These Highlights Do Not Include All The Information Needed To Use Perseris ®

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)] .

Storage and Handling

Store in refrigerator at 2°C to 8°C (36°F to 46°F). Allow PERSERIS kit to come to room temperature, 20°C to 25°C (68°F to 77°F), for at least 15 minutes prior to mixing.

PERSERIS may be stored in its unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 30 days prior to administration. After removal from the refrigerator, use PERSERIS within 30 days or discard.

Principal Display Panel - Perseris Kit 90 mg Carton Label

NDC 12496-0090-1

once-monthly

PERSERIS ^®

(risperiDONE)

for extended-release

injectable suspension

90 mg

Liquid

Syringe

+

Mix

Powder

Syringe

1 Injection

Rx only

Sterile

Single-dose only

For subcutaneous injection only. Please read complete instructions prior to use.

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.

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.

Priapism has been reported during postmarketing surveillance for other risperidone products. Severe priapism may require surgical intervention.

PERSERIS contains risperidone, an atypical antipsychotic. Risperidone belongs to the chemical class of benzisoxazole derivatives. The chemical designation 3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl) piperidin-1-yl] ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a] pyrimidin-4-one. Its molecular formula is C ₂₃H ₂₇FN ₄O ₂and its molecular weight is 410.5 g/mol.

The structural formula is:

Risperidone is a white to off-white powder. It is practically insoluble in water and soluble in methanol and 0.1 N HCl.

PERSERIS is available as a sterile two-syringe mixing system: a liquid syringe prefilled with the delivery system (colorless to yellow solution), and a powder syringe prefilled with risperidone (white to yellow).

PERSERIS for extended release injectable suspension, for subcutaneous use, is available in 90 mg and 120 mg risperidone strengths. The quantitative composition is provided below ( Table 6).

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)] .

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 Warningand Warnings and Precautions ( 5.1, 5.2)] .

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). The results at each scheduled visit are displayed in 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.

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.

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.

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

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warningand 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 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.

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 ( 2.2) and Clinical Pharmacology ( 12.3)] .

PERSERIS was not studied in patients with renal impairment, however, such effect has been investigated with oral risperidone.

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.

Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT ₂), dopamine Type 2 (D ₂), α ₁and α ₂ adrenergic, and H ₁histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT _1C, 5HT _1D, and 5HT _1Areceptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D ₁and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations > 10 ^-5M) for cholinergic muscarinic or β ₁and β ₂adrenergic receptors.

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 1.2 to 1.7 based on mean area under the curve (AUC), and from 0.9 to 1.3 based on overall mean peak plasma concentrations (overall C _max), indicating no to modest accumulation. For 9-hydroxyrisperidone, accumulation ratios ranged from 1.2 to 1.6 (AUC) and 0.99 to 1.3 (overall C _max). For total active moiety, accumulation ratios ranged from 1.2 to 1.6 (AUC _tau) and 0.97 to 1.3 (overall C _max).

Following multiple doses of PERSERIS, plasma exposure (AUC _tauand C _max) of risperidone, 9-hydroxyrisperidone, and total active moiety increased in an approximately dose proportional manner over the dose range of 60 to 120 mg. At steady-state, a 2-fold increase in dose resulted in a 1.7-fold increase in C _max(6.33 to 10.9 ng/mL) and AUC _tau(2262 to 3891 ng*hr/mL) for risperidone. For 9-hydroxyrisperidone, a 2-fold increase in dose resulted in a 2.1-fold increase in C _max(13.7 to 28.9 ng/mL) and 2-fold increase in AUC _tau(5706 to 11658 ng*hr/mL). For total active moiety, a 2-fold increase in dose resulted in a 2.0-fold increase in C _max(19.6 to 38.5 ng/mL) and a 1.9-fold increase in AUC _tau(8102 to 15370 ng*hr/mL).

Plasma exposures at steady-state were compared between oral risperidone and PERSERIS. The average plasma concentrations (C _avg) of total active moiety were 18.3 ng/mL and 18.1 ng/mL for 3 mg oral risperidone and 90 mg PERSERIS, respectively. The C _avgof total active moiety were 25.2 ng/mL and 22.9 ng/mL for 4 mg oral risperidone and 120 mg PERSERIS, respectively.

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.

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.

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.

As with other drugs that antagonize dopamine D ₂receptors, 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.

