PERSERIS- risperidone

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 2 [see Clinical Pharmacology ( 12. 3 2 2 Risperidone is a monoaminergic antagonist with high affinity (Ki of 0. 3 nM) for the serotonin Type 2 (5HT 2 2 1 2 1 1C 1D 1A 1 -5 1 2 The pharmacokinetics of risperidone and total active moiety following subcutaneous injection of PERSERIS was evaluated in patients with clinically stable schizophrenia after single doses (60 mg, 90 mg, and 120 mg) (n = 101) and repeated doses [60 mg, 90 mg, 120 mg, 180 mg (1. 5 times the maximum recommended dosage of PERSERIS)] (n = 68) separated by 28 days for up to 4 doses following oral risperidone. Plasma concentrations of risperidone, 9-hydroxyrisperidone and total active moiety approached steady-state levels after the first dose of PERSERIS. Mean accumulation ratios for risperidone ranged from 1. 7 based on mean area under the curve (AUC), and from 0. 3 based on overall mean peak plasma concentrations (overall C max max tau max Following multiple doses of PERSERIS, plasma exposure (AUC tau max max tau max tau max tau Plasma exposures at steady-state were compared between oral risperidone and PERSERIS. The average plasma concentrations (C avg avg Absorption PERSERIS contains risperidone in a liquid delivery system. Following subcutaneous injection, it forms a depot that provides sustained plasma levels of risperidone over the monthly dosing interval. After single subcutaneous injection, PERSERIS shows two absorption peaks for risperidone in plasma. The first peak of risperidone occurs with a T max max Distribution Following a subcutaneous injection of PERSERIS, the apparent volume of distribution is large. The extensively large values are because PERSERIS is administered as a depot injection. Risperidone is bound to albumin and alpha1-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 displaces each other from plasma binding sites. Elimination 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. Plasma exposure to total active moiety was similar in CYP2D6 extensive, intermediate and poor metabolizers following subcutaneous injection with PERSERIS, supporting no need for dose adjustment based on genotype of CYP2D6. 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 Following a single subcutaneous injection of PERSERIS, the apparent terminal half-life of risperidone ranges between 9 and 11 days on average. This half-life is related to the slow release of risperidone from the subcutaneous depot and subsequent absorption of risperidone into the systemic circulation. The mean apparent terminal half-life ranges between 8 to 9 days for both 9-hydroxyrisperidone and total active moiety. Drug Interaction Studies No specific drug interaction studies have been performed with PERSERIS. 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 total active moiety 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 Total Active Moiety 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. 8 folds and 3 to 9 folds, 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. , 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 PERSERIS. Amitriptyline, Cimetidine, Ranitidine, Clozapine, Topiramate Clinically meaningful pharmacokinetic interaction between PERSERIS 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 Valproate Repeated doses of oral risperidone (4 mg once daily) did not affect the pre-dose 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 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 0-12 Digoxin Oral risperidone (0. 25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. CYP2D6 Substrates (Donepezil and Galantamine) In vitro Specific Populations Based on population pharmacokinetic analyses, age, sex and race do not have a clinically meaningful effect on the pharmacokinetics of PERSERIS. Renal Impairment PERSERIS 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 total active moiety was decreased by 60% in patients with moderate to severe renal disease compared with young healthy subjects [see Use in Specific Populations ( 8. 6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of PERSERIS has not been studied. The effect of hepatic impairment on the pharmacokinetics of oral risperidone has been evaluated in a dedicated 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 alpha1-acid glycoprotein [see Use in Specific Populations ( 8.

PERSERIS is indicated for the treatment of schizophrenia in adults [see Clinical Studies ( 14 PERSERIS is an atypical antipsychotic indicated for the treatment of schizophrenia in adults.

