Volume 3

KOL Commentary

Identifying Patients Who May Be Candidates for UZEDY: Insight From a Thought Leader

February 2025 | 9 min read

We interviewed Dr Jonathan Meyer, Voluntary Clinical Professor of Psychiatry at the University of California, San Diego, for insights on patients who may benefit from UZEDY® (risperidone), a subcutaneous long-acting injectable (LAI) antipsychotic used to treat adult patients with schizophrenia.

Please tell us about LAI antipsychotics and why they are an important treatment option for patients with schizophrenia.

LAI antipsychotics were developed as an alternative to daily oral antipsychotics and are designed to provide sustained release of medication over weeks to months. As such, LAIs reduce the opportunity to miss doses. Not surprisingly, LAIs have been shown to help reduce relapse risk.

No clinical studies have been conducted to show that UZEDY affects nonadherence or the consequences of relapse discussed here.

What do you look for when selecting an LAI?

The first question I ask is "Does the molecule have an established efficacy and safety profile?" Most clinicians are aware of the efficacy and safety profile of risperidone for schizophrenia. It was approved on December 29, 1993, more than 30 years ago.

After that, one important factor is the pharmacokinetic profile. I consider how long it takes for the LAI to achieve therapeutic plasma drug levels and whether it maintains those levels across the dosing interval.

Other key considerations when selecting an LAI are patients’ needs and preferences. For example, in the outpatient setting, it may be inconvenient for those who live a great distance from the clinic to return for a second loading dose injection. Often in these cases the burden falls on the caregivers because many individuals living with schizophrenia don’t drive and therefore are reliant on others for transportation to a clinic or pharmacy to receive subsequent injections. Products that require oral bridging at the beginning of therapy present another source of concern, as patients may be nonadherent with the oral therapy and experience subtherapeutic antipsychotic levels.

What is UZEDY and what makes it a different kind of LAI?

UZEDY is risperidone plus SteadyTeq^TM, a novel drug delivery system that allows for rapid absorption of risperidone—within 6 to 24 hours—and also provides sustained release over the duration of the dosing interval. UZEDY achieves therapeutic plasma levels quickly following a single, small-volume injection and does not require oral bridging doses or additional loading dose injections.

Avoiding extra injections or oral coverage helps streamline therapy initiation, and for me, as a clinician, helps reduce the concern that the patient will either miss their second loading injection or their oral bridging doses. In certain settings, such as a psychiatric inpatient unit or jail setting, having a second injection requirement at initiation can be challenging because it can delay discharge from the psychiatric unit or may be missed if the patient is released from custody before it is administered. The absence of that requirement can help with concerns that the patient has not completed the loading dose process.

An important consideration for me relates to missed dose guidelines. For most LAIs, restarting can be complex because of the need for oral supplementation, a loading dose injection, calculation of dosing requirements based on the length of time since the last dose, and an increased frequency of visits during the reinitiation period. In short, one missed treatment could result in a significant amount of time and commitment for patients.

Another aspect of UZEDY that I find personally useful is restarting after a missed injection. There are no complex missed dose guidelines because the pharmacokinetic properties of UZEDY result in therapeutic levels soon after administration. Patients who are late for the scheduled UZEDY injection simply receive the next dose as soon as possible, and thereby achieve therapeutic levels within 24 hours after injection. There is no need to know how long it’s been since the prior injection was missed because the prior stable dose is administered as soon as possible.

Of course, one must be certain that the patient has had prior exposure to risperidone before starting UZEDY. If they haven’t, they need to be evaluated for tolerability. If the patient has taken risperidone before and the prior daily dose is known, you can start them on the corresponding dose of UZEDY.

In addition to the pharmacokinetic parameters, what other features of UZEDY might be of interest to clinicians and patients?

Clinicians and patients should be aware that UZEDY is administered subcutaneously, that there are 2 injection site options—upper arm and abdomen—and that it is delivered through a short needle (5/8") and in a small injection volume. In addition, it comes in a ready-to-use prefilled syringe, so no reconstitution is required, and it can be stored at room temperature for up to 90 days.

How might UZEDY be used as patients transition through the settings of care?

Because of its clinical attributes, UZEDY can be used to help increase the likelihood that patients with schizophrenia who are being released from inpatient settings will have therapeutic blood levels of risperidone until they can connect with their outpatient provider. That is, we can administer a 1- or 2-month dose of UZEDY prior to release, knowing that patients will reach a therapeutic level of medication within 24 hours and sustain that level throughout the dosing interval.

For example, I can discharge an individual from an acute inpatient setting with a 2-month injection knowing that they will be covered for that period of time. In my experience, this patient now has a reasonable chance of making that clinician connection to receive ongoing injections with no gap in therapeutic levels of the medication.

The relationship between pharmacokinetics and efficacy has not been established.

What types of patients are appropriate for UZEDY?

In my opinion—and I think we’ve come to this conclusion as a field—all adults living with schizophrenia should be offered an LAI, including those at the beginning of their illness. Given the clinical course of schizophrenia, the stakes are too high to do otherwise, and patients should be offered oral and LAI antipsychotic options so they can make an informed decision about their treatment. I consider prescribing UZEDY for any patient with schizophrenia when offering them an antipsychotic.

