SummarY

• In a pooled analyses of double-blind, placebo-controlled, acute treatment trials in patients with schizophrenia, extrapyramidal symptoms (EPS) were among the most common drug-associated adverse events (AEs; at least 5% in patients treated with INVEGA SUSTENNA and more than twice the placebo rate).¹ No occurrences of these AEs reached this threshold in the long-term double-blind, placebo-controlled study in subjects with schizoaffective disorder.²
• Tardive dyskinesia (TD) is a syndrome of potentially irreversible, involuntary, dyskinetic movements. Occurrence of TD is associated with treatment with several medication classes, including antipsychotic drugs.³ If signs and symptoms of TD appear in a patient treated with INVEGA SUSTENNA, drug discontinuation should be considered.

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate extended-release injectable suspension may be expressed in milligram equivalents of paliperidone (active moiety) or milligrams of paliperidone palmitate. Dosage information in this response has been converted to mg of paliperidone palmitate to reflect the commercially available INVEGA SUSTENNA and INVEGA TRINZA dosage strengths. The conversion factor from mg eq. to mg is 1.56.

• INVEGA SUSTENNA doses expressed as 25, 50, 75, 100, and 150 mg eq. are equal to 39, 78, 117, 156, and 234 mg of paliperidone palmitate, respectively.
• INVEGA TRINZA doses expressed 546 and 819 mg of paliperidone palmitate are equal to 350 and 525 mg eq., respectively.

CLINICAL STUDIES

CASE REPORTS

Naguy et al (2024)²² described a case of a 16-year-old male patient with schizoaffective disorder who was maintained on INVEGA SUSTENNA 156 mg every 4 weeks with partial response and presented to the hospital with recurrent constipation and fecal impaction. From the patient’s medical history, a temporal association was noted between constipation and an increase in the paliperidone dose of 6 mg to 9 mg/day, resulting in a diagnosis of anismus due to paliperidone-induced dystonia. The patient was administered procyclidine (2 doses of 2.5 mg/day), and over 3 days, bowel movements and rigidity improved. Three months after the initial presentation, the patient has remained well-maintained on this treatment regimen with stable mental health and no incidents of constipation, tenesmus, fecal impaction, or encopresis.

Zhang et al (2024)²³ described the case of a Black female patient in her early 20s with BD-1 who, at the time of the presentation to the outpatient clinic, was treated with INVEGA SUSTENNA 156 mg for the last 4 months and had been considered to switch to INVEGA TRINZA due to complete resolution of symptoms after treatment with INVEGA SUSTENNA. However, involuntary orofacial movements of the jaw were noted, including clenching, chewing, and retraction of the corners of the mouth, indicating possible paliperidone-induced tardive dyskinesia. The patient’s Abnormal Involuntary Movement Scale (AIMS) score was 11, and it was decided to reduce her INVEGA SUSTENNA dose (100 mg eq. to 75 mg eq. monthly) and not proceed with the switch to INVEGA TRINZA. Two months later, the patient’s AIMS score had reduced to 4.

Nersesjan et al (2024)²⁴ described the case of a female patient in her 60s with bipolar disorder who presented with severe confusion and dystonia. The patient has been receiving treatment with INVEGA SUSTENNA for 8 years with daily concomitant medications including, pantoprazole (80 mg), atorvastatin (20 mg), vitamin D3 (38 μg), varenicline (1.5 mg), fluticasone nasal spray (27.5 μg), budesonide inhalation (400 μg), and valproic acid (1500 mg). Eight days before her current presentation, the patient received her last INVEGA SUSTENNA 100 mg eq. injection in the gluteal muscle. It was reported that the patient’s kidney function was mildly impaired at the time of the last INVEGA SUSTENNA injection following a recent episode of acute kidney injury requiring dialysis. A case of paliperidone poisoning was suspected and then confirmed by bloodwork, which revealed plasma levels 5× higher than the therapeutic range. Although the specific cause(s) remained unknown, a few suspected causes were that the patient received a substantially higher dose of the last INVEGA SUSTENNA injection (>100 mg eq.) coupled with chronic paliperidone accumulation due to a rapid accumulation of paliperidone around the latest episode of acute kidney injury, or inhibition in paliperidone clearance due to concomitant treatment with valproic acid for several years. A treatment plan to accelerate paliperidone clearance was initiated, and after a 2-month hospital stay, the patient was discharged on a reduced dose of biperiden for symptomatic treatment. In the 2-year follow-up, despite complete discontinuation of all antipsychotic treatments after the hospitalization, the patient’s plasma paliperidone concentrations remained detectable 2.5 years after her last INVEGA SUSTENNA injection, and biperiden treatment was still necessary to manage extrapyramidal symptoms.