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 ( 2.2) and Clinical Pharmacology ( 12.3)] .

PERSERIS was not studied in patients with hepatic impairment, however, such effect has been investigated with oral risperidone.

PERSERIS is indicated for the treatment of schizophrenia in adults [see Clinical Studies ( 14)] .

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

• 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)

• 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)

PERSERIS (risperidone) for extended-release injectable suspension for subcutaneous use is available in strengths of 90 mg and 120 mg.

Each strength is provided as a kit which includes: one pre-filled syringe containing a white to yellow risperidone powder in a sealed pouch, one pre-filled syringe containing a colorless to yellow delivery system in a sealed pouch, and one 18-gauge, 5/8-inch needle.

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.

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.

• Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1)
• 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. ( 8.6, 8.7)

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.

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.

PERSERIS (risperidone) for extended-release injectable suspension, for subcutaneous use is, when fully mixed a viscous suspension that, varies from white to yellow-green and is available in dosage strengths of 90 mg and 120 mg.

PERSERIS 90 mg is supplied in a single-dose kit, packaged in a carton (NDC 12496-0090-1), containing the following:

• One pouch with a sterile syringe (labelled ‘P’) prefilled with risperidone powder
• One pouch with a sterile syringe (labelled ‘L’) prefilled with the delivery system, and desiccant.
• One 18-gauge, 5/8-inch sterile safety needle.

PERSERIS 120 mg is supplied in a single-dose kit, packaged in a carton (NDC 12496-0120-1), containing the following:

• One pouch with a sterile syringe (labelled ‘P') prefilled with risperidone powder.
• One pouch with a sterile syringe (labelled ‘L') prefilled with the delivery system, and desiccant.
• One 18-gauge, 5/8-inch sterile safety needle.

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.

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.

• 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 Syringeupright 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 Syringeon 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 Syringeinto the Powder Syringe.
• Gently push the Powder Syringeplunger 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 5for 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 Syringemay 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 Syringeplunger and
  • pull back gentlyon the Liquid Syringeplunger 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 notinject 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

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 ³and follow their WBC until recovery.

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.

Table 5includes clinically significant drug interactions with PERSERIS.

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.

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)] .

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)].

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)] .

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. PERSERIS ^® is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.1)].

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)] .

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)] .

Storage and Handling

Store in refrigerator at 2°C to 8°C (36°F to 46°F). Allow PERSERIS kit to come to room temperature, 20°C to 25°C (68°F to 77°F), for at least 15 minutes prior to mixing.

PERSERIS may be stored in its unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 30 days prior to administration. After removal from the refrigerator, use PERSERIS within 30 days or discard.

Principal Display Panel - Perseris Kit 90 mg Carton Label

NDC 12496-0090-1

once-monthly

PERSERIS ^®

(risperiDONE)

for extended-release

injectable suspension

90 mg

Liquid

Syringe

+

Mix

Powder

Syringe

1 Injection

Rx only

Sterile

Single-dose only

For subcutaneous injection only. Please read complete instructions prior to use.

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.

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.

Priapism has been reported during postmarketing surveillance for other risperidone products. Severe priapism may require surgical intervention.

PERSERIS contains risperidone, an atypical antipsychotic. Risperidone belongs to the chemical class of benzisoxazole derivatives. The chemical designation 3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl) piperidin-1-yl] ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a] pyrimidin-4-one. Its molecular formula is C ₂₃H ₂₇FN ₄O ₂and its molecular weight is 410.5 g/mol.

The structural formula is:

Risperidone is a white to off-white powder. It is practically insoluble in water and soluble in methanol and 0.1 N HCl.

PERSERIS is available as a sterile two-syringe mixing system: a liquid syringe prefilled with the delivery system (colorless to yellow solution), and a powder syringe prefilled with risperidone (white to yellow).

PERSERIS for extended release injectable suspension, for subcutaneous use, is available in 90 mg and 120 mg risperidone strengths. The quantitative composition is provided below ( Table 6).

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)] .

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 Warningand Warnings and Precautions ( 5.1, 5.2)] .

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). The results at each scheduled visit are displayed in 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.

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.

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.

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

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warningand 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 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.

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 ( 2.2) and Clinical Pharmacology ( 12.3)] .

PERSERIS was not studied in patients with renal impairment, however, such effect has been investigated with oral risperidone.

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.

Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT ₂), dopamine Type 2 (D ₂), α ₁and α ₂ adrenergic, and H ₁histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT _1C, 5HT _1D, and 5HT _1Areceptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D ₁and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations > 10 ^-5M) for cholinergic muscarinic or β ₁and β ₂adrenergic receptors.

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 1.2 to 1.7 based on mean area under the curve (AUC), and from 0.9 to 1.3 based on overall mean peak plasma concentrations (overall C _max), indicating no to modest accumulation. For 9-hydroxyrisperidone, accumulation ratios ranged from 1.2 to 1.6 (AUC) and 0.99 to 1.3 (overall C _max). For total active moiety, accumulation ratios ranged from 1.2 to 1.6 (AUC _tau) and 0.97 to 1.3 (overall C _max).

Following multiple doses of PERSERIS, plasma exposure (AUC _tauand C _max) of risperidone, 9-hydroxyrisperidone, and total active moiety increased in an approximately dose proportional manner over the dose range of 60 to 120 mg. At steady-state, a 2-fold increase in dose resulted in a 1.7-fold increase in C _max(6.33 to 10.9 ng/mL) and AUC _tau(2262 to 3891 ng*hr/mL) for risperidone. For 9-hydroxyrisperidone, a 2-fold increase in dose resulted in a 2.1-fold increase in C _max(13.7 to 28.9 ng/mL) and 2-fold increase in AUC _tau(5706 to 11658 ng*hr/mL). For total active moiety, a 2-fold increase in dose resulted in a 2.0-fold increase in C _max(19.6 to 38.5 ng/mL) and a 1.9-fold increase in AUC _tau(8102 to 15370 ng*hr/mL).

Plasma exposures at steady-state were compared between oral risperidone and PERSERIS. The average plasma concentrations (C _avg) of total active moiety were 18.3 ng/mL and 18.1 ng/mL for 3 mg oral risperidone and 90 mg PERSERIS, respectively. The C _avgof total active moiety were 25.2 ng/mL and 22.9 ng/mL for 4 mg oral risperidone and 120 mg PERSERIS, respectively.

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.

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.

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.

As with other drugs that antagonize dopamine D ₂receptors, 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.

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 ( 2.2) and Clinical Pharmacology ( 12.3)] .

PERSERIS was not studied in patients with hepatic impairment, however, such effect has been investigated with oral risperidone.

PERSERIS is indicated for the treatment of schizophrenia in adults [see Clinical Studies ( 14)] .

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

• 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)

• 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)

PERSERIS (risperidone) for extended-release injectable suspension for subcutaneous use is available in strengths of 90 mg and 120 mg.

Each strength is provided as a kit which includes: one pre-filled syringe containing a white to yellow risperidone powder in a sealed pouch, one pre-filled syringe containing a colorless to yellow delivery system in a sealed pouch, and one 18-gauge, 5/8-inch needle.

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.

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.

• Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1)
• 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. ( 8.6, 8.7)

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.

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.

PERSERIS (risperidone) for extended-release injectable suspension, for subcutaneous use is, when fully mixed a viscous suspension that, varies from white to yellow-green and is available in dosage strengths of 90 mg and 120 mg.

PERSERIS 90 mg is supplied in a single-dose kit, packaged in a carton (NDC 12496-0090-1), containing the following:

• One pouch with a sterile syringe (labelled ‘P’) prefilled with risperidone powder
• One pouch with a sterile syringe (labelled ‘L’) prefilled with the delivery system, and desiccant.
• One 18-gauge, 5/8-inch sterile safety needle.

PERSERIS 120 mg is supplied in a single-dose kit, packaged in a carton (NDC 12496-0120-1), containing the following:

• One pouch with a sterile syringe (labelled ‘P') prefilled with risperidone powder.
• One pouch with a sterile syringe (labelled ‘L') prefilled with the delivery system, and desiccant.
• One 18-gauge, 5/8-inch sterile safety needle.

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.

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.

• 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 Syringeupright 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 Syringeon 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 Syringeinto the Powder Syringe.
• Gently push the Powder Syringeplunger 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 5for 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 Syringemay 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 Syringeplunger and
  • pull back gentlyon the Liquid Syringeplunger 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 notinject 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

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 ³and follow their WBC until recovery.

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.

Table 5includes clinically significant drug interactions with PERSERIS.

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.

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)] .

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)].

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)] .

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. PERSERIS ^® is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.1)].

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)] .