome CYP2D6 with minor contribution by CYP3A4. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone). CYP2D6 is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP2D6 is subject to genetic polymorphism (about 6 to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone; whereas, poor CYP2D6 metabolizers convert it much more slowly. Population PK analysis demonstrates that plasma exposure to risperidone and 9-hydroxyrisperidone combined was similar in CYP2D6 extensive, intermediate, poor and non-poor metabolizers following subcutaneous injection with UZEDY. Excretion Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14 C-risperidone administered as a solution to three healthy male volunteers, total recovery of radioactivity at 1-week was 84%, including 70% in the urine and 14% in the feces. Specific Populations Based on population pharmacokinetic analyses, age, sex, race and weight do not have a clinically meaningful effect on the pharmacokinetics of UZEDY. Patients with Renal Impairment UZEDY was not studied in patients with renal impairment; however, such effect has been investigated with oral risperidone. In patients with moderate to severe renal disease treated with oral risperidone, the apparent clearance (CL/F) of risperidone and 9-hydroxyrisperidone combined was decreased by 60% in patients with moderate to severe renal disease compared with young healthy subjects [see Use in Specific Populations ( 8.6 )] . Patients with Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of UZEDY has not been studied. The effect of hepatic impairment on the pharmacokinetics of oral risperidone has been evaluated in a phase I study. While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein [see Use in Specific Populations ( 8.7 )] . Drug Interaction Studies No specific drug interaction studies have been performed with UZEDY. The drug interaction data provided in this section is based on studies with oral risperidone. Effects of other drugs on the exposures of risperidone, 9-hydroxyrisperidone, and risperidone and 9-hydroxyrisperidone combined as well as the effects of risperidone on the exposures of other drugs is summarized below. Effects of Other Drugs on Risperidone, 9-hydroxyrisperidone, and Risperidone and 9-hydroxyrisperidone Combined Pharmacokinetics Strong CYP2D6 Inhibitors (Fluoxetine and Paroxetine) Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), potent CYP2D6 inhibitors, have been shown to increase the plasma concentration of risperidone by 2.5- to 2.8-fold and 3- to 9-fold, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied. Moderate CYP3A4 Inhibitor (Erythromycin) There were no significant interactions between oral risperidone and erythromycin, a moderate CYP3A4 inhibitor. Strong CYP3A4 Inducer (Carbamazepine) Carbamazepine co-administration with oral risperidone decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. Co-administration of other known CYP3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of UZEDY treatment. Amitriptyline, Cimetidine, Ranitidine, Clozapine Clinically meaningful pharmacokinetic interaction between UZEDY and other drugs, such as amitriptyline, cimetidine, ranitidine, and clozapine, is not expected. Amitriptyline did not affect the pharmacokinetics of risperidone or of risperidone and 9-hydroxyrisperidone combined following concomitant administration with oral risperidone. Cimetidine and ranitidine increased the bioavailability of oral risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of risperidone and 9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9-hydroxyrisperidone combined by 20%. Chronic administration of clozapine with oral risperidone have shown to affect the clearance of risperidone; however, clinical relevance is unknown. There was no clinically relevant effect of oral risperidone (1 to 6 mg/day) on the pharmacokinetics of topiramate 400 mg/day. Effects of Oral Risperidone on Pharmacokinetics of Other Drugs Lithium Repeated doses of oral risperidone (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C max ) of lithium (n = 13). Valproate Repeated doses of oral risperidone (4 mg once daily) did not affect the predose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n = 21). However, there was a 20% increase in valproate peak plasma concentration (C max ) after concomitant administration of oral risperidone. Topiramate Oral risperidone administered at doses from 1 to 6 mg/day concomitantly with topiramate 400 mg/day resulted in a 23% decrease in risperidone C max and a 33% decrease in risperidone AUC 0‑12 hour at steady state. Minimal reductions in the exposure to risperidone and 9-hydroxyrisperidone combined, and no change for 9-hydroxyrisperidone were observed. This interaction is unlikely to be of clinical significance. There was no clinically relevant effect of oral risperidone on the pharmacokinetics of topiramate. Digoxin Oral risperidone (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. CYP2D6 Substrates In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP2D6. Therefore, UZEDY is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, oral risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP2D6.