Goverti et al (2018)²⁵ presented the case of a 35-year-old male with schizophrenia who experienced early-onset TD after 2 injections of INVEGA SUSTENNA. The patient had a 7year history of schizophrenia. At diagnosis, the patient was treated with quetiapine 600 mg, which relieved psychotic symptoms. Due to nonadherence, the patient began experiencing symptoms and was switched to INVEGA SUSTENNA. Ten days after receiving a loading dose of 234 mg on day 1 followed by 156 mg on day 7, the patient developed facial, lingual, and perioral dyskinetic movements (AIMS score for facial, lingual, and perioral items=3 each). INVEGA SUSTENNA was discontinued, and quetiapine was restarted. Dyskinetic movements resolved 1 month later.

Patel et al (2018)²⁶ presented the case of a 28-year-old male with schizophrenia who experienced tardive tourettism with INVEGA SUSTENNA. After 6 months of treatment with INVEGA SUSTENNA, the patient developed involuntary movements and vocalizations, including side to side hip swaying and the recurrent tendency to take his hands and try to stretch open his mouth, touch his brow and face, drum, and toss items. A few months later, the patient developed recurrent blinking, tongue and lip biting, forceful tongue protrusion, repetitive snorting, strong forced air exhalation, whistling, and gagging to the point of vomiting. The patient had no prior history of tics or obsessive-compulsive behavior.

Omer (2018)²⁷ presented the case of a 23-year-old male with schizoaffective disorder who experienced subtle TD with INVEGA SUSTENNA. The patient had a 2-month history of mood and psychotic symptoms and underwent a 6-week admission where he was prescribed olanzapine 20 mg. The olanzapine dose was reduced after discharge, and the patient was subsequently switched to risperidone 2 mg and then to INVEGA SUSTENNA. Patient received 2 loading doses of INVEGA SUSTENNA and was on a maintenance dose of INVEGA SUSTENNA 156 mg monthly. Nine months later, patient presented with subtle, writhing lingual movements in the absence of other EPS. Patient did not have a history of neurological disorders. INVEGA SUSTENNA was discontinued due to suspected TD. Lingual movements subsided 3 months later.

Takada et al (2018)²⁸ presented the case of a 64-year-old male with a 40-year history of schizophrenia who experienced persistent EPS following 6 months of consecutive INVEGA SUSTENNA injections. The patient was diagnosed with schizophrenia at the age of 23 years. He was prescribed several oral antipsychotics, including haloperidol, risperidone (6 mg/day), olanzapine (20 mg/day), and aripiprazole (24 mg/day) which were administered nonconcurrently. The patient reported nonadherence to treatment due to delusions of being poisoned. INVEGA SUSTENNA injections were initiated after repeated hospitalizations due to cyclical remissions and relapses. After receiving the standard initiation regimen, the patient was maintained on INVEGA SUSTENNA 156 mg monthly. The patient’s psychotic symptoms gradually improved; however, after 6 months of continuous INVEGA SUSTENNA injections, the patient experienced severe EPS that continued for 6 weeks after INVEGA SUSTENNA discontinuation. Four years prior to INVEGA SUSTENNA initiation, the patient had complained of spontaneous EPS. The patient exhibited hand tremors, lead-pipe rigidity, gait instability, sialorrhea, oral dyskinesia, and severe hallucinatory delusions (Positive and Negative Syndrome Scale [PANSS] score of 125; Drug-Induced Extrapyramidal Symptoms Scale [DIEPSS] score of 22). Antipsychotic cessation over 6 weeks after admission demonstrated no improvement in the patient’s EPS. Levodopa was initiated and increased to a dose of 400 mg/day and his EPS gradually improved after 1 month. Aripiprazole was initiated at 6 mg/day and increased to 18 mg/day with monitoring of EPS. The patient’s psychotic symptoms gradually improved after 2 months with no sign of EPS worsening. Neither EPS nor psychotic symptoms deteriorated over the following 6 months. To detect the presence of dopamine transporters (DaT) in the brain, researchers conducted a DaT scan of the patient. The DaT scan indicated moderate DaT loss in the striatum, while a magnetic resonance imaging (MRI) scan showed atrophy of the dorsal brainstem.