Establish tolerability with oral risperidone prior to initiating PERSERIS. 1 Administer monthly by subcutaneous injection in the abdomen or back of the upper arm by a healthcare provider. Do not administer by any other route. 1 PERSERIS may be initiated at a dose of 90 mg or 120 mg once monthly. Do not administer more than one dose per month. 1 Supplementation with oral risperidone is not recommended. 1 See Full Prescribing Information for important preparation and administration information. Failure to fully mix the medication could result in incorrect dosage. 4 Administer PERSERIS by a healthcare provider as a subcutaneous injection in the abdomen or back of the upper arm. Do not administer PERSERIS by any other route. For detailed preparation and administration instructions, see Dosage and Administration ( 2. 4 For patients who have never taken risperidone, establish tolerability with oral risperidone prior to initiating PERSERIS. Initiate PERSERIS at a dose of 90 mg or 120 mg once monthly by subcutaneous injection. Do not administer more than one dose (90 mg or 120 mg total) per month. For patients switching from oral risperidone: 3 mg of oral risperidone per day, administer a 90 mg PERSERIS dose one day after the last oral risperidone dose. 4 mg of oral risperidone per day, administer a 120 mg PERSERIS dose one day after the last oral risperidone dose. Patients who are on stable oral risperidone doses lower than 3 mg per day or higher than 4 mg per day may not be candidates for PERSERIS [see Clinical Pharmacology ( 12. 3 14 Neither a loading dose nor any supplemental oral risperidone is recommended. When a dose of PERSERIS is missed, administer the next PERSERIS injection as soon as possible. Prior to initiating treatment with PERSERIS in patients with renal or hepatic impairment, titrate with oral risperidone up to at least 3 mg daily. Following oral titration, and based on clinical response and tolerability, the recommended dosage of PERSERIS is 90 mg once monthly [see Use in Specific Populations ( 8. 3 Co-administration with Strong CYP2D6 Inhibitors Between 2 to 4 weeks prior to initiating a strong CYP2D6 inhibitor (such as fluoxetine or paroxetine), switch patients (if applicable) to the lowest PERSERIS dosage (90 mg once monthly) to adjust for the expected increase in plasma concentrations of risperidone [see Drug Interactions ( 7. 1 Co-administration with Strong CYP3A4 Inducers With concomitant use of PERSERIS 90 mg and strong CYP3A4 inducers (such as carbamazepine), increase the PERSERIS dosage to 120 mg once monthly and consider starting additional oral risperidone therapy. In patients already receiving PERSERIS 120 mg once monthly, additional oral risperidone therapy may need to be considered. Upon discontinuation of a strong CYP3A4 inducer in a patients receiving PERSERIS 120 mg once monthly, re-evaluate the dosage of PERSERIS or any additional oral risperidone therapy and, if necessary, decrease to adjust for the expected increase in plasma concentration of risperidone. Upon discontinuation of a strong CYP3A4 inducer in a patient receiving PERSERIS 90 mg once monthly, continue treatment with the 90 mg dose unless clinical judgment necessitates interruption of PERSERIS treatment [see Drug Interactions ( 7. 