Volume 2

Clinical Data

UZEDY: A Different LAI With an Innovative Delivery Platform

December 2024 | 8 min read

Schizophrenia is a complex mental illness, the clinical course of which is characterized by recurrent relapse.¹ LAI antipsychotic medications have been shown to prevent relapse in patients with schizophrenia.^2,3 When selecting among the available LAIs, key considerations include time to reach steady-state levels, loading dose or oral supplementation requirements, extended post-injection monitoring, and coordination of missed doses.^3-5 In addition, some patient-related factors also need to be considered such as needle size, injection site pain, injection volume, and dosing intervals.^3,6-8

UZEDY is a treatment for schizophrenia in adults that utilizes SteadyTeq™, an innovative drug-delivery system, to deliver risperidone as a long acting injectable subcutaneous antipsychotic medication.^9-12 This article describes the pharmacokinetic profile of UZEDY and highlights the key findings from the pivotal trial, RISE, and the long-term safety study, SHINE.

SteadyTeq™: An Innovative Delivery Platform

SteadyTeq™ is a copolymer solution of organic molecules that controls the release of risperidone over time.^10,11 When injected subcutaneously, the active ingredient, risperidone, is released into the subcutaneous space, allowing rapid achievement of therapeutic concentrations.^9-12 Simultaneously, as the copolymer formulation comes into contact with an aqueous environment, a porous depot forms, trapping risperidone (Figure 1).^9-11 As the depot slowly degrades over time due to hydrolysis, risperidone is continuously released in a controlled manner providing sustained therapeutic plasma levels over the entire 1- or 2-month dosing interval.^10,11 Over time, the bioresorbable depot completely degrades.^10,11

Figure 1. Mechanism of SteadyTeq™

In pharmacokinetic studies, each dose of UZEDY demonstrated a rapid absorption phase, with therapeutic plasma levels of risperidone rapidly achieved within 6 to 24 hours, and a secondary absorption phase over several weeks (Figure 2).^9,10,12 No oral supplementation or loading dose is needed, resulting in a streamlined initiation or reinitiation for patients who miss their regularly scheduled dose.⁹ A single injection of UZEDY rapidly reaches therapeutic plasma levels that are sustained for the entire 1- or 2-month dosing interval.^9-12

Figure 2. Plasma Levels of Active Drug* After UZEDY Q1M and Q2M Dosing

*Risperidone and 9-hydroxyrisperidone.
^†The relationship between pharmacokinetics and efficacy has not been established. The threshold for clinically relevant plasma levels of risperidone is defined as levels ≥10 ng/mL.
Q1M, once monthly; Q2M, once every 2 months.

No oral supplementation or loading dose is needed, resulting in a streamlined initiation or reinitiation for patients who miss their regularly scheduled dose.⁹

A single injection of UZEDY rapidly reaches therapeutic plasma levels that are sustained for the entire 1- or 2-month dosing interval.^9-12

In addition to the pharmacokinetic benefits, SteadyTeq™ confers other features of UZEDY that are relevant to patients and providers (Table 1).⁹

Table 1. Administration and Usage Features of UZEDY

RISE: Largest and Longest Pivotal Trial for a Risperidone LAI in Schizophrenia to Date

UZEDY was evaluated in RISE, a phase 3, double-blinded, placebo-controlled, randomized relapse-prevention study that compared UZEDY once-monthly (Q1M) or once-every-2-months (Q2M) versus placebo in adult patients with schizophrenia.^13,14 RISE was the largest and longest pivotal trial for a risperidone LAI in schizophrenia to date.^9,15-16

After a 4-week screening period, patients were stabilized on 2 mg to 5 mg oral risperidone per day for 12 weeks.¹³ After this oral stabilization phase, they were randomized 1:1:1 to UZEDY Q1M, UZEDY Q2M, or placebo.¹³ Patients were given a dose of UZEDY corresponding to the oral dose of risperidone on which they had been stabilized.¹³ They remained in the study until they relapsed or met discontinuation/withdrawal criteria.¹³ The primary endpoint was time to impending relapse, and the trial was halted when 90 relapse events were recorded across all study patients (Figure 3).¹³