Keep in mind that the concerns around relapse are high, even among first-episode patients, and relapse can have devastating consequences. With UZEDY, there’s no chance for a missed dose during the 1- or 2-month dosing interval. The pivotal clinical trial for UZEDY, the RISE study, showed a significant reduction in the rate of relapse.

It’s important to know that the purpose of the pivotal RISE study of UZEDY was to evaluate whether this drug could effectively prevent relapse in patients with schizophrenia. The study included adults living with schizophrenia who were first stabilized on 2 to 5 mg of oral risperidone per day, according to their needs. They were then randomized to either placebo or the 1- or 2-month dose of UZEDY that corresponded to their oral risperidone dose. The primary endpoint was time to impending relapse.

In the RISE study, the relapse risk was significantly lower for patients taking UZEDY every month or every other month vs placebo. The 1- and 2-month intervals had a reduction in relapse risk of 80% and 62.5%, respectively, compared with placebo. Note that the study was not designed to compare the 1-month dosing interval to the 2-month interval.

Under what circumstances might a patient be switched from another LAI to UZEDY?

Risperidone is converted by the liver to its active metabolite, 9-hydroxyrisperidone, which also goes by the name paliperidone. Let’s say you have people who are on other risperidone or paliperidone LAIs. Why might you switch them to UZEDY? Well, in some instances, the patient may prefer or may need a longer dosing interval, such as when they don’t live near a clinic or pharmacy, or following release from an inpatient setting.

In other instances, one may have patients who are taking an LAI that is given via intramuscular injection. They’re looking for an alternative to receive a similar type of molecule, and UZEDY may be a suitable option for these patients because it’s administered via subcutaneous injection and has a short, 5/8-inch, 21-gauge needle.

What kind of injection site reactions may occur with UZEDY?

We've noticed that injection site discomfort with LAIs is mostly seen with the first injection, as observed in the clinical trials of UZEDY.

One thing we do see with UZEDY is that it may form a nodule. It's important to note, though, that in the RISE trial, <1% of nodules were >1 cm in diameter. Please see injection site reactions below within the Important Safety Information.

Remember that UZEDY can be given in the upper arm or abdomen. I prefer to use the upper arm as the injection site.

How do the data from the SHINE clinical trial companion survey influence your treatment decisions and conversations with patients?

The SHINE trial companion survey was a prospective, cross-sectional survey assessing perceptions regarding ease of use and satisfaction with UZEDY in 63 patients, 24 physicians, and 25 nurses. The survey was administered after a minimum of 2 experiences prescribing, administering, or receiving UZEDY. Typically, we enroll individuals in schizophrenia trials who are not naive to the trial process itself, so these patients had previously tried both oral treatments and other LAIs. The fact that 90% or more of patients reported that they were satisfied with UZEDY and would prefer to remain on it over their previous medication, I think, speaks to their satisfaction with UZEDY.

These data give me further confidence that I’m providing a therapy with features that my patients may be interested to learn about when considering an LAI. I let patients know about these data, particularly if they are nervous about trying it.

Administration options are something we have to appreciate from the patient’s perspective. For some who receive UZEDY on an ongoing basis, the convenience of rolling up their sleeve every 1 or 2 months to get a small volume subcutaneous injection is very appealing. Of course, it’s important to discuss all aspects of therapy with patients so that they are fully aware of what to expect when deciding whether to try UZEDY.

References

American Psychiatric Association. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. 3rd ed. Washington, DC: American Psychiatric Association; fact sheet. Accessed November 14, 2024. https://www.tac.org/reports_publications/schizophrenia-fact-sheet/

Bravo-Mehmedbasic A. Risperidone in the treatment of schizophrenia. Med Arh. 2011;65(6):345-347.

Brissos S, Veguilla MR, Taylor D, Balanzá-Martinez V. The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal. Ther Adv Psychopharmacol. 2014;4(5):198-219.

Citrome L. Long-acting injectable antipsychotics update: lengthening the dosing interval and expanding the diagnostic indications. Expert Rev Neurother. 2017;17(10):1029-1043.

Correll CU, Citrome L, Haddad PM, et al. The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry. 2016;77(suppl 3):1-24.

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.

Kane JM, Harary E, Eshet R, et al. Efficacy and safety of TV-46000, a long-acting, subcutaneous, injectable formulation of risperidone, for schizophrenia: a randomised clinical trial in the USA and Bulgaria. Lancet Psychiatry. 2023;10(12):934-943.

Llorca PM, Abbar M, Courtet P, Guillaume S, Lancrenon S, Samalin L. Guidelines for the use and management of long-acting injectable antipsychotics in serious mental illness. BMC Psychiatry. 2013;13:340.

Risperidone. Science Direct. Accessed November 14, 2024. https://www.sciencedirect.com/topics/nursing-and-health-professions/risperidone

Robinson DG, Suett M, Wilhelm A, et al. Patient and healthcare professional preferences for characteristics of long-acting injectable antipsychotic agents for the treatment of schizophrenia. Adv Ther. 2023;40(5):2249-2264.

Schizophrenia Fact Sheet. Treatment Advocacy Center. Accessed November 15, 2024. https://www.tac.org/reports_publications/schizophrenia-fact-sheet/

Stępnicki P, Kondej M, Kaczor AA. Current concepts and treatments of schizophrenia. Molecules. 2018;23(8):2087.

Clinical Data

Initiation of Treatment With UZEDY®, a Long-Acting Injectable Using Innovative Technology for the Treatment of Adults With 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.