1 Read the instructions for preparation and administration below and consider referring to the separate Healthcare Provider “Instructions for Use” for additional preparation and administration considerations. For subcutaneous injection only. Do not inject by any other route. Allow package to come to room temperature for at least 15 minutes prior to preparation. Prepare medication when you are ready to administer the dose. 1 CHECK CONTENTS Each carton of PERSERIS contains ( Figure 1 One Liquid Syringe One Powder Syringe One sterile 18-gauge, 5/8-inch safety needle. Figure 1 2 TAP POWDER SYRINGE Hold the Powder Syringe Figure 2 Figure 2 3 UNCAP LIQUID AND POWDER SYRINGES Remove the cap from the Liquid Syringe Powder Syringe Figure 3 Holding both syringes in your non-dominant hand can help with this step. Figure 3 4 CONNECT THE SYRINGES Place the Liquid Syringe Powder Syringe Figure 4 Keep your fingers off the plungers during this step to avoid spillage of the medication. Figure 4 5 MIX THE PRODUCT Failure to fully mix the medication could result in incorrect dosage. Premixing Transfer the contents of the Liquid Syringe Powder Syringe Gently push the Powder Syringe Repeat this gentle back-and-forth process for 5 cycles Complete mixing Continue mixing the syringes for an additional 55 cycles This mixing can be more vigorous than when premixing. See Figure 5 Figure 5 When fully mixed, the product should be a cloudy suspension that is uniform in color. It can vary from white to yellow-green in color. If you see any clear areas in the mixture, continue to mix until the distribution of the color is uniform. The product is designed to deliver risperidone 90 mg or 120 mg. 6 PREPARE INJECTION SYRINGE Failure to aspirate the liquid from the Powder Syringe First, transfer all contents into the Liquid Syringe Figure 6 Next, perform the following actions SIMULTANEOUSLY maintain slight pressure on the Powder Syringe pull back gently Liquid Syringe Finally, attach the safety needle by twisting until finger tight. Check that medication is uniform in color and free from foreign particles. Figure 6 7 PREPARE THE SUBCUTANEOUS INJECTION SITE(S) This medication is to be injected subcutaneously in the abdomen or back of the upper arm ( Figure 7 Choose an injection site with adequate subcutaneous tissue that is free of skin conditions (e. , nodules, lesions, excessive pigment). Do not Clean the injection site well with an alcohol pad. To help minimize irritation, rotate injection sites following a pattern similar to the illustration. If you want to use the same injection site, make sure it is not the same spot on the injection site you used the last time. Figure 7 8 REMOVE EXCESS AIR FROM SYRINGE Hold the syringe upright for several seconds to allow air bubbles to rise. Remove needle cover and slowly depress the plunger to push out the excess air from the syringe ( Figure 8 If medication is seen at the needle tip, pull back slightly on the plunger to prevent medication spillage. Due to the viscous nature of the medication, bubbles will not rise as quickly as those in an aqueous solution. Figure 8 9 PINCH INJECTION SITE Pinch the skin around the injection area. Be sure to pinch enough skin to accommodate the size of the needle ( Figure 9 Figure 9 10 INJECT THE MEDICATION Insert needle fully into the subcutaneous tissue. Inject the medication slow and steady ( Figure 10 PERSERIS is for subcutaneous administration only. Actual angle of injection will depend on the amount of subcutaneous tissue. Figure 10 11 WITHDRAW NEEDLE Withdraw the needle at the same angle used for insertion and release pinched skin ( Figure 11 Do not rub the injection area after the injection. If there is bleeding, apply a gauze pad or bandage but use minimal pressure. Figure 11 12 LOCK THE NEEDLE GUARD AND DISPOSE OF SYRINGE Lock the needle guard into place by pushing it against a hard surface such as a table ( Figure 12 Figure 12 13 INSTRUCT THE PATIENT The patient may have a lump for several weeks that will decrease in size over time ( Figure 13 Figure 13 Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure.