20230508

3

3 DOSAGE FORMS AND STRENGTHS Extended-release injectable suspension: sterile, white to off-white opaque viscous suspension available in the following strengths: 50 mg/0.14 mL, 75 mg/0.21 mL, 100 mg/0.28 mL, 125 mg/0.35 mL, 150 mg/0.42 mL, 200 mg/0.56 mL, and 250 mg/0.7 mL. Each strength is provided as a kit, which includes: one single-dose prefilled syringe and one 21 gauge, 5/8-inch needle. Extended-release injectable suspension: 50 mg/0.14 mL, 75 mg/0.21 mL, 100 mg/0.28 mL, 125 mg/0.35 mL, 150 mg/0.42 mL, 200 mg/0.56 mL, and 250 mg/0.7 mL single-dose prefilled syringes. ( 3 )

UZEDY risperidone RISPERIDONE RISPERIDONE DIMETHYL SULFOXIDE white to off white UZEDY risperidone RISPERIDONE RISPERIDONE DIMETHYL SULFOXIDE white to off white UZEDY risperidone RISPERIDONE RISPERIDONE DIMETHYL SULFOXIDE white to off white UZEDY risperidone RISPERIDONE RISPERIDONE DIMETHYL SULFOXIDE white to off white UZEDY risperidone RISPERIDONE RISPERIDONE DIMETHYL SULFOXIDE white to off white UZEDY risperidone RISPERIDONE RISPERIDONE DIMETHYL SULFOXIDE white to off white UZEDY risperidone RISPERIDONE RISPERIDONE DIMETHYL SULFOXIDE white to off white

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenicity studies were conducted with subcutaneous risperidone suspension. Carcinogenicity studies were conducted with oral risperidone in mice and rats. Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18-months to mice and for 25-months to rats. These doses are equivalent to approximately 0.2-, 0.75-, and 3-times (mice) and 0.4-, 1.5-, and 6-times (rats) the oral MRHD of 16 mg/day, based on a mg/m 2 body surface area. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human dose on a mg/m 2 (mg/kg) basis at which these tumors occurred. Table 10: Summary of Tumor Occurrence at the Multiples of the Human Oral Dose on a mg/m 2 (mg/kg) Basis with Oral Risperidone Dosing Tumor Type Species Sex Multiples of Maximum Human Dose in mg/m 2 (mg/kg) Lowest Effect Level Highest No-Effect Level Pituitary adenomas mouse Female 0.75 (9.4) 0.2 (2.4) Endocrine pancreas adenomas rat Male 1.5 (9.4) 0.4 (2.4) Mammary gland adenocarcinomas mouse Female 0.2 (2.4) none rat Female 0.4 (2.4) none rat Male 6.0 (37.5) 1.5 (9.4) Mammary gland neoplasm, Total rat Male 1.5 (9.4) 0.4 (2.4) Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5- to 6-fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions ( 5.6 )] . Mutagenesis No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitro tests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivo oral micronucleus test in mice and the sex-linked recessive lethal test in Drosophila. No evidence of mutagenic potential was found in the in vitro Ames reverse mutation test for the copolymer mixture of methoxy-poly(ethylene glycol)- co -poly(D,L-lactide) and poly(D,L-lactide)- co -poly(ethylene glycol)- co -poly(D,L-lactide) dissolved in dimethyl sulfoxide. Impairment of Fertility No mating and fertility studies were conducted with subcutaneous risperidone suspension. Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1- to 3-times the oral MRHD, of 16 mg/day based on mg/m 2 body surface area. The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6- to 10-times the oral MRHD based on mg/m 2 body surface area. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenicity studies were conducted with subcutaneous risperidone suspension. Carcinogenicity studies were conducted with oral risperidone in mice and rats. Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18-months to mice and for 25-months to rats. These doses are equivalent to approximately 0.2-, 0.75-, and 3-times (mice) and 0.4-, 1.5-, and 6-times (rats) the oral MRHD of 16 mg/day, based on a mg/m 2 body surface area. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human dose on a mg/m 2 (mg/kg) basis at which these tumors occurred. Table 10: Summary of Tumor Occurrence at the Multiples of the Human Oral Dose on a mg/m 2 (mg/kg) Basis with Oral Risperidone Dosing Tumor Type Species Sex Multiples of Maximum Human Dose in mg/m 2 (mg/kg) Lowest Effect Level Highest No-Effect Level Pituitary adenomas mouse Female 0.75 (9.4) 0.2 (2.4) Endocrine pancreas adenomas rat Male 1.5 (9.4) 0.4 (2.4) Mammary gland adenocarcinomas mouse Female 0.2 (2.4) none rat Female 0.4 (2.4) none rat Male 6.0 (37.5) 1.5 (9.4) Mammary gland neoplasm, Total rat Male 1.5 (9.4) 0.4 (2.4) Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5- to 6-fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions ( 5.6 )] . Mutagenesis No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitro tests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivo oral micronucleus test in mice and the sex-linked recessive lethal test in Drosophila. No evidence of mutagenic potential was found in the in vitro Ames reverse mutation test for the copolymer mixture of methoxy-poly(ethylene glycol)- co -poly(D,L-lactide) and poly(D,L-lactide)- co -poly(ethylene glycol)- co -poly(D,L-lactide) dissolved in dimethyl sulfoxide. Impairment of Fertility No mating and fertility studies were conducted with subcutaneous risperidone suspension. Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1- to 3-times the oral MRHD, of 16 mg/day based on mg/m 2 body surface area. The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6- to 10-times the oral MRHD based on mg/m 2 body surface area. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog.

