linenavheadernavheader

Volume 2

KOL Commentary

Expert Insights on Relapse in Schizophrenia

December 2024 | 9 min read

Henry A. Nasrallah, MD

The clinical course of schizophrenia is characterized by recurrent relapse, often due to partial adherence or nonadherence to medication. Dr. Henry A. Nasrallah reflects on the consequences of relapse in patients with schizophrenia and the multiple factors contributing to relapse, and provides insights on his approach to relapse prevention with the use of long acting injectable (LAI) antipsychotic medications.

No clinical studies have been conducted to show that UZEDY affects adherence or the consequences of relapse discussed in this article.

What are the consequences of relapse for patients with schizophrenia, and why is it important to prevent it?
Henry A. Nasrallah, MD

Most clinicians consider rehospitalization as the primary concern when patients with schizophrenia relapse; however, with successive relapses, patients can experience functional disability. I have seen patients who are unable to return to school, go back to work, or participate within their family. They essentially lose the capacity to live their lives. Furthermore, with multiple relapses, patients become treatment resistant, requiring greater doses of medications for treatment, and experience persistent psychotic symptoms.

What are the key predictors of relapse in patients with schizophrenia?
Henry A. Nasrallah, MD

Relapse occurs due in part to poor adherence to antipsychotic medication, which unfortunately is ubiquitous in patients with schizophrenia. In a 3-year longitudinal study of 341 patients after first-episode psychosis, patients who missed more than 1 out of 10 days of medication were more likely to relapse than adherent patients. Taking daily medication can be difficult for the general population, but for patients with schizophrenia, lack of insight or awareness of their disease may exacerbate the problem. Patients may refuse medication if they don’t understand they need the medicine because they don’t believe they are sick. Even with patients who do understand the need for their medication, barriers such as poor memory, cognitive dysfunction, and avolition can make taking daily medication difficult. Clinicians must recognize the challenges patients with schizophrenia face and take them into consideration when deciding on treatment.

“Even with patients who do understand the need for their medication, barriers such as poor memory, cognitive dysfunction, and avolition can make taking daily medication difficult.”
How has the availability of LAIs shaped your approach to relapse prevention in patients with schizophrenia?
Henry A. Nasrallah, MD

Antipsychotic medications require consistent therapeutic plasma levels to be effective. In my opinion, an appropriate time to initiate treatment with an LAI would be at discharge from the first hospitalization. Unfortunately, clinicians today wait until their patients have multiple relapses before initiating LAIs. Yet when I ask clinicians how they would treat a family member with schizophrenia, knowing that LAIs have been shown to reduce relapse, they frequently say they would choose them. It is my hope that by giving LAIs after the first psychotic episode, I can prevent future relapses.

“In my opinion, an appropriate time to initiate treatment with an LAI would be at discharge from the first hospitalization.”
The pharmacokinetic (PK) profile of UZEDY allows for a streamlined initiation with no loading dose or oral supplementation. How do these features affect clinical decisions?
Henry A. Nasrallah, MD

With UZEDY, therapeutic plasma levels are rapidly reached within 6 to 24 hours after injection and then maintained for either 1 or 2 months. Additionally, if a patient misses an appointment reinitiation is streamlined: give a single injection of UZEDY at their next appointment and adjust the dosing schedule accordingly. Because of the PK features and the lack of a loading dose or oral supplementation, UZEDY is an important option for me to have for my patients who are in the hospital after presenting with their first psychotic episode.
The relationship between pharmacokinetics and efficacy has not been established.

“With UZEDY, therapeutic plasma levels are rapidly reached within 6 to 24 hours after injection and then maintained for either 1 or 2 months, based on the chosen dosing interval.”
Which features or attributes of UZEDY are most important to clinicians and their patients?
Henry A. Nasrallah, MD

UZEDY is risperidone, which has an established efficacy and safety profile, delivered using an innovative drug-delivery technology. With UZEDY, clinicians can be confident that therapeutic plasma levels of risperidone are rapidly reached within 6 to 24 hours and, importantly, sustained for the duration of either the 1- or 2-month dosing interval. UZEDY does not need to be refrigerated and can be stored for up to 90 days at room temperature. There is also no reconstitution required.