Jang et al (2017)²⁹ presented the case of a 53-year-old female with a 30-year history of schizophrenia who experienced persistent EPS for 5 months following a single INVEGA SUSTENNA injection. Four months prior to admission, the patient experienced an acute relapse of psychotic symptoms and received INVEGA SUSTENNA 156 mg via deltoid intramuscular (IM) injection due to poor oral medication adherence. Seven days post-injection she presented with severe EPS and gait instability with frequent falls which persisted over the next month despite administration of medications to reduce EPS symptoms and discontinuation of antipsychotics. To control her psychotic symptoms, trials of aripiprazole (5 mg/day) and quetiapine (titrated to 150 mg/day) were prescribed over 3 months prior to admission but resulted in worsening EPS symptoms. The patient presented with uncontrolled psychotic symptoms and severe EPS (tremor, rigidity, and gait instability; SimpsonAngus Scale [SAS]=17). Antipsychotics were held for the next month, but EPS did not fully remit even with the initiation of procyclidine (10 mg/day), propranolol (40 mg/day), lorazepam (2 mg/day), and flunitrazepam (1 mg/day). Clozapine was carefully titrated up to 150 mg over the next month resulting in stabilization of psychotic symptoms and eventual discharge. EPS persisted for a total of 5 months following the initial INVEGA SUSTENNA injection.

Marques (2017)³⁰ presented the case of a 64-year-old female with schizoaffective disorder who experienced oral facial dystonia following treatment with INVEGA SUSTENNA. The patient was initiated on paliperidone extended release (ER) 12 mg/day for refractory persecutory delusional ideation. The patient achieved symptomatic remission 2 weeks later. To maximize adherence, INVEGA SUSTENNA 234 mg IM was initiated prior to discharge. One month later, the patient presented with Meige syndrome (bilateral blepharospasm and oromandibular dystonia). Past medical history was negative for antipsychotic-associated EPS. The Naranjo Scale was used to estimate the probability of INVEGA SUSTENNA-induced Meige syndrome, in which the patient scored a 7. INVEGA SUSTENNA was discontinued, and the patient was started on clozapine 100 mg daily. All signs of Meige syndrome resolved 6 months later.

Singh et al (2016)³¹ presented the case of a 22-year-old male with a 4.5-year history of unspecified nonorganic psychosis who experienced severe refractory TD and tardive dystonia following treatment with INVEGA SUSTENNA. The patient transitioned to INVEGA SUSTENNA (234 mg x 1; 156 mg monthly) plus oral paliperidone (3-6 mg) after 1 year of noncompliance with oral olanzapine. Treatment was tolerated for 1.5 years until the patient gradually developed spontaneous, abnormal, repetitive, and nonrhythmic facial movements (frowning, blepharospasm, grimacing, puckering, and pouting). Intermittent sustained contractions of the right hand and shoulder muscles, resulting in twisting of the right hand followed by right-sided torticollis, accompanied the facial movements. Gradually, the patient developed involuntary movements of the cranial, cervical, trunk, and bilateral upper extremities. INVEGA SUSTENNA was tapered and stopped; however, the patient went on to develop painful muscular spasms and sustained contractions of the neck and back muscles leading to retrocollis and arching of the back with opisthotonus posturing. Choreoathetoid movements involving the upper and lower extremities were also present. Psychiatric symptoms were managed with olanzapine (7.5 mg) and quetiapine (50 mg/day). The patient was diagnosed with TD and tardive dystonia (AIMS score of 25; Unified Dystonia Rating Scale score of 41). Treatment attempts with trihexyphenidyl, lorazepam, tetrabenazine, baclofen, botulinum toxin type A injections (cervical dystonia), and deep brain stimulation surgery were unsuccessful at providing sustained symptomatic relief or functional improvement. The patient gradually improved over the next 3 months with a daily combination of clozapine (400 mg), clonazepam (6 mg), tetrabenazine (75 mg), baclofen (60 mg), and trihexyphenidyl (2 mg). At discharge, the patient’s dyskinetic movements and dystonia reduced significantly (AIMS score of 11; Unified Dystonia Rating Scale score of 6), and he continues to remain well 6 months post discharge.