NDA213586

UZEDY

risperidone

51759-630

HUMAN PRESCRIPTION DRUG

SUBCUTANEOUS

Package/Label Display Panel 1 month dosing For administration by a healthcare professional Rx Only UZEDY ™ (risperiDONE) extended-release injectable suspension FOR SUBCUTANEOUS USE ONLY NDC 51759- 305 -10 One single-dose prefilled syringe 50 mg/0.14 mL administered every one month Store in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Allow UZEDY to sit in its packaging at room temperature at 20°C to 25°C(68°F to 77°F) for at least 30 minutes prior to administration . UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days. Once the carton is opened, administer UZEDY or discard. OPEN HERE teva image

17 PATIENT COUNSELING INFORMATION Neuroleptic Malignant Syndrome (NMS) Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact the healthcare provider or report to the emergency room if they experience signs and symptoms of NMS [see Warnings and Precautions ( 5.3 )] . Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions ( 5.4 )] . Metabolic Changes Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions ( 5.5 )] . Hyperprolactinemia Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of UZEDY. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction, or gynecomastia in males [see Warnings and Precautions ( 5.6 )] . Orthostatic Hypotension and Syncope Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment or increasing the dose [see Warnings and Precautions ( 5.7 )]. Leukopenia/Neutropenia Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia that they should have their CBC monitored while being treated with UZEDY [see Warnings and Precautions ( 5.9 )] . Potential for Cognitive and Motor Impairment Inform patients that UZEDY has the potential to impair judgement, thinking, and motor skills. Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle, until they are reasonably certain that UZEDY therapy does not affect them adversely [see Warnings and Precautions ( 5.10 )]. Priapism Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions ( 5.13 )] . Heat Exposure and Dehydration Educate patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions ( 5.14 )] . Concomitant Medication Advise patients to inform their healthcare providers if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interaction [see Drug Interactions ( 7 )] . Alcohol Advise patients to avoid alcohol during treatment with UZEDY [see Drug Interactions ( 7.1 )] . Pregnancy Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with UZEDY. Advise patients that UZEDY may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to UZEDY during pregnancy [see Use in Specific Populations ( 8.1 )] . Lactation Advise breastfeeding women using UZEDY to monitor infants for somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations ( 8.2 )] . Infertility Advise females of reproductive potential that UZEDY may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations ( 8.3 )]. UZE-002 Manufactured for: Teva Neuroscience, Inc. Parsippany, NJ 07054 ©2023 Teva Neuroscience, Inc.

