Summary

• No cases of post-injection delirium/sedation syndrome (PDSS) were observed in patients who received INVEGA SUSTENNA in an evaluation that used an algorithm to identify reports of PDSS in data from 10 completed clinical trials (a total of 3,817 patients and 33,906 injections). One case of PDSS (as defined by meeting all algorithm requirements) was observed in a patient who received placebo.¹
• No cases of PDSS were observed in the pivotal clinical trials for INVEGA TRINZA or INVEGA HAFYERA^2,3
• Case reports of possible PDSS with INVEGA SUSTENNA have been identified in the literature.
  • Eker et al, (2024)⁴ reported on a 48-year-old male patient with bipolar affective disorder (BAD) who was treated for a manic episode with two 234 mg doses of INVEGA SUSTENNA injections one week apart and 900 mg/day lithium. He developed trembling, rigidity, weakness, drowsiness, slurred speech, difficulty walking and talking 2 days after the second injection. Despite symptomatology, patient was discharged during which he discontinued lithium. Symptoms of disorientation, severe somnolence and diurnal confusion followed. Twenty days later he was taken to the ER where rigidity and delirium were noted and after 3 days he was diagnosed with PDSS. The patient was treated with an anticholinergic and benzodiazepine and after 4 days symptoms subsided. INVEGA SUSTENNA is not indicated for BAD, and the second initiation dose used in this case was higher than what is directed in the Prescribing Information.
  • Held et al, (2019)⁵ reported on a 63-year-old male who was hospitalized with decompensation from schizoaffective disorder and reported previous stabilization on INVEGA SUSTENNA 234 mg, but his last documented injection was approximately 6 months earlier. After 3 days of oral paliperidone, an INVEGA SUSTENNA 234 mg injection was administered and the patient became unresponsive within 4 hours. His alertness improved without intervention within 24 hours and inadvertent intravascular administration was suspected as the cause.
  • Mirza et al, (2018)⁶ report on the case of 16-year-old adolescent male prescribed INVEGA SUSTENNA who developed acute-onset delirium 10 days after the second initiation dose and was hospitalized with unusual perceptual experiences and was observed to have fluctuating levels of consciousness, disordered speech and flailing movements of his extremities. INVEGA SUSTENNA is not indicated for use in patients with schizophrenia who are under 18 years old.  

BACKGROUND

During clinical trials for one long-acting injectable antipsychotic, there were reports of a syndrome referred to as PDSS (McDonnell et al, 2008⁷; Citrome 2009⁸). The syndrome, while not clearly defined, included symptoms of sedation, dizziness, confusion, slurred speech, altered gait, weakness, or unconsciousness that occur typically within a few hours following the intramuscular injection. The mechanism for PDSS may be related to the solubility of the long-acting injectable antipsychotic formulation in blood or plasma. It has been suggested that PDSS may occur when a long-acting injectable antipsychotic is highly soluble and there is contact with blood from partial injection into the vasculature, vessel injury during IM administration, or substantial bleeding at the injection site. It is unclear if this syndrome is a side effect that can be expected with the use of other long-acting injectable antipsychotics.

CLINICAL STUDIES

Alphs et al, (2011)¹ evaluated the incidence of PDSS with INVEGA SUSTENNA and risperidone long-acting injection. Data from 10 completed clinical trials (a total of 3,817 patients and 33,906 injections) were used in the INVEGA SUSTENNA analysis.

The investigators created an algorithm to identify PDSS according to the approximated methods and terms used in reports of PDSS with another long-acting injectable antipsychotic.

• Step 1: The algorithm first identified patients who experienced sedation/somnolence events (SSE) of interest (sedation, somnolence, hypersomnia, lethargy, narcolepsy, or sudden onset of sleep at any time).
• Step 2: The search was then limited to those patients who experienced ≥1 severe SSE within one day of receiving injections.
• Step 3: Next, the search was further limited to those patients who also experienced ≥1 excessive SSE within one day of the injection linked to the severe SSE. The following were considered to be excessive SSEs: cataplexy, coma, fluctuating consciousness, depressed level of consciousness, loss of consciousness, sopor, stupor, unresponsiveness to stimuli, any preferred term under the MedDRA term seizures, any term within the standardized MedDRA query (SMQ) of extrapyramidal syndrome, gait disturbance, gait deviation, parkinsonian gait, tachycardia, sinus tachycardia, hypotension, orthostatic hypotension, diastolic hypotension, or any term within the SMQ of torsades de pointes.
• Step 4: Finally, a manual review of the cases identified from the algorithm was conducted.

This review was limited to those patients who were hospitalized or in whom hospitalization was prolonged due to the sedation/somnolence event.

No cases of PDSS in patients receiving INVEGA SUSTENNA were identified with the algorithm. However, one patient who received placebo in an INVEGA SUSTENNA trial did experience a generalized seizure followed by drowsiness, urinary incontinence, and postictal confusion within hours after receiving a placebo injection and was hospitalized.