Figure 3. UZEDY Study Design

Proven Efficacy: A Significant Reduction in Risk of Relapse

Patients taking UZEDY had significantly longer time to impending relapse compared with patients taking placebo (Figure 4).^13,14 At the end of the trial, 7% of patients receiving UZEDY Q1M and 13% receiving UZEDY Q2M experienced impending relapse compared with 29% receiving placebo.^13,14 UZEDY Q1M significantly reduced the risk of relapse by 80% compared with placebo (HR: 0.200; 95% CI, 0.109 to 0.367, P<0.0001).^13,14 UZEDY Q2M significantly reduced the risk of relapse by 62.5% compared with placebo (HR: 0.375; 95% CI, 0.227 to 0.618, P<0.0001).^13,14

Figure 4. Significant Reduction in Risk of Relapse With UZEDY Versus Placebo

Safety and Tolerability Profile

The safety of UZEDY for patients with schizophrenia is based on adequate and well-controlled studies of oral risperidone.⁹ The safety of oral risperidone has been well characterized in adults with schizophrenia.⁹ The safety profile of UZEDY is expected to be similar to that of corresponding oral risperidone doses of 2 to 5 mg daily. The most common adverse reactions occurring in more than 5% of patients and twice the rate of placebo in three 4- to 8-week, double-blinded, placebo-controlled trials of oral risperidone, are listed in Table 2.⁹

Table 2. The Most Common Adverse Reactions in Clinical Trials of Oral Risperidone (>5% and Twice Placebo)

URTI, upper respiratory tract infection.

The systemic safety profile for UZEDY is consistent with the known safety profile of risperidone (Table 3).¹⁴ The adverse events occurring in 5% or more of patients taking UZEDY and more frequently than with placebo were nasopharyngitis, weight increase, and extrapyramidal disorder.¹⁴ Frequently occurring adverse reactions were generally rated as mild or moderate in severity. Approximately 13% of patients treated with UZEDY discontinued treatment due to an adverse event, compared with 11% who received placebo.¹⁴ The randomized withdrawal study design of RISE, in which patients were first stabilized on oral risperidone, may have reduced the observed rate of adverse reactions with UZEDY.

Table 3. The Systemic Safety Profile of UZEDY Is Consistent With the Known Safety Profile of Risperidone

*Those occurring in ≥2% of patients treated with UZEDY and with higher frequency than in patients receiving placebo.
Q1M, every month; Q2M, every two months.

Most injection site adverse events were mild or moderate.¹⁷ The majority of nodule assessments were mild or moderate and less than 1% of all injections resulted in nodule size >1 cm.¹⁸ Body mass index scores did not have an impact on nodule size.¹⁸ In the RISE clinical trial, 32% of patients received UZEDY in the upper arm and 68% received UZEDY in the abdomen.¹⁴ ISRs were more frequent in the abdomen than in the arm (Table 4).²¹ Overall, injection-site reactions decreased in frequency after the first injection and led to treatment discontinuation in 7 patients receiving UZEDY.¹⁷

Table 4. Frequency of Injection Site Reactions With UZEDY Q1M and Q2M

*The location of the injection was preassigned by clinical site.
AE, adverse event.

The SHINE study was designed to evaluate the long-term safety of UZEDY once monthly and once every 2 months in adults with schizophrenia.¹⁹ Safety data in the long-term safety study SHINE were consistent with those in RISE, with no new safety signals.¹⁹

Dosing Interval and Strength Can Be Tailored to Individual Patient Needs

UZEDY is available in 8 dosages, comparable to 2 mg to 5 mg of daily oral risperidone, over 2 dosing intervals to allow individualization of patient care (Table 5).⁹ Patients can start UZEDY by administering on the day they would normally receive oral risperidone and have the option of a 1-month or 2-month dosing interval.⁹ UZEDY is administered as a subcutaneous injection in either the abdomen or the back of the upper arm.¹² Read the Preparation and Administration Instructions in the Prescribing Information before administering UZEDY.⁹