14 CLINICAL STUDIES The efficacy of UZEDY for the treatment of schizophrenia in adults is based, in part, on the established effectiveness of oral risperidone as well as in a randomized withdrawal study (Study 1: NCT03503318) with UZEDY in adults who met the DSM-5 criteria for schizophrenia. The results from Study 1 are presented below. Study 1 was 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. UZEDY was administered once monthly or once every 2 months at doses of 50 mg to 250 mg compared with monthly placebo injections in adult patients meeting DSM-5 criteria for schizophrenia. Patients were required to have a Positive and Negative Syndrome Scale (PANSS) total score lower than 100 at the screening visit. Eligible screened patients were enrolled into an oral conversion and stabilization stage (12 weeks). Patients were administered oral risperidone (2 mg to 5 mg per day) to establish stability and tolerability. Eligible patients were randomized into the double-blind period of the study if they met the following randomization criteria for at least 4 consecutive weeks prior to the baseline visit: outpatient status, PANSS total ≤80, Minimal presence of specific psychotic symptoms on the PANSS, as measured by a score of ≤4 on each of the following items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content [CGI-S score ≤4 (moderately ill); CGI-SS score ≤2 (mildly suicidal) on Part 1 and ≤5 (minimally worsened) on Part 2]. In the double-blind stage (variable in duration), patients were randomized to receive placebo, once monthly UZEDY, or once every 2 months UZEDY in doses based on the oral dose on which they were previously stabilized in the oral conversion and stabilization stage. The primary efficacy endpoint was time to impending relapse. Relapse was defined as one or more of the following items: Clinical Global Impression–Improvement (CGI-I) of ≥5 (greater than or equal to minimally worse, i.e., minimally worse, much worse or very much worse), AND an increase of any of the following individual Positive and Negative Syndrome Scale (PANSS) items: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content, to a score of >4 with an absolute increase of ≥2 on that specific item since randomization, OR an increase in any of the following 4 individual PANSS items: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content, to a score of >4 and an absolute increase of ≥4 on the combined score of these 4 PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) since randomization hospitalization due to worsening of psychotic symptoms (including partial hospitalization programs), excluding hospitalization for psychosocial reasons Clinical Global Impression-Severity of Suicidality (CGI-SS) of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much worse) or 7 (very much worse) on Part 2 violent behavior resulting in clinically significant self-injury, injury to another person, or property damage The mean baseline PANSS total score was similar across the groups (approximately 61 in each group). Most patients were male (61% per group) and the median age was 52 years. Most patients in this study were black or African American (57% to 61% per group). Of the 544 patients randomized to treatment, 543 were included in the intent-to-treat (ITT) population. The study met its prespecified primary endpoint for both the UZEDY once monthly and once every 2 months dosing regimens. Time to relapse was statistically significantly longer in the UZEDY-treated groups compared to the placebo group. The cumulative percentage of relapse over time was calculated using Kaplan-Meier product limit estimate of the time to relapse during the randomized withdrawal trial as shown in Figure 1 . Subgroup analyses by gender, age, and race did not suggest any clear evidence of differential responsiveness to UZEDY. Figure 1: Kaplan-Meier Curve of Cumulative Proportion of UZEDY-Treated Patients with Relapse Over Time image

8.5 Geriatric Use Clinical studies of UZEDY in the treatment of schizophrenia did not include patients older than 65 years to determine whether or not they respond differently from younger patients. In general, dose selection for geriatric patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. UZEDY is substantially excreted by the kidneys, and the risk of reactions may be greater in patients with impaired renal function. Because geriatric patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Warnings and Precautions ( 5.7 ) and Clinical Pharmacology ( 12.3 )] . Elderly patients with dementia-related psychosis treated with UZEDY are at an increased risk of death compared to placebo. UZEDY is not approved for the treatment of patients with dementia‑related psychosis [see Boxed Warning and Warnings and Precautions ( 5.1 , 5.2 )] .

