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    Safety

    Injection Site Reactions

    PERSERIS—a once-monthly subcutaneous long-acting injectable (LAI)1

    After subcutaneous injection, a majority of patients reported no injection pain (≥75%), no tenderness (≥79%), no erythema (≥92%), and no inflammation (≥88%) after receiving PERSERIS in an 8-week, Phase III study.1

    • Less than 1% of patients reported moderate tenderness at any time point, and 1 patient reported severe tenderness. Additionally, 1 or 2 patients reported cases of moderate pain, erythema, and inflammation/swelling1

    Mean injection site pain scores in a 12-month extension study (EXT)2

    Injection site pain was measured using the Visual Analog Scale (VAS)
    (0=no pain to 100=unbearably painful)1

    All patients Patients who received 11 injections
    Time post-injection Injection 1-EXT
    (N=500)
    Injection 1-EXT
    (N=248)
    Injection 11-EXT
    (N=248)
    1 minute 24.9 25.6 15.8
    5 minutes 11.2 10.7 7.2
    30 minutes 5.6 5.4 3.9
    60 minutes 4.2 4.6 3.3

    Injections were measured from the start of the 12-month EXT. Rollover patients received 2 prior injections of PERSERIS.2

    Mean injection site pain VAS scores for all patients (N=500) 1 minute after injection 1 decreased from ~25 to ~16 by injection 11 (N=248).2

    • The percentage of patients who reported burning/stinging at 1 minute following the injection decreased from 43.4% on Day 1 to 35.7% on Day 3372
    • Severe injection site tenderness immediately post-dose was reported in one patient each on Days 29 and 1132
    • Injection site pain and injection site nodule led to study discontinuation in one patient each2

    Most patients reported little to no injection site pain in a 12-month extension study1,2



      Injection site reactions occurring in ≥5% of patients
    • In an 8-week study, the most common injection site reactions were injection site pain (90 mg: 16%; 120 mg: 22%; placebo: 20%), injection site erythema (90 mg: 6%; 120 mg: 4%; placebo: 5%), and induration/nodule (90 mg: 2.6%; 120 mg: 3.4%; placebo: 5.1%)2
    • In a 12-month extension study, the most common injection site reactions for all patients were injection site pain (13%), injection site nodule (7%), injection site induration (6%), and injection site pruritus (5%)2




    Safety Summary

    The systemic safety profile of PERSERIS is consistent with the known safety profile of oral risperidone1

    The safety and tolerability of PERSERIS were studied in a Phase III, 8-week, randomized, double-blind, placebo-controlled clinical study1,2


    Adverse drug reactions (ADRs) occurring in ≥5% of patients1

    ADRs 90 mg
    (n=115)
    %
    120 mg
    (n=117)
    %
    Placebo
    (n=118)
    %
    Weight increased 13 13 3
    Constipation 7 8 5
    Sedation/somnolence 7 8 0
    Pain in extremity 1 8 5
    Anxiety 3 7 5
    Back pain 4 7 4
    Akathisia 3 7 4
    Musculoskeletal pain 5 5 3



    • A typical increase in mean prolactin levels was observed for both doses of PERSERIS from baseline to end of study; mean prolactin for the placebo group remained stable during the study1
    • Extrapyramidal symptom (EPS)-related ADRs ≥2% were akathisia (90 mg: 3%; 120 mg: 7%; placebo: 4%), extrapyramidal disorder (90 mg: 4%; 120 mg: 2%; placebo: 1%), and dystonia (90 mg: 0%; 120 mg: 1%; placebo: 3%)1
    • There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥2% (and greater than placebo) in PERSERIS-treated patients1,2
    • Mean weight of patients taking PERSERIS 90 mg and 120 mg increased ~10 pounds (4.4 kg) and ~12 pounds (5.3 kg), respectively, from baseline to Day 57; mean weight of patients in the placebo arm increased ~6 lbs (2.6 kg)1
      • Weight gain ≥7% from baseline occurred in 33% of patients in the 90 mg group, 42% in the 120 mg group, and 18% in the placebo group1

    An open-label, Phase III extension study (N=500) following an 8-week pivotal study evaluated the safety and tolerability of PERSERIS2

    Treatment-emergent adverse events (TEAEs) occurring in ≥5% of all patients2

    TEAEs All Patients (N=500)
    %
     
    Weight increased 13  
    Schizophrenia 8  
    Insomnia 7  
    Akathisia 6  
    Upper respiratory tract infection 5  
    Headache 5  



    12% of patients receiving PERSERIS discontinued due to TEAEs in the open-label, 12-month extension study.2

    The most commonly reported ADRs leading to discontinuation2

    ADRs All Patients (N=500)
    %
     
    Weight increased 1  
    Akathisia 1  
    Sedation/somnolence 1  
    Tremor 1  
    Galactorrhea 1  


    • The most commonly reported ADRs associated with EPS for all patients were akathisia (6%), tremor (2%), and extrapyramidal disorder (2%)2
    • Mean weight of all patients receiving PERSERIS increased ~4 pounds (2 kg) from baseline to Day 85 and then remained stable for the remainder of the study1

    Click here to view the 12-month, Phase III, open-label extension study design.




    References: 1. PERSERIS [prescribing information]. North Chesterfield, VA: Indivior Inc; 2018. 2. Data on file. Indivior Inc. North Chesterfield, VA; 2018.