Case reports

Eker et al, (2024)⁴ reported on a 48-year-old male patient with a history of manic episodes and diagnosis of bipolar affective disorder (BAD) who was hospitalized after his latest manic episode, during which he was treated with two 234 mg doses of INVEGA SUSTENNA 1 week apart and started on lithium 900 mg/d. Two days after his second injection, he developed trembling, rigidity, weakness, and drowsiness, and was discharged with these symptoms. The patient discontinued the lithium after discharge. In the following days, he developed additional symptoms, including slurred speech and difficulty walking and talking, and these symptoms worsened over time until the patient was unable to eat or walk and was spending the majority of the day asleep or in bed.

His wife brought him to the emergency department 20 days after his prior discharge, where he presented with confusion, disorientation of time and place, sleepiness, slurred speech, bilateral lead pipe rigidity and cogwheel phenomenon. Neuroleptic malignant syndrome was ruled out for lack of fever and absence of leukocytosis. Patient was admitted to the neurology department after 3 days, where a nasogastric tube was inserted for feeding and biperiden (4mg/d) and supportive treatment were initiated due to rigidity. The results of contrast-enhanced cranial magnetic resonance imaging, electroencephalography, and cerebrospinal fluid sampling with lumbar puncture were evaluated within normal limits, and no neurological disorder causing delirium was found. As a result, PDSS was considered. The patient’s sedation, delirium, and rigidity gradually improved with treatment. Once he resumed oral intake, diazepam 5 mg/day was added to his treatment and he was transferred to the psychiatry department. Biperiden was initially increased to 6 mg/day and diazepam was increased to 10 mg/day. As the patient continued to improve, diazepam was tapered and discontinued, and the biperiden dose was reduced prior to discharge.

INVEGA SUSTENNA is not indicated for use in BAD and the second initiation dose used in this case was higher than what is directed in the prescribing information (234 mg/234 mg vs 234 mg/156 mg per label). While PDSS has been reported to occur within a few hours after an olanzapine injection, cases have been reported up to 12 hours later.  

Held et al, (2019)⁵ reported on a 63-year-old male who was hospitalized with disorganization, mania and delusions due to decompensated schizoaffective disorder. Prior to admission he was treated with carbamazepine 200 mg twice daily and quetiapine 50 mg at bedtime. Patient reported having been previously stabilized on INVEGA SUSTENNA at the 234 mg dose, but his last documented injection was approximately 6 months earlier and the patient denied receiving subsequent injections.

Carbamazepine and quetiapine were discontinued and the patient was treated for 3 days with oral paliperidone before being administered INVEGA SUSTENNA 234 mg in the left deltoid muscle. The patient began experiencing waxing and waning sedation and difficulty speaking within 75 minutes of the injection. Four hours after the injection, the patient became unresponsive with brief eye opening upon sternal rub. Patient was transferred to internal medicine and medical causes for the change in mental status were ruled out. Without intervention, the patient’s level of mental alertness improved over 24 hours and he was transferred back to psychiatry where he was stabilized on oral haloperidol and discharged.

Based on the patient’s prior tolerability of INVEGA SUSTENNA, the PDSS observed was hypothesized to have resulted from inadvertent intravascular administration.  

Mirza et al, (2018)⁶ reported on a 16-year-old male with a history of low mood, anxiety, paranoia, and social isolation who was referred to the Child & Adolescent Mental Health Services of the South London & Maudsley National Health Service Foundation Trust for worsening psychotic symptoms, specifically paranoid ideation.

After poor compliance with oral olanzapine, the patient was transitioned LAI olanzapine 300 mg every 2 weeks, but this was discontinued due to lack of observation and transport services. Oral risperidone was prescribed for two months, after which LAI risperidone was commenced and titrated to 50 mg every 2 weeks. The patient remained poorly complaint (refusing injections and not attending injection appointments) and was restarted on oral risperidone for 1 month prior to initiating INVEGA SUSTENNA (off-label because of the patients age) with the standard initiation regimen (234 mg on day 1; 156 mg on day 8).

The patient experienced a positive initial response, but 10 days after the second initiation dose developed acute onset altered sensorium and was admitted to the hospital. The patient reported unusual perceptual experiences and insomnia and was observed to have fluctuating levels of consciousness, disordered speech and flailing movements of his extremities. Neurological impairment was minor and there was no evidence of neuroleptic malignant syndrome. After regaining full consciousness, patient was discharged against medical advice to the care of his mother. Further treatment with zuclopenthixol decanoate injections, initially at 100 mg and titrated to 200 mg monthly, resulted in significant improvement in psychotic symptoms without reporting any serious side-effects. After 3 months of treatment, the patient remained stable and eventually returned to premorbid functioning.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 09 May 2024.

If you would like information about INVEGA SUSTENNA, INVEGA TRINZA or INVEGA HAFYERA and a particular symptom associated with PDSS, please call the Medical Information Center at 1-800-JANSSEN (1-800-526-7736).