8.4 Pediatric Use The safety and effectiveness of UZEDY have not been established in pediatric patients. Juvenile Animal Toxicity Data No juvenile animal studies were conducted with subcutaneous risperidone suspension. Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day. Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUC of risperidone plus its active metabolite paliperidone (9-hydroxyrisperidone) that were similar to those in children and adolescents receiving the oral MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period. Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the oral MRHD of 6 mg/day for children, based on mg/m 2 body surface area. This dose produced plasma AUC of risperidone plus paliperidone about half the exposure observed in humans at the oral MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the oral MRHD and produced plasma AUC of risperidone plus paliperidone that were about two thirds of those observed in humans at the oral MRHD of 6 mg/day for children.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including UZEDY, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinicaland-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery ( see Clinical Considerations ). Overall, available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes ( see Data ). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including UZEDY, during pregnancy ( see Clinical Considerations ). Oral administration of risperidone to pregnant mice caused cleft palate at doses 3- to 4-times the oral maximum recommended human dose (MRHD) of 16 mg/day with maternal toxicity observed at 4-times MRHD based on mg/m 2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the oral MRHD based on mg/m 2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the oral MRHD based on mg/m 2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the oral MRHD and offspring mortality increased at doses 0.1- to 3-times the oral MRHD based on mg/m 2 body surface area. The background risks of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR = 1.26, 95% CI = 1.02 to 1.56) and of cardiac malformations (RR = 1.26, 95% CI = 0.88 to 1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal data No developmental toxicity studies were conducted with subcutaneous risperidone suspension. Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3-times the oral MRHD of 16 mg/day based on mg/m 2 body surface area; maternal toxicity occurred at 4-times the oral MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6-times the oral MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6-times the oral MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6- and 1.2-times the oral MRHD based on mg/m 2 body surface area; postnatal development and growth of the offspring were also delayed. Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1- to 3-times the oral MRHD of 16 mg/day based on mg/m 2 body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5-times the oral MRHD based on mg/m 2 body surface area. In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3-times the oral MRHD based on mg/m 2 and the only dose tested in the study.