    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. PERSERIS is not approved for the treatment of patients with dementia-related psychosis and has not been studied in this population.

    INDICATIONS AND USAGE

    PERSERIS is indicated for the treatment of schizophrenia in adults.

    CONTRAINDICATIONS:

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

    WARNINGS AND PRECAUTIONS

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

    Neuroleptic Malignant Syndrome, a potentially fatal symptom complex, has been reported with antipsychotic medications. Clinical manifestations include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (see full Prescribing Information). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems.

    Tardive Dyskinesia (TD): TD may develop in patients treated with antipsychotic drugs. The risk of developing TD and likelihood that it will become irreversible are believed to increase with treatment duration and total cumulative dose. Less commonly, TD can develop after relatively brief treatment periods at low doses. Elderly patients, especially elderly women, appear to be at increased risk, but it is impossible to predict which patients will develop TD. Therefore, PERSERIS should be prescribed in a manner that is most likely to minimize the occurrence of TD. Discontinue treatment if clinically appropriate.

    Metabolic Changes that may increase cardiovascular/cerebrovascular risk, have been associated with atypical antipsychotics (APs).

    • 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 APs, including risperidone. Patients with DM who are started on atypical APs, including PERSERIS, should be monitored regularly for worsening of glucose control. Patients at risk for DM (e.g., obesity, family history of diabetes) who are starting treatment with atypical APs, including PERSERIS, should undergo fasting blood glucose (FBG) testing at the beginning of treatment and periodically while treated. Any patient treated with atypical APs, including PERSERIS, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical APs, including PERSERIS, should undergo FBG testing. In some cases, hyperglycemia has resolved when risperidone was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of risperidone.

    • Dyslipidemia has been observed in patients treated with atypical APs.

    • Weight Gain has been observed with atypical AP use. Monitoring weight is recommended.

    Hyperprolactinemia: Risperidone elevates prolactin levels, and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents. Hyperprolactinemia may inhibit reproductive function in female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating drugs. Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in females and males.

    Orthostatic Hypotension: Risperidone may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope. Use with particular caution in patients with known cardiovascular disease, cerebrovascular disease, and conditions which predispose patients to hypotension, and in the elderly and patients with renal or hepatic impairment. Monitor such patients and consider a dose reduction if hypotension occurs.

    Falls: Somnolence, postural hypotension, motor instability, and sensory instability have been reported with the use of antipsychotics, including PERSERIS, which may lead to falls, and consequently, fractures or other fall-related injuries. Assess the risk of falls when initiating treatment and recurrently during treatment.

    Leukopenia, Neutropenia, and Agranulocytosis have been reported with antipsychotic agents, including risperidone. In patients with a history of a clinically significant low white blood count (WBC) or a drug-induced leukopenia/neutropenia, perform a complete blood count frequently during the first few months of therapy. Consider discontinuation 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/signs of infection and treat promptly if such symptoms/signs occur. Discontinue PERSERIS in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow WBC until recovery.

    Potential for Cognitive and Motor Impairment: Risperidone may impair judgment, thinking, or motor skills. Caution patients about operating machinery, including automobiles, until they are reasonably certain PERSERIS does not affect them adversely.

    Seizures have been observed in risperidone studies in adults with schizophrenia. PERSERIS should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

    Dysphagia: Esophageal dysmotility and aspiration can occur. Use cautiously in patients at risk for aspiration pneumonia.

    Priapism has been reported with other risperidone products. Severe priapism may require surgical intervention.

    Disruption of Body Temperature Regulation has been attributed to antipsychotic agents. Use with caution in patients who will be exposed to temperature extremes.

    Adverse Reactions:

    The most common adverse reactions in a clinical trial (≥ 5% and greater than placebo) were increased weight, constipation, sedation/somnolence, pain in extremity, back pain, akathisia, anxiety, and musculoskeletal pain. The most common injection site reactions (≥ 5%) were injection site pain and erythema. This is not a complete list of potential adverse events. Please see the full Prescribing Information for a complete list.

    DRUG INTERACTIONS

    • Carbamazepine and other strong CYP3A4 inducers decrease risperidone plasma concentration.

    • Fluoxetine, paroxetine, and other strong CYP2D6 inhibitors increase risperidone plasma concentration.

    • Use with other CNS drugs or alcohol may increase nervous system disorders.

    • PERSERIS may enhance hypotensive effects of hypotensive agents.

    • PERSERIS may antagonize the pharmacologic effects of dopamine agonists.

    USE IN SPECIFIC POPULATIONS

    Pregnancy: PERSERIS may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become or intend to become pregnant during treatment with PERSERIS. Patients exposed to PERSERIS during pregnancy may be registered with the National Pregnancy Registry for Atypical Antipsychotics (1-866-961-2388 or http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/).

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

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

    Renal or Hepatic Impairment: Carefully titrate on oral risperidone up to at least 3 mg before initiating treatment with PERSERIS at a dose of 90 mg.

    To report pregnancy or side effects associated with taking PERSERIS, please call 1-877-782-6966.

    For more information about PERSERIS, see the full Prescribing Information including BOXED WARNING.

    To report SUSPECTED ADVERSE REACTIONS, contact Indivior Inc. at 1-877-782-6966 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.