UZEDY is also a subcutaneous injection that can be administered in either the back of the upper arm or the abdomen, which gives patients and HCPs the opportunity to discuss their preferred injection site. In addition, patients don’t have to take off their clothes for a gluteal injection, which is important in an outpatient setting. The summation of these features supports my decision to offer UZEDY to my patients.

How does the clinical and safety data for RISE, the longest and largest phase 3 study of a risperidone LAI to date, influence your treatment decisions?
Henry A. Nasrallah, MD

For me, the 2 most important features of any medication are efficacy and safety. RISE was a relapse prevention study, which investigated the efficacy of UZEDY compared with placebo. Patients treated with UZEDY experienced a statistically significant delay in time to relapse, with 29% of patients receiving placebo experiencing impending relapse compared with only 7% of patients receiving UZEDY Q1M. Risk of relapse was reduced by 80% with UZEDY Q1M and in a post hoc analysis at 1 year, a 92% relapse-free rate was demonstrated with UZEDY Q1M compared with 63% with placebo. Results with UZEDY Q2M were also statistically significant compared with placebo.

The safety profile of UZEDY was also demonstrated to be consistent with that of oral risperidone. Adverse events occurring in 5% or more of patients taking UZEDY and more frequently than with placebo were nasopharyngitis, weight increase, and extrapyramidal disorder. The safety data from the long-term safety study, SHINE, were consistent with those in RISE with no new safety signals. These findings are important, as I always discuss a medication’s safety profile with my patients. In addition, most injection site reactions (ISRs) were mild or moderate and decreased in frequency after the first injection. Patients are often hesitant about receiving injections, but results from a companion survey of UZEDY showed that both patients and clinicians perceived administration as easy.

What do your conversations with patients about UZEDY entail? What are patients’ greatest concerns?
Henry A. Nasrallah, MD

When I discuss LAIs, I start by explaining the consequences of relapse and the importance of preventing these events. I describe UZEDY to patients as a type of medication that they do not have to remember to take daily and has been shown to prevent relapse. We then discuss their concerns about administration. I explain to them the differences between a subcutaneous and intramuscular injection. Patients also appreciate seeing how short the needle is with UZEDY. The streamlined administration process—without the need for extra pills or additional injections—is also well received. Adverse events are also an important topic for patients. I talk to them about the safety profile of UZEDY and highlight how it is consistent with the known profile of oral risperidone. I also discuss that most injection-site adverse events were mild or moderate and ISRs decreased in frequency over time.

“I describe UZEDY to patients as a type of medication that they do not have to remember to take daily and has been shown to prevent relapse.”
In your opinion, who is the ideal patient for UZEDY?
Henry A. Nasrallah, MD

Every patient is a potential candidate for UZEDY, across all phases of disease: patients experiencing their first psychotic episode, patients who have had suboptimal response on previous medications, or patients who don’t want to take daily medications. The exception would be those patients who are allergic to risperidone. Since risperidone is widely used across every clinical setting, many patients will have been exposed to it at one point in their treatment journey. At discharge, I will review a patient’s medical history to see if they have ever received risperidone in the past, and if so, it is a streamlined initiation since UZEDY requires no loading dose or oral supplementation. In my opinion, UZEDY enables a seamless transition from oral medication to an LAI.

When a patient has a heart attack, the primary goal of their cardiologist is to prevent another. I take the same approach to relapse in patients with schizophrenia. When a patient has a psychotic episode, my goal is to prevent another. In this sense, starting a patient on UZEDY after the first relapse may be an appropriate option, but it can be used at any point along the treatment journey where the clinician or patient believes an LAI should be considered. In addition, UZEDY has features relating to administration that are different, so it should not be assumed that patients who have refused an LAI in the past would refuse a different option.