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including UZEDY, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinicaland-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery ( see Clinical Considerations ). Overall, available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes ( see Data ). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including UZEDY, during pregnancy ( see Clinical Considerations ). Oral administration of risperidone to pregnant mice caused cleft palate at doses 3- to 4-times the oral maximum recommended human dose (MRHD) of 16 mg/day with maternal toxicity observed at 4-times MRHD based on mg/m 2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the oral MRHD based on mg/m 2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the oral MRHD based on mg/m 2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the oral MRHD and offspring mortality increased at doses 0.1- to 3-times the oral MRHD based on mg/m 2 body surface area. The background risks of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR = 1.26, 95% CI = 1.02 to 1.56) and of cardiac malformations (RR = 1.26, 95% CI = 0.88 to 1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal data No developmental toxicity studies were conducted with subcutaneous risperidone suspension. Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3-times the oral MRHD of 16 mg/day based on mg/m 2 body surface area; maternal toxicity occurred at 4-times the oral MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6-times the oral MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6-times the oral MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6- and 1.2-times the oral MRHD based on mg/m 2 body surface area; postnatal development and growth of the offspring were also delayed. Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1- to 3-times the oral MRHD of 16 mg/day based on mg/m 2 body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5-times the oral MRHD based on mg/m 2 body surface area. In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3-times the oral MRHD based on mg/m 2 and the only dose tested in the study. 8.2 Lactation Risk Summary Limited data from published literature reports the presence of risperidone and its metabolite, 9-hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2.3 and 4.7% of the maternal weight-adjusted dosage. There are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone (see Clinical Considerations). There is no information on the effects of risperidone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for UZEDY and any potential adverse effects on the breastfed child from UZEDY or from the mother’s underlying condition. Clinical Considerations Infants exposed to UZEDY through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements). 8.3 Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of risperidone (D 2 receptor antagonism), treatment with UZEDY may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions ( 5.6 )]. 8.4 Pediatric Use The safety and effectiveness of UZEDY have not been established in pediatric patients. Juvenile Animal Toxicity Data No juvenile animal studies were conducted with subcutaneous risperidone suspension. Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day. Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUC of risperidone plus its active metabolite paliperidone (9-hydroxyrisperidone) that were similar to those in children and adolescents receiving the oral MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period. Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the oral MRHD of 6 mg/day for children, based on mg/m 2 body surface area. This dose produced plasma AUC of risperidone plus paliperidone about half the exposure observed in humans at the oral MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the oral MRHD and produced plasma AUC of risperidone plus paliperidone that were about two thirds of those observed in humans at the oral MRHD of 6 mg/day for children. 8.5 Geriatric Use Clinical studies of UZEDY in the treatment of schizophrenia did not include patients older than 65 years to determine whether or not they respond differently from younger patients. In general, dose selection for geriatric patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. UZEDY is substantially excreted by the kidneys, and the risk of reactions may be greater in patients with impaired renal function. Because geriatric patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Warnings and Precautions ( 5.7 ) and Clinical Pharmacology ( 12.3 )] . Elderly patients with dementia-related psychosis treated with UZEDY are at an increased risk of death compared to placebo. UZEDY is not approved for the treatment of patients with dementia‑related psychosis [see Boxed Warning and Warnings and Precautions ( 5.1 , 5.2 )] . 8.6 Renal Impairment In patients with renal impairment, titrate with oral risperidone (up to at least 2 mg daily) before initiating treatment with UZEDY [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )] . UZEDY was not studied in patients with renal impairment. 8.7 Hepatic Impairment In patients with hepatic impairment, titrate with oral risperidone (up to at least 2 mg daily) before initiating treatment with UZEDY [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )] . UZEDY has not been studied in patients with hepatic impairment; however, such effect has been investigated with oral risperidone. 8.8 Patients with Parkinson's Disease or Dementia with Lewy Bodies Patients with Parkinson’s disease or dementia with Lewy bodies can experience increased sensitivity to UZEDY. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied UZEDY (risperidone) extended-release injectable suspension, for subcutaneous use is a sterile, white to off-white opaque viscous suspension. UZEDY is supplied in single-dose kits as follows: 50 mg/0.14 mL single-dose prefilled syringe, packaged in a carton with one 21 gauge, 5/8-inch needle (NDC 51759-305-10) 75 mg/0.21 mL single-dose prefilled syringe, packaged in a carton with one 21 gauge, 5/8-inch needle (NDC 51759-410-10) 100 mg/0.28 mL single-dose prefilled syringe, packaged in a carton with one 21 gauge, 5/8-inch needle (NDC 51759-520-10) 125 mg/0.35 mL single-dose prefilled syringe, packaged in a carton with one 21 gauge, 5/8-inch needle (NDC 51759-630-10) 150 mg/0.42 mL single-dose prefilled syringe, packaged in a carton with one 21 gauge, 5/8-inch needle (NDC 51759-740-10) 200 mg/0.56 mL single-dose prefilled syringe, packaged in a carton with one 21 gauge, 5/8-inch needle (NDC 51759-850-10) 250 mg/0.7 mL single-dose prefilled syringe, packaged in a carton with one 21 gauge, 5/8-inch needle (NDC 51759-960-10) The prefilled syringe cap is not made with natural rubber latex. Storage and Handling Store in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days. Once the carton is opened, administer UZEDY or discard.

WARNING: 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. UZEDY is not approved for the treatment of patients with dementia-related psychosis and has not been studied in this patient population [see Warnings and Precautions ( 5.1 )]. WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. UZEDY is not approved for use in patients with dementia-related psychosis. ( 5.1 )