Table 5. UZEDY Dosing Interval and Dosage Strengths

Summary

For patients with schizophrenia, recurrent relapse can contribute to severe consequences. LAI antipsychotic medications have been shown to prevent relapse in patients with schizophrenia.^2,3

UZEDY is a different LAI that uses SteadyTeq™, an innovative drug delivery system that allows therapeutic plasma levels to be reached within 6 to 24 hours and sustains these levels for the duration of the 1-month or 2-month dosing interval.^9,10,12 The result is a streamlined initiation or reinitiation process that does not require a loading dose or oral supplementation.⁹

UZEDY was evaluated in the phase 3 RISE trial, a double-blind, placebo-controlled, randomized relapse-prevention study with a primary endpoint of time to impending relapse.^13,14 Patients treated with UZEDY experienced a statistically significant delay in the time to relapse, with 29% of patients receiving placebo experiencing impending relapse compared with 7% of patients receiving UZEDY Q1M and 13% of patients receiving UZEDY Q2M.^13,14

The safety profile of UZEDY is expected to be similar to that of corresponding oral risperidone doses of 2 mg to 5 mg daily. Adverse events occurring in more than 5% of patients taking UZEDY and more frequently than placebo were nasopharyngitis, weight increase, and extrapyramidal disorder.¹⁴ Most injection site adverse events were mild or moderate and decreased in frequency after the first injection.¹⁷ Safety data in the long-term safety study SHINE were consistent with those in RISE, with no new safety signals.¹⁹

Relapse prevention is a primary concern for clinicians treating patients with schizophrenia.^1,20 The novel delivery system, SteadyTeq™, enables UZEDY to have rapid absorption, streamlined initiation, and one-step reinitiation, affording clinicians additional features to treat patients with schizophrenia.⁹

References: 1. Kane JM, Correll CU. Optimizing treatment choices to improve adherence and outcomes in schizophrenia. J Clin Psychiatry. 2019;80(5):IN18031AH1C. 2. Nasrallah HA. 10 devastating consequences of psychotic relapses. Curr Psychiatry. 2021;20(5):9-12. 3. Citrome L. Long-acting injectable antipsychotics update: lengthening the dosing interval and expanding the diagnostic indications. Expert Rev Neurother. 2017;17(10):1029-1043. 4. Gardner KN, Nasrallah HA. Managing first-episode psychosis: rationale and evidence for nonstandard first-line treatments for schizophrenia. Curr Psychiatry. 2015;14(7):33-45. 5. INVEGA SUSTENNA® (paliperidone palmitate) extended-release injectable suspension. Prescribing Information. Titusville, NJ; Janssen Pharmaceuticals, Inc. 6. Gill HS, Prausnitz MR. Does needle size matter? J Diabetes Sci Technol. 2007;1(5):725-729. 7. Zolezzi M. Long-acting injectable antipsychotics. Review and recent developments. Neurosciences (Riyadh). 2005;10(2):126-131. 8. Wilkinson J, Ajulo D, Tamburrini V, et al. Lipid based intramuscular long-acting injectables: current state of the art. Eur J Pharm Sci. 2022;178:106253. 9. UZEDY™ (risperidone) extended-release injectable suspension. Prescribing Information. Parsippany, NJ; Teva Neuroscience, Inc. 10. Perlstein I, Merenlender Wagner A, Gomeni R, et al. Population pharmacokinetic modeling and simulation of TV-46000: a long-acting injectable formulation of risperidone. Clin Pharmacol Drug Dev. 2022;11(7):865-877. 11. Roberge C, Cros JM, Serindoux J, et al. BEPO®: bioresorbable diblock mPEG-PDLLA and triblock PDLLA-PEG-PDLLA based in situ forming depots with flexible drug delivery kinetics modulation. J Control Release. 2020;319:416-427. 12. Merenlender Wagner A, Elgart A, Perlstein I, et al. Phase 1 open-label study assessing the pharmacokinetics and safety of TV-46000, a novel long-acting subcutaneous injectable formulation of risperidone. Presented at: European Congress of Neuropathology; October 2-5, 2021; Lisbon, Portugal. Poster P.0463. 13. Kane JM, Harary E, Tohami O, et al. Subcutaneous risperidone (TV-46000) efficacy and safety in schizophrenia: a phase 3, randomized, double-blind, relapse prevention study (RISE study). Presented at Psych Congress 2021; October 29-November 1, 2021; San Antonio, TX. 14. Data on file. Teva Neuroscience, Inc. Parsippany, NJ. 15. Risperdal Consta® (risperidone) long-acting injection. Prescribing Information. Titusville, NJ: Janssen Pharmaceuticals, Inc. 16. Perseris® (risperidone) extended-release injectable suspension. Prescribing Information. North Chesterfield, VA: Indivior, Inc. 17. Correll CU, Kane JM, Suett M, et al. Efficacy and safety of TV-46000, subcutaneous long-acting risperidone, by injection site (upper arm/abdomen): post hoc analysis of the RISE study. Presented at Psych Congress 2021; October 29-November 1, 2021; San Antonio, TX. 18. Correll CU, Kane JM, Suett M, et al. TV-46000–A long-acting subcutaneous antipsychotic (LASCA) for the treatment of schizophrenia: local tolerability and injection site reactions. Presented at: Psych Congress; September 8-September 10, 2023; Nashville, TN. 19. Kane JM, Harary E, Tohami O, et al. Long-term safety, tolerability, and effectiveness of a long-acting subcutaneous antipsychotic (LASCA) agent (TV-46000) in patients with schizophrenia: a phase 3, randomized, double-blind study (SHINE). Poster presented at the 5th Annual Congress of the Schizophrenia International Research Society; May 11-15, 2023; Toronto, Canada. 20. American Psychiatric Association. The American Psychiatric Association Practice Guideline for the Treatment of Schizophrenia. 3rd ed. Washington, DC: American Psychiatric Association; 2021.

