PERSERIS

1 INDICATIONS AND USAGE 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. ( 1 )

2 DOSAGE AND ADMINISTRATION Establish tolerability with oral risperidone prior to initiating PERSERIS. ( 2.1 ) 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. ( 2.1 ) PERSERIS may be initiated at a dose of 90 mg or 120 mg once monthly. Do not administer more than one dose per month. ( 2.1 ) Supplementation with oral risperidone is not recommended. ( 2.1 ) See Full Prescribing Information for important preparation and administration information. Failure to fully mix the medication could result in incorrect dosage. ( 2.4 ) 2.1 Recommended Dosage 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 ) and Clinical Studies ( 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. 2.2 Dosage Recommendations for Patients with Renal or Hepatic Impairment 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 ( 8.6 , 8.7 ) and Clinical Pharmacology ( 12.3 )]. 2.3 Dosage Recommendations for Concomitant Use with Strong CYP2D6 Inhibitors and Strong CYP3A4 Inducers 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 )] . 2.4 Preparation and Administration Instructions 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 ( ) prefilled with the delivery system. Inspect liquid solution for foreign particles. This is the syringe you will use to inject the patient. One Powder Syringe ( ) prefilled with Risperidone powder. Inspect syringe for consistency of powder color and for foreign particles. One sterile 18-gauge, 5/8-inch safety needle. Figure 1 2 TAP POWDER SYRINGE Hold the Powder Syringe upright and tap the barrel of the syringe to dislodge the packed powder ( Figure 2 ). Note: Powder can become packed during shipping. Figure 2 3 UNCAP LIQUID AND POWDER SYRINGES Remove the cap from the Liquid Syringe , then remove the cap from the 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 on top of the Powder Syringe (to prevent powder spillage) and connect the syringes by twisting approximately ¾ turn ( Figure 4 ). Do not over tighten. 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 into the Powder Syringe . Gently push the Powder Syringe plunger until you feel resistance (to wet powder and avoid compacting). 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 for an illustration of a correct full cycle. 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 may result in incorrect dosage. First, transfer all contents into the Liquid Syringe ( Figure 6 ). Next, perform the following actions SIMULTANEOUSLY : maintain slight pressure on the Powder Syringe plunger and pull back gently on the Liquid Syringe plunger while twisting the syringes apart. 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.g., nodules, lesions, excessive pigment). Do not inject into an area where the skin is irritated, reddened, bruised, infected or scarred in any way. 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 ). Lift the adipose tissue from the underlying muscle to prevent accidental intramuscular injection. 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. Do not inject by any other route. 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 ). It is important that the patient not rub or massage the injection site and to be aware of the placement of any belts, waistbands, sleeves, cuffs or other parts of clothing. Figure 13 Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure

4 CONTRAINDICATIONS 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. ( 4 )

5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions, in Elderly Patients with Dementia-Related Psychosis: Increased risk of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack). ( 5.2 ) Neuroleptic Malignant Syndrome (NMS): Manage with immediate discontinuation and close monitoring. ( 5.3 ) Tardive Dyskinesia: Discontinue treatment if clinically appropriate. ( 5.4 ) Metabolic Changes: Monitor for hyperglycemia, dyslipidemia, and weight gain. ( 5.5 ) Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. ( 5.6 ) Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular disease or cerebrovascular disease, and risk of dehydration or syncope. ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with a history of a clinically significant low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing PERSERIS if a clinically significant decline in WBC occurs in absence of other causative factors. ( 5.9 ) Potential for Cognitive and Motor Impairment: Use caution when operating machinery. ( 5.10 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. ( 5.11 ) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10-weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients between 1.6- to 1.7-times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. PERSERIS is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.2 )] . 5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85-years; range 73 to 97) in trials of oral risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse reactions in patients treated with oral risperidone compared to patients treated with placebo. PERSERIS is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.1 )] . 5.3 Neuroleptic Malignant Syndrome (NMS) NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue PERSERIS and provide symptomatic treatment and monitoring. 5.4 Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase with the duration of treatment and the total cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, PERSERIS should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment. If signs and symptoms of tardive dyskinesia appear in a patient treated with PERSERIS, drug discontinuation should be considered. However, some patients may require treatment with PERSERIS despite the presence of the syndrome. 5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including risperidone. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including PERSERIS, should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including PERSERIS, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including PERSERIS, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including PERSERIS, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of risperidone. Data from an 8-week double-blind, placebo-controlled study with PERSERIS in adult patients with schizophrenia are presented in Table 1 . Table 1 Changes in Fasting Glucose from Baseline to End of Study (EOS) and Postbaseline Abnormal Values of Glucose > 126 mg/dL in an 8-Week Double-Blind, Placebo-Controlled Study in Adult Patients with Schizophrenia † The “n”s in the Serum Glucose mean row are the number of patients with data at baseline and EOS visits. ‡ Data shown as number of patients with at least one postbaseline value as denominator and number of patients satisfying the predefined criterion as numerator. PERSERIS 90 mg PERSERIS 120 mg Placebo n = 98 n = 106 n = 96 Serum Glucose, mg/dL, mean † Mean Change from Baseline to EOS 5.7 6.3 -0.9 Glucose, > 126 mg/dL Proportion of Patients with Postbaseline Abnormal Values ‡ 12/104 (11.5%) 14/111 (12.6%) 8/109 (7.3%) Similar changes from baseline in serum glucose were observed in patients receiving PERSERIS during an open-label, 12-month long-term safety study. Additionally, the mean HbA 1c increased from 5.6 to 5.7% over the 12-months. Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Before or soon after initiation of antipsychotic medications, obtain a fasting lipid profile at baseline and monitor periodically during treatment. Data from an 8-week double-blind, placebo-controlled study with PERSERIS in adult patients with schizophrenia are presented in Table 2 . Table 2 Changes in Cholesterol from Baseline to End of Study (EOS) and Postbaseline Abnormal Values of Cholesterol ≥ 300 mg/dL in an 8-Week Double-Blind, Placebo-Controlled Study in Adult Patients with Schizophrenia † The “n”s in the Cholesterol mean row are the number of patients with data at baseline and EOS visits. ‡ Data shown as number of patients with at least one postbaseline value as denominator and number of patients satisfying the predefined criterion as numerator. PERSERIS 90 mg PERSERIS 120 mg Placebo Cholesterol, mg/dL, mean † n = 98 n = 106 n = 96 Mean Change from Baseline to EOS -0.5 -0.5 1.1 Cholesterol, ≥ 300 mg/dL Proportion of Patients with Postbaseline Abnormal Values ‡ 2/104 (1.9%) 2/111 (1.8%) 2/109 (1.8%) Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Data from an 8-week double-blind, placebo-controlled study with PERSERIS in adult patients with schizophrenia are presented in Table 3 . Table 3 Changes in Body Weight from Baseline to End of Study (EOS) and ≥ 7% Increase from Baseline in an 8-Week Double-Blind, Placebo-Controlled Study in Adult Patients with Schizophrenia † The “n”s in the Weight Change mean row are the number of patients with data at baseline and end of study visits. ‡ Data shown as number of patients with at least one postbaseline value as denominator and number of patients satisfying the predefined criterion as numerator. PERSERIS 90 mg PERSERIS 120 mg Placebo Weight † n = 105 n = 112 n = 107 Mean Change from Baseline to EOS, kg 4.4 5.3 2.6 Weight Gain ≥ 7% Increase from Baseline ‡ 35/107 (32.7%) 48/114 (42.1%) 20/111 (18.0%) In an open-label, 12-month long-term safety study, for all patients receiving PERSERIS, mean weight increased approximately 2 kg from baseline to Day 85, then remained stable for the remainder of the study. 5.6 Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients [see Use in Specific Populations ( 8.3 )] . Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology ( 13.1 )] . Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer. 5.7 Orthostatic Hypotension and Syncope Risperidone may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose, probably reflecting its alpha-adrenergic antagonistic properties. PERSERIS should be used with particular caution in (1) patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia, and (2) in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of oral risperidone and antihypertensive medication. 5.8 Falls Somnolence, postural hypotension, motor instability, and sensory instability have been reported with the use of antipsychotics, including PERSERIS, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. 5.9 Leukopenia, Neutropenia, and Agranulocytosis In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including risperidone. Agranulocytosis has also been reported. Possible risk factors for leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and a history of drug-induced leukopenia or neutropenia. In patients with a pre-existing history of a clinically significant low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of PERSERIS at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue PERSERIS in patients with absolute neutrophil count <1000/mm 3 and follow their WBC until recovery. 5.10 Potential for Cognitive and Motor Impairment PERSERIS, like other antipsychotics, may cause somnolence and has the potential to impair judgement, thinking, and motor skills. In an 8-week, double-blind, placebo-controlled study, somnolence/sedation was reported by 7.0% and 7.7% of patients treated with PERSERIS 90 mg and 120 mg, respectively. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that treatment with PERSERIS does not affect them adversely. 5.11 Seizures Seizures were observed during premarketing studies of risperidone in adult patients with schizophrenia. PERSERIS should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. 5.12 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. Antipsychotic drugs, including PERSERIS, should be used cautiously in patients at risk for aspiration [see Warnings and Precautions ( 5.1 )] . 5.13 Priapism Priapism has been reported during postmarketing surveillance for other risperidone products. Severe priapism may require surgical intervention. 5.14 Body Temperature Regulation Atypical antipsychotics may disrupt the body's ability to reduce core body temperature. Both hyperthermia and hypothermia have been reported in association with oral risperidone use. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use PERSERIS with caution in patients who may experience these conditions.