The following are discussed in more detail in previous sections of the labeling: Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning 5. 1 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5. 2 Neuroleptic Malignant Syndrome (NMS) [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 in clinical trials (>= 5% and greater than twice placebo) were increased weight, sedation/somnolence, and musculoskeletal pain. ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Indivior Inc. at 1-877-782-6966 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 practice. The safety of PERSERIS was evaluated in a total of 837 adult patients with schizophrenia who received at least 1 dose of PERSERIS during the clinical development program. A total of 322 patients were exposed to PERSERIS for at least 6 months, of which 234 patients were exposed to PERSERIS for at least 12 months; 281 and 176 of these, respectively, received the 120 mg dose. Adverse drug reactions in adult patients with schizophrenia (>= 5% in any PERSERIS-treated group and greater than placebo) during the 8-week double-blind, placebo-controlled study) were weight increased, constipation, sedation/somnolence, pain in extremity, back pain, akathisia, anxiety, and musculoskeletal pain. In addition, the frequency of reported injection site reactions was similar across treatment groups with both PERSERIS and placebo; the most common (>= 5%) of which were injection site pain, and erythema. The systemic safety profile for PERSERIS was consistent with the known safety profile of oral risperidone. Commonly-Observed Adverse Drug Reactions in Double-Blind, Placebo-Controlled Clinical Studies en dash Schizophrenia Adverse Reactions with an incidence of 2% or more and greater than placebo are shown in Table 4 Table 4 Adverse Drug Reactions in 2% or More of PERSERIS-Treated Patients (and Greater than Placebo) in an 8-Week Double-Blind, Placebo-Controlled Study * Sedation includes sedation and somnolence System Organ Class PERSERIS 90 mg (n = 115) PERSERIS 120 mg (n = 117) Placebo (n = 118) Percentage of Patients Reporting ADR Gastrointestinal disorders Constipation 7. 1 Abdominal discomfort 2. 7 Dry mouth 1. 7 Investigations Weight increased 13. 4 Metabolism and nutrition disorders Increased appetite 1. 7 Musculoskeletal and connective tissue disorders Back pain 3. 2 Pain in extremity 0. 1 Musculoskeletal pain 5. 5 Musculoskeletal stiffness 2. 7 Muscle spasms 0 2. 6 0 Nervous system disorders Sedation* 7. 7 0 Akathisia 2. 2 Extrapyramidal disorder 4. 8 Psychiatric disorders Anxiety 2. 1 Other Adverse Drug Reactions Observed During the Clinical Trial Evaluation of PERSERIS The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) which are part of the disease state, 3) for which a drug cause was remote, 4) which were so general as to be uninformative, or 5) which were not considered to have significant clinical implications. Blood and Lymphatic System Disorders: Ear and Labyrinth Disorders: Endocrine Disorders: Eye Disorders: Gastrointestinal Disorders: General Disorders and Administration Site Conditions: Investigations: Metabolism and Nutrition Disorders: Musculoskeletal, Connective Tissue, and Bone Disorders: Nervous System Disorders: Psychiatric Disorders: Reproductive System and Breast Disorders: Skin and Subcutaneous Tissue Disorders: Vascular Disorders: Other Adverse Reactions Observed During the Clinical Trial Evaluations of Oral Risperidone The following is a list of additional ADRs that have been reported during the clinical trial evaluation of oral risperidone, regardless of frequency of occurrence: Blood and Lymphatic System Disorders: Cardiac Disorders: Ear and Labyrinth Disorders: Eye Disorders: Gastrointestinal Disorders: General Disorders: Immune System Disorders: Infections and Infestations: Investigations: Metabolism and Nutrition Disorders: Musculoskeletal, Connective Tissue, and Bone Disorders: Nervous System Disorders: Psychiatric Disorders: Renal and Urinary Disorders: Reproductive System and Breast Disorders: Respiratory, Thoracic, and Mediastinal Disorders: Skin and Subcutaneous Tissue Disorders: Vascular Disorders: Discontinuations Due to Adverse Drug Reactions (ADRs) There was no single adverse reaction leading to discontinuation that occurred at a rate of >= 2% in PERSERIS-treated patients and greater than placebo. Dose Dependency of Adverse Drug Reactions in Clinical Trials Changes in Body Weight Data from the double-blind placebo-controlled study indicated there was a dose-dependent increase in mean changes in weight from baseline to postdose assessments in the PERSERIS 90 mg and 120 mg groups compared with the placebo group [see Warnings and Precautions ( 5. 