Ustohal et al (2014)³² described the case of a 22-year-old male with paranoid schizophrenia who experienced severe acute dystonia/akathisia following treatment with INVEGA SUSTENNA. The patient received risperidone long-acting injection (RLAI) 37.5 mg every 2 weeks for 9 months without incident. A switch to INVEGA SUSTENNA 117 mg via gluteal injection every 4 weeks was initiated. The patient remained clinically stable and free of AEs until the fifth INVEGA SUSTENNA injection when he experienced acute dystonia of the orofacial and neck muscles, akathisia, and breathing problems. Dystonia and akathisia reached their peak intensity about 24 hours after this fifth injection. The patient received 10 mg diazepam IM and 2 mg of ground biperiden orally. His condition improved so he received an additional dose of biperiden 2 mg and clonazepam 2 mg. Dystonic symptoms diminished later in the day and akathisia was less pronounced. The patient continued to receive biperiden 4 mg daily and clonazepam 2 mg daily and experienced resolution of dystonia and akathisia symptoms 3 days later. On day 5, biperiden was decreased to 2 mg daily followed by discontinuation of clonazepam on day 15. The patient was discharged and continued to receive INVEGA SUSTENNA 117 mg every 4 weeks. For more than half a year at the time of report, no further AEs were reported.

Hsu et al (2013)³³ described the case of a 39-year-old Chinese female with a history of psychosis who experienced TD following a switch from haloperidol decanoate to INVEGA SUSTENNA. The patient received haloperidol decanoate 40 mg/month for 9 months but due to prominent negative symptoms, was switched to INVEGA SUSTENNA (156 mg IM on days 1 and day 8, followed by 156 mg monthly). Her negative symptoms improved, but prior to her fourth dose, a mild tongue protrusion was noted. Over the next month, symptoms progressed to involuntary tongue and jaw movements which were moderate to severe in intensity. INVEGA SUSTENNA was discontinued, and aripiprazole 5 mg daily was initiated. Improvement in movement symptoms was observed 6 weeks later with full remission at 3 months and controlled psychiatric symptoms.

Lally et al (2013)³⁴ described the case of a 49-year-old female with paranoid schizophrenia who developed orofacial dyskinesia during treatment with INVEGA SUSTENNA. The patient was readmitted to the hospital following a florid psychotic relapse due to medication nonadherence. She received INVEGA SUSTENNA initiation doses (234 mg IM on day 1; 156 mg on day 8) followed by monthly maintenance doses of 234 mg. Up until the fourth 234 mg dose, INVEGA SUSTENNA was well tolerated. At that time, mild tongue protrusions were noted for 2 weeks which progressed over the next month to involuntary movements (mild/moderate intensity) of the lips, tongue, and jaw. Past medical history was negative for movement disorders. Probable TD was diagnosed on follow-up (AIMS jaw and tongue items=3 each). INVEGA SUSTENNA was discontinued, and olanzapine 10 mg daily with clonazepam 2 mg daily was initiated. After 6 weeks, some improvement was noted, and at 3 months, her symptoms subsided with the exception of ongoing involuntary tongue movements.

Coffey et al (2012)³⁵ presented the case of a 79-year-old female with paranoid schizophrenia who presented with catatonia and encephalopathy during treatment with INVEGA SUSTENNA. INVEGA SUSTENNA initiation doses were administered (234 mg on day 1; 156 mg on day 8) followed by a monthly maintenance dose of 117 mg which was increased to 156 mg due to persistent psychotic symptoms. A day after receiving her sixth monthly injection of INVEGA SUSTENNA 156 mg, the patient developed stupor, mutism, diffuse analgesia, rigidity (all 4 extremities, neck, and jaw), posturing, Gegenhalten, and bilateral upper extremity resting tremor. While she had experienced akathisia and bradykinesia during trials of quetiapine and ziprasidone, respectively, her past medical history was negative for parkinsonism, dystonia, or catatonia. Electroencephalography (EEG) showed diffuse slowing with occasional triphasic waves. Concomitant medical conditions included insulindependent diabetes, pulmonary hypertension, normocytic anemia, and central sleep apnea. A continuous lorazepam infusion of 16 mg/24 hours was initiated. While rigidity, posturing, and Gegenhalten resolved (Bush Francis Catatonia Rating Scale score decreased from 25 to 12), stupor persisted. Given the incomplete response to lorazepam and the addition of bromocriptine (5 mg every 6 hours), a course of ECT 4 times/week for 12 treatments was recommended. Motor features of her catatonia resolved after 2 treatments, but stupor and encephalopathy showed no improvement. The patient’s family elected to discontinue ECT after the 12th treatment and pursue hospice care with resumed lorazepam. While mild rigidity recurred, there was no recurrence of posturing, Gegenhalten, or tremor. The patient died from respiratory distress 1 month later. No autopsy was performed.

LITERATURE SEARCH

A literature search of Ovid MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 12 September 2024.

Open-label studies, indirect treatment comparisons and post hoc analyses were not included in this response unless the primary outcome focused on movement disorders observed during use of paliperidone palmitate.