Clinical Data & KOL Commentary

VOLUME 1 | Understanding the Role of UZEDY in Treating Patients With Schizophrenia

KOL Commentary

Expert Insights on Relapse in Schizophrenia

INDICATION AND USAGE

UZEDY (risperidone) extended-release injectable suspension for subcutaneous use is indicated for the treatment of schizophrenia in adults.

IMPORTANT SAFETY INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. UZEDY is not approved for use in patients with dementia-related psychosis and has not been studied in this patient population.

INDICATION AND USAGE

UZEDY (risperidone) extended-release injectable suspension for subcutaneous use is indicated for the treatment of schizophrenia in adults.

IMPORTANT SAFETY INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

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

WARNINGS AND PRECAUTIONS

Cerebrovascular Adverse Reactions: In trials of elderly patients with dementia-related psychosis, there was a significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in patients treated with oral risperidone compared to placebo. UZEDY is not approved for use in patients with dementia-related psychosis.

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 UZEDY and provide symptomatic treatment and monitoring.

Tardive Dyskinesia (TD): TD, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause TD is unknown.

The risk of developing TD and the likelihood that it will become irreversible are believed to increase with the duration of treatment and the cumulative dose. The syndrome can develop, after relatively brief treatment periods, even at low doses. It may also occur after discontinuation. TD may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

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

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 (DM), in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics, including risperidone. Patients with an established diagnosis of DM who are started on atypical antipsychotics, including UZEDY, should be monitored regularly for worsening of glucose control. Patients with risk factors for DM (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including UZEDY, should undergo fasting blood glucose (FBG) testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including UZEDY, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including UZEDY, should undergo FBG testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of risperidone.
Dyslipidemia has been observed in patients treated with atypical antipsychotics.
Weight gain has been observed with atypical antipsychotic use. Monitoring weight is recommended.