“When a patient has a heart attack, the primary goal of their cardiologist is to prevent another. I take the same approach to relapse in patients with schizophrenia.”
Suggested Reading:
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. Milz R, Benson C, Knight K, et al. The effect of longer dosing intervals for long-acting injectable antipsychotics on outcomes in schizophrenia. Neuropsychiatr Dis Treat. 2023;19:531-545. 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. Correll C, Howes OD. Treatment-resistant schizophrenia: definition, predictors, and therapy options. J Clin Psychiatry. 2021;82(5):MY20096AH1C. 6. Rivelli A, Fitzpatrick V, Nelson M, et al. Real-world predictors of relapse in patients with schizophrenia and schizoaffective disorder in a large health system. Schizophrenia (Heidelb). 2024;10(1):28. 7. Sher L, Kahn RS. Suicide in schizophrenia: an educational overview. Medicina (Kaunas). 2019;55(7):361. 8. National Institute of Mental Health. Accessed July 26, 2024. https://www.nimh.nih.gov/health/statistics/suicide 9. Alvarez-Jimenez M, Priede A, Hetrick SE, et al. Risk factors for relapse following treatment for first episode psychosis: a systematic review and meta-analysis of longitudinal studies. Schizophr Res. 2012;139(1-3):116-128. 10. Pelayo-Terán JM, Gajardo Galán VG, de la Ortiz-García de la Foz V, et al. Rates and predictors of relapse in first-episode non-affective psychosis: a 3-year longitudinal study in a specialized intervention program (PAFIP). Eur Arch Psychiatry Clin Neurosci. 2017;267(4):315-323. 11. Bergé D, Mané A, Salgado P, et al. Predictors of relapse and functioning in first-episode psychosis: a two-year follow-up study. Psychiatr Serv. 2016;67(2):227-233. 12. Acosta FJ, Hernández JL, Pereira J, Herrera J, Rodríguez CJ. Medication adherence in schizophrenia. World J Psychiatry. 2012;2(5):74-82. 13. Haddad PM, Brain C, Scott J. Nonadherence with antipsychotic medication in schizophrenia: challenges and management strategies. Patient Relat Outcome Meas. 2014;5:43-62. 14. Citrome L. Long-acting injectable antipsychotics update: lengthening the dosing interval and expanding the diagnostic indications. Expert Rev Neurother. 2017;17(10):1029-1043. 15. Subotnik KL, Casaus LR, Ventura J, et al. Long-acting injectable risperidone for relapse prevention and control of breakthrough symptoms after a recent first episode of schizophrenia. A randomized clinical trial. JAMA Psychiatry. 2015;72(8):822-829. 16. UZEDY™ (risperidone) extended-release injectable suspension. Prescribing Information. Parsippany, NJ; Teva Neuroscience, Inc. 17. 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. 18. 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. 19. Merenlender Wagner A, 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. 20. 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. 21. Data on file. Teva Neuroscience, Inc. Parsippany, NJ. 22. Kane JM, Correll CU, Tohami O, et al. TD-46000 provided continued symptom improvement in patients with schizophrenia in the phase 3, randomized, double-blind relapse prevention RISE study. Presented at Psych Congress; October 29-November 1, 2021; San Antonio, TX. 23. 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. 24. Potkin S, Bera R, Zubek D, Lau G. Patient and prescriber perspectives on long-acting injectable (LAI) antipsychotics and analysis of in-office discussion regarding LAI treatment for schizophrenia. BMC Psychiatry. 2013;13:261. 25. Ascher-Svanum H, Zhu B, Faries DE, Furiak NM, Montgomery W. Medication adherence levels and differential use of mental-health services in the treatment of schizophrenia. BMC Res Notes. 2009;2:6. 26. Robinson DG, Suett M, Wilhelm A, et al. Healthcare professional preferences and treatment experiences with TV-46000, a long-acting injectable risperidone formulation. Presented at Psych Congress 2021; October 29-November 1, 2021; San Antonio, TX. 27. Robinson DG, Suett M, Wilhelm A, et al. Patient preferences and treatment experiences with TV-46000, a long-acting subcutaneous injectable risperidone formulation. Presented at Psych Congress 2021; October 29-November 1, 2021; San Antonio, TX. 
Previous

Clinical Data

UZEDY: A Different LAI With an Innovative Delivery Platform

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

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.

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

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.

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.