5 Table 4 Increased Prolactin In the 8-week double-blind, placebo-controlled study, there was a typical increase in mean prolactin levels in fasting blood samples from baseline to the EOS assessments in both the PERSERIS 90 mg and 120 mg groups, while mean prolactin for the placebo group remained stable during the study. Changes in mean prolactin were dose-dependent and more pronounced in female patients than male patients. Extrapyramidal Symptoms (EPS) Several methods were used to measure EPS, including: (1) the Barnes Akathisia Rating Scale (BARS) global clinical rating score which evaluates akathisia, (2) the Abnormal Involuntary Movement Scale (AIMS) scores which evaluates dyskinesia, (3) the Simpson-Angus Scale (SAS) global score which broadly evaluates parkinsonism, and (4) the incidence of spontaneous reports of EPS-related adverse reactions. In the 8-week double-blind, placebo-controlled study, the mean changes from baseline in BARS, AIMS, and SAS total scores were comparable between PERSERIS- and placebo-treated patients. At all postbaseline assessments, mean changes from baseline were between -0. 2 (inclusive) for the BARS, between 0 and 0. 2 (inclusive) for the AIMS and between -0. 2 (inclusive) for the SAS. The rates of ADRs associated with EPS were similar across treatment groups, including placebo. There was a higher incidence of akathisia in the PERSERIS 120 mg (6. 8%) group compared with the PERSERIS 90 mg (2. 6%) and placebo group (4. 2%); reports of extrapyramidal disorders were higher in the PERSERIS 90 mg group (4. 3%) compared with the PERSERIS 120 mg (1. 7%) and placebo group (0. In contrast, there was a higher incidence of dystonia in the placebo group (2. 5%) compared with the PERSERIS groups (0 and 0. 9%, respectively). 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. Although 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 has been observed in males and younger age groups. Changes in ECG In the 8-week double-blind, placebo-controlled study, there were no clinically relevant differences in mean changes from baseline to EOS in ECG parameters, including QT c Pain Assessment and Local Injection Site Reactions Local injection site pain was assessed using patient-reported VAS scales (0 = no pain to 100 = unbearably painful). In the 8-week, double-blind placebo-controlled study, the mean patient-reported injection site pain VAS scores were similar for all treatment groups following both injections. Pain scores decreased from a mean of 27 (VAS score) 1 minute after the first dose to a range of 3 to 7 (VAS score) 30 to 60 minutes postdose. In the 12-month, long-term safety study, the 1-minute postdose injection site pain VAS scores were highest on Day 1 (mean of 25) and decreased over time with subsequent injections (14 to 16 following last injection). The local injection site was assessed by appropriately trained personnel. Throughout the clinical development program, the maximum reported intensity at any time point for each injection site assessment (pain, tenderness, inflammation/swelling and erythema) was none or mild for most patients receiving PERSERIS. Most patients (>= 79%) reported no tenderness and most who had tenderness reported mild severity. Less than 1% of patients had moderate tenderness at any time point and 1 patient at Injections 1, 2, and 5 had severe tenderness. At each time point, most patients (>= 75%) reported no pain on injection. Of patients who did have pain on injection, almost all of these were mild at each time point; only 1 or 2 patients at Injections 1, 2, 7, and 12 had moderate pain on injection. At least 92% of patients reported no erythema on each injection. All reports of erythema were of mild severity except for 2 cases of moderate erythema on Injection 1. Inflammation/swelling had a similar profile, with at least 88% of patients reporting no inflammation/swelling and only mild symptoms except for 1 case of moderate severity on Injection 1. 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.

PERSERIS 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 other components of PERSERIS.

Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. 1 Renal or Hepatic Impairment: Carefully titrate on oral risperidone up to at least 3 mg before initiating treatment with PERSERIS at a dose of 90 mg. 7 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including PERSERIS, 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/clinical-and-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 (see Data (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 the MRHD based on mg/m 2 2 2 2 Subcutaneous administration of the delivery system to pregnant rats and rabbits during the period of organogenesis caused developmental toxicity that included post-implantation loss, decreased number of live fetuses, decreased fetal weight and fetal malformations (external, skeletal, and visceral), at doses that are 52 (rat) and 43 (rabbit) times the delivery system amount present in 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 N (see Data 2 The estimated 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. 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. 56) and of cardiac malformations (RR = 1. 26, 95% CI 0. 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 2 2 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 2 2 Subcutaneous administration of the delivery system to pregnant rats and rabbits during the period of organogenesis caused maternal toxicity (decreased body weight, weight gain and food intake), post-implantation loss, decrease in number of live fetuses and decrease in fetal weight at doses that are 52 (rat), and 43 (rabbit) times the delivery system amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 2 2 N 2 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. 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). Clinical Considerations Infants exposed to PERSERIS through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements). Infertility Females Based on the pharmacologic action of risperidone (D 2 [see Warnings and Precautions ( 5. 1 Safety and effectiveness of PERSERIS have not been established in pediatric patients. Clinical studies of PERSERIS in the treatment of schizophrenia did not include patients aged 65 and older to determine whether or not they respond differently from younger patients. In general, dose selection for an elderly patient 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. Elderly patients with dementia-related psychosis treated with PERSERIS are at an increased risk of death compared to placebo. PERSERIS is not approved for the treatment of patients with dementia related psychosis [see Boxed Warning 5. 2 In patients with renal impairment, carefully titrate with oral risperidone (up to at least 3 mg) before initiating treatment with PERSERIS [see Dosage and Administration ( 2. 3 PERSERIS was not studied in patients with renal impairment, however, such effect has been investigated with oral risperidone. In patients with hepatic impairment, carefully titrate with oral risperidone (up to at least 3 mg) before initiating treatment with PERSERIS [see Dosage and Administration ( 2. 3 PERSERIS was not studied in patients with hepatic impairment, however, such effect has been investigated with oral risperidone. Patients with Parkinson's disease or dementia with Lewy bodies can experience increased sensitivity to risperidone. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

The interactions of PERSERIS 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. Carbamazepine and other strong CYP3A4 inducers decrease plasma concentrations of risperidone. 1 Fluoxetine, paroxetine, and other strong CYP2D6 inhibitors increase risperidone plasma concentration. 1 Table 5 Table 5 Clinically Important Drug Interactions with PERSERIS Strong CYP2D6 Inhibitors Clinical Impact: Concomitant use of PERSERIS 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 (90 mg) of PERSERIS between 2 to 4 weeks before the planned start of strong CYP2D6 inhibitors to adjust for the expected increase in plasma concentrations of risperidone. When strong CYP2D6 inhibitors is initiated in patients receiving PERSERIS 90 mg, it is recommended to continue treatment with 90 mg unless clinical judgment necessitates interruption of PERSERIS 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 PERSERIS 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 PERSERIS [see Clinical Pharmacology ( 12. 3 Intervention: Changes in efficacy and safety should be carefully monitored with any dose adjustment of PERSERIS. 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 PERSERIS 90 mg, consider increasing the dose to 120 mg. In patients receiving PERSERIS 120 mg, additional oral risperidone therapy may need to be considered. On discontinuation of a strong CYP3A4 inducer, the dosage of PERSERIS or any additional oral risperidone therapy should be re-evaluated and, if necessary, decreased to adjust for the expected increase in plasma concentration of risperidone and 9-hydroxyrisperidone. For patients treated with PERSERIS 90 mg and discontinuing from a strong CYP3A4 inducer, it is recommended to continue treatment with the 90 mg dose unless clinical judgment necessitates interruption of PERSERIS 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 PERSERIS is administered in combination with other centrally-acting drugs or alcohol. Hypotensive Agents Clinical Impact: Because of its potential for inducing hypotension, PERSERIS may enhance the hypotensive effects of other therapeutic agents with this potential. Intervention: Caution should be used when PERSERIS is administered in combination with other therapeutic agents with hypotensive effects. Dopamine Agonists Clinical Impact: Agents with central antidopaminergic activity such as PERSERIS may antagonize the pharmacologic effects of dopamine agonists. Intervention: Caution should be used when PERSERIS 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 PERSERIS and methylphenidate. Based on pharmacokinetic studies with oral risperidone, no dosage adjustment of PERSERIS 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 PERSERIS [see Clinical Pharmacology ( 12.

OVERDOSAGE
No cases of overdose were reported in premarketing studies with PERSERIS. Because PERSERIS is to be administered by healthcare providers, the potential for overdosage by patients is low. In case of overdosage, consult a Poison Control Center at 1-800-222-1222. In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT prolonging effects that might be additive to those of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of risperidone, resulting in problematic hypotension. There is no specific antidote to risperidone. Appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers. Consider the long-acting nature of PERSERIS when assessing treatment needs and recovery.