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

Orthostatic Hypotension and Syncope: UZEDY may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope. UZEDY should be used with particular caution in patients with known cardiovascular disease, cerebrovascular disease, and conditions which would predispose patients to hypotension and 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.

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

Leukopenia, Neutropenia, and Agranulocytosis have been reported with antipsychotic agents, including risperidone. In patients with a pre-existing history of a clinically significant low white blood cell count (WBC) or absolute neutrophil count (ANC) or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of UZEDY at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue UZEDY in patients with ANC < 1000/mm³) and follow their WBC until recovery.

Potential for Cognitive and Motor Impairment: UZEDY, like other antipsychotics, may cause somnolence and has the potential to impair judgement, thinking, and motor skills. Somnolence was a commonly reported adverse reaction associated with oral risperidone treatment. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that treatment with UZEDY does not affect them adversely.

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

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Antipsychotic drugs, including UZEDY, should be used cautiously in patients at risk for aspiration.

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

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

ADVERSE REACTIONS

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

The most common injection site reactions with UZEDY (≥5% and greater than placebo) were pruritus and nodule.

DRUG INTERACTIONS

Carbamazepine and other strong CYP3A4 inducers decrease plasma concentrations of risperidone.
Fluoxetine, paroxetine, and other strong CYP2D6 inhibitors increase risperidone plasma concentration.
Due to additive pharmacologic effects, the concomitant use of centrally-acting drugs, including alcohol, may increase nervous system disorders.
UZEDY may enhance the hypotensive effects of other therapeutic agents with this potential.
UZEDY may antagonize the pharmacologic effects of dopamine agonists.
Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS)

USE IN SPECIFIC POPULATIONS

Pregnancy: May cause EPS and/or withdrawal symptoms in neonates with third trimester exposure. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including UZEDY, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinicaland-research-programs/pregnancyregistry/.

Lactation: Infants exposed to risperidone through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and EPS.

Fertility: UZEDY may cause a reversible reduction in fertility in females.

Pediatric Use: Safety and effectiveness of UZEDY have not been established in pediatric patients.

Renal or Hepatic Impairment: Carefully titrate on oral risperidone up to at least 2 mg daily before initiating treatment with UZEDY.

Patients with Parkinson's disease or dementia with Lewy bodies can experience increased sensitivity to UZEDY. Manifestations and features are consistent with NMS.

Please see the accompanying full Prescribing Information for UZEDY, including Boxed WARNING.

INDICATION AND USAGE

UZEDY (risperidone) extended-release injectable suspension for subcutaneous use is indicated for the treatment of schizophrenia in adults.

IMPORTANT SAFETY INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

WARNINGS AND PRECAUTIONS

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Antipsychotic drugs, including UZEDY, should be used cautiously in patients at risk for aspiration.

ADVERSE REACTIONS

The most common injection site reactions with UZEDY (≥5% and greater than placebo) were pruritus and nodule.

DRUG INTERACTIONS

Carbamazepine and other strong CYP3A4 inducers decrease plasma concentrations of risperidone.
Fluoxetine, paroxetine, and other strong CYP2D6 inhibitors increase risperidone plasma concentration.
Due to additive pharmacologic effects, the concomitant use of centrally-acting drugs, including alcohol, may increase nervous system disorders.
UZEDY may enhance the hypotensive effects of other therapeutic agents with this potential.
UZEDY may antagonize the pharmacologic effects of dopamine agonists.
Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS)

USE IN SPECIFIC POPULATIONS

Lactation: Infants exposed to risperidone through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and EPS.

Fertility: UZEDY may cause a reversible reduction in fertility in females.

Pediatric Use: Safety and effectiveness of UZEDY have not been established in pediatric patients.

Renal or Hepatic Impairment: Carefully titrate on oral risperidone up to at least 2 mg daily before initiating treatment with UZEDY.

Patients with Parkinson's disease or dementia with Lewy bodies can experience increased sensitivity to UZEDY. Manifestations and features are consistent with NMS.

Please see the accompanying full Prescribing Information for UZEDY, including Boxed WARNING.