7 DRUG INTERACTIONS 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. ( 2.3 , 7.1 ) Fluoxetine, paroxetine, and other strong CYP2D6 inhibitors increase risperidone plasma concentration. ( 2.3 , 7.1 ) 7.1 Drugs Having Clinically Important Interactions with PERSERIS Table 5 includes clinically significant drug interactions with PERSERIS. 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. 7.2 Drugs Having No Clinically Important Interactions with PERSERIS 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 ( 12.3 )] .

6 ADVERSE REACTIONS 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 and Warnings and Precautions ( 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.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 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 – 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 Preferred Term PERSERIS 90 mg (n = 115) PERSERIS 120 mg (n = 117) Placebo (n = 118) Percentage of Patients Reporting ADR Gastrointestinal disorders Constipation 7.0 7.7 5.1 Abdominal discomfort 2.6 2.6 1.7 Dry mouth 1.7 2.6 1.7 Investigations Weight increased 13.0 12.8 3.4 Metabolism and nutrition disorders Increased appetite 1.7 3.4 1.7 Musculoskeletal and connective tissue disorders Back pain 3.5 6.8 4.2 Pain in extremity 0.9 7.7 5.1 Musculoskeletal pain 5.2 5.1 2.5 Musculoskeletal stiffness 2.6 0.9 1.7 Muscle spasms 0 2.6 0 Nervous system disorders Sedation* 7.0 7.7 0 Akathisia 2.6 6.8 4.2 Extrapyramidal disorder 4.3 1.7 0.8 Psychiatric disorders Anxiety 2.6 6.8 5.1 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: neutropenia Ear and Labyrinth Disorders: vertigo Endocrine Disorders: hyperprolactinemia Eye Disorders: blepharospasm Gastrointestinal Disorders: nausea, dyspepsia, vomiting, diarrhea, abdominal pain upper, salivary hypersecretion, hypoesthesia oral, tongue movement disturbance General Disorders and Administration Site Conditions: injection site reaction (including injection site pain, induration, pruritus, bruising, erythema, inflammation, swelling and irritation) fatigue, edema peripheral, asthenia, chest discomfort Investigations: blood prolactin increased, blood glucose increased, glycosylated hemoglobin increased, electrocardiogram abnormal, electrocardiogram QT prolonged, blood creatine phosphokinase increased Metabolism and Nutrition Disorders: diabetes mellitus, decreased appetite Musculoskeletal, Connective Tissue, and Bone Disorders: arthralgia, muscle twitching, joint stiffness, trismus Nervous System Disorders: headache, dizziness, tremor, drooling, dyskinesia, lethargy, dystonia, hypoesthesia, oromandibular dystonia, tardive dyskinesia, cogwheel rigidity, dysarthria, balance disorder, parkinsonian rest tremor, parkinsonism, slow speech Psychiatric Disorders: insomnia, libido decreased, bruxism, restlessness, anorgasmia, loss of libido Reproductive System and Breast Disorders: erectile dysfunction, galactorrhea, breast tenderness, breast pain, amenorrhea, breast engorgement, ejaculation delayed, ejaculation disorder, gynecomastia, hypomenorrhea, breast discharge, breast enlargement, ejaculation failure, menstruation delayed, menstruation irregular, polymenorrhea Skin and Subcutaneous Tissue Disorders: night sweats Vascular Disorders: hypertension, hypotension, orthostatic hypotension 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: anemia, granulocytopenia Cardiac Disorders: tachycardia, 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 Eye Disorders: vision blurred, oculogyration, 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: thirst, gait disturbance, 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: nasopharyngitis, upper respiratory tract infection, sinusitis, urinary tract infection, 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, alanine aminotransferase increased, heart rate increased, eosinophil count increased, white blood cell count decreased, hemoglobin decreased, blood creatine phosphokinase increased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased Metabolism and Nutrition Disorders: polydipsia, anorexia Musculoskeletal, Connective Tissue, and Bone Disorders: joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, muscle rigidity, muscle contracture, rhabdomyolysis Nervous System Disorders: dizziness postural, disturbance in attention, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypokinesia, bradykinesia, transient ischemic attack, coordination abnormal, cerebrovascular accident, masked facies, speech disorder, syncope, loss of consciousness, muscle contractions involuntary, Parkinson's disease, tongue paralysis, akinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness Renal and Urinary Disorders: enuresis, dysuria, pollakiuria, urinary incontinence Reproductive System and Breast Disorders: vaginal discharge, menstrual disorder, retrograde ejaculation, sexual dysfunction Respiratory, Thoracic, and Mediastinal Disorders: nasal congestion, dyspnea, epistaxis, wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema Skin and Subcutaneous Tissue Disorders: rash, dry skin, erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, acne, hyperkeratosis, seborrheic dermatitis, rash generalized, rash maculopapular Vascular Disorders: flushing 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 ), Adverse Reactions (6.1, 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 -0.1 and 0.2 (inclusive) for the BARS, between 0 and 0.2 (inclusive) for the AIMS and between -0.1 and 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 (0.8%). 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 F (Fridericia's corrected QT interval), QRS and PR intervals, and heart rate, in patients in either PERSERIS treatment group (90 mg and 120 mg) compared with placebo. Similarly, in the 12-month, long-term safety study, there were no clinically relevant changes in mean ECG interval values from baseline to postdose assessments. 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. 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.

8.1 Pregnancy 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 ) . 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 PERSERIS, 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 the 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. 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 body surface area. These effects could be attributed to N -methyl-2-pyrrolidone (NMP) an excipient in the delivery system based on information in the published literature (see Data ) . Subcutaneous administration of the delivery system to pregnant and lactating rats had no effect on embryofetal and postnatal development at doses up to 17 times the delivery system amount present in 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area. 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. 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. 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 body surface area. Developmental toxicity in both rat and rabbit included skeletal and visceral malformations at doses 35 (rat), and 43 (rabbit) times the delivery system amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area. The NOAEL dose for these effects in both species is 17 times the delivery system amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area. These effects could be related to N -methyl-2-pyrrolidone (NMP), an excipient present in the delivery system. In published animal developmental toxicity studies, NMP administered orally daily to pregnant rats during organogenesis produced developmental toxicity below maternally toxic levels and resulted in dose-dependent decrease in fetal body weights, increased incidence of post-implantation loss, incomplete ossification and increased incidence of external, visceral and skeletal malformations. These toxicities occurred at doses that are ~3 to 12 times the NMP amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area.