NONCLINICAL TOXICOLOGY
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. 5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 0. 75, and 3 times (mice) and 0. 5, and 6 times (rats) the oral MHRD of 16 mg/day, based on a mg/m 2 2 Table 7 Summary of Tumor Occurrence at the Multiples of the Human Dose on a mg/m 2 Multiples of Maximum Human Oral Dose in mg/m 2 (mg/kg) Tumor Type Species Sex Lowest Effect Level Highest No-Effect Level Pituitary adenomas mouse Female 0. 4) Endocrine pancreas adenomas rat Male 1. 4) Mammary gland adenocarcinomas mouse Female 0. 4) None rat Female 0. 4) None rat Male 6 (37. 4) Mammary gland neoplasm, Total rat Male 1. 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 in vivo No evidence of mutagenic potential was observed with risperidone subcutaneous injectable suspension or its delivery system alone at doses of 150 mg/kg risperidone or 943 mg/kg delivery system in an in vivo 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 maximum recommended human dose (MRHD), of 16 mg/day based on mg/m 2 2 Subcutaneous administration of the delivery system to rats had no effect on fertility parameters in either sex up to a dose that is 17 (delivery system), and 23 ( N 2.
CLINICAL STUDIES
Efficacy for PERSERIS was demonstrated in an 8-week, randomized, double-blind, placebo-controlled study (Study 1, NCT #02109562). The study evaluated the efficacy, safety and tolerability of PERSERIS (90 and 120 mg subcutaneous every 4-weeks) compared with placebo in adults (age 18- to 55-years, inclusive) experiencing acute exacerbations of schizophrenia. Patients were required to have a Positive and Negative Syndrome Scale (PANSS) total score of 80- to 120-inclusive (moderate to severely ill) at the screening visit, occurring 3- to 8-days before the start of double-blind treatment, without an improvement in the PANSS total score of >= 20% between screening and the first dosing day. At the screening visit, all patients received two doses of 0. 25 mg oral risperidone 24-hours apart to establish tolerability. Patients were then placed in an inpatient setting, if not already hospitalized, and tapered off their current oral antipsychotic medication (if they were taking one) over a period of 3- to 8-days. Patients were randomized to receive 2 doses of subcutaneous PERSERIS (90 mg or 120 mg) or placebo 28-days apart (on Day 1 and Day 29). No supplemental oral risperidone was permitted during the study. The primary endpoint was the change in PANSS total score from baseline to end of study (Day 57). Both PERSERIS 90 and 120 mg doses demonstrated a statistically significant improvement compared with placebo based on the primary endpoint ( Table 8 Figure 14 Characteristics of the patient population were balanced across the treatment groups. The mean baseline PANSS total score ranged from 94 to 96 across the groups. Most patients were male (74 to 83% per group), and the mean ages were 40 to 43 in each group. Most patients in this study were black or African American (71 to 75% per group). Of the 354 patients randomized to treatment, 337 were included in the intent-to-treat (ITT) population, and 259 (73%) completed the study. Subgroup analyses by gender, age, and race did not suggest any clear evidence of differential responsiveness to PERSERIS. Table 8 Primary Efficacy Analysis Results for Study 1 ITT: intent-to-treat; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval ªDifference (drug minus placebo) in least-squares mean change from baseline *Doses that are statistically significantly superior to placebo Primary Efficacy Measure: PANSS Treatment Group N (# ITT patients) Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI) PERSERIS 90 mg* 111 95. 13)* PERSERIS 120 mg* 114 94. 85)* Placebo 112 94. 58) -- Figure 14. Least Square Mean Change from Baseline (+/- Standard Error) in PANSS Total Scores by Days The secondary efficacy endpoint was defined as the CGI-S score at Day 57. Both PERSERIS treatment groups demonstrated statistically significantly better CGI-S scores versus placebo.

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