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Adverse Event - INVEGA HAFYERA and Movement Disorders

Last Updated: 05/26/2024

Summary

  • A phase 3, 12-month, randomized, double-blind (DB), active-controlled, parallel-group, non-inferiority trial was conducted to evaluate the efficacy and safety of INVEGA HAFYERA (N=478) relative to INVEGA TRINZA® (N=224) in delaying time to first relapse in adults with schizophrenia who were previously stabilized on corresponding doses of INVEGA SUSTENNA® or INVEGA TRINZA.1
    • Akathisia, dyskinesia, dystonia, parkinsonism, and tremor were reported in 3.6%, 1.7%, 1.0%, 5.0%, 0.2% of patients in the INVEGA HAFYERA group, respectively, and 3.6%, 0.9%, 0.9%, 3.6%, 0% of patients in the INVEGA TRINZA group, respectively.2
    • In a post hoc subgroup analysis of patients enrolled in European investigational sites, akathisia, parkinsonism, and dyskinesia were reported in 3 (2.4%), 1 (0.8%), and zero patients, respectively, in the INVEGA TRINZA group, and 8 (3.1%), 4 (1.5%), and 4 (1.5%) patients, respectively, in the INVEGA HAFYERA group, during the DB phase.3
    • In another post hoc subgroup analysis of the Asian population, parkinsonism and akathisia were reported in 1 (3.6%) and 3 (10.7%) patients in the INVEGA TRINZA group, respectively, and 6 (9.7%) and 2 (3.2%) patients in the INVEGA HAFYERA group, respectively, during the DB phase.4
  • In a 2-year, single-arm, open-label extension (OLE) of the phase 3, DB, noninferiority study, tremor was reported in 3 (1.7%) patients on INVEGA HAFYERA.5
  • Tardive dyskinesia (TD), a syndrome of potentially irreversible, involuntary, dyskinetic movements, is associated with treatment involving several medication classes, including antipsychotic drugs.6
    • TD can develop after short-term or long-term use of medications as well as after reduction or discontinuation of medications.6
    • Although it is impossible to predict which patients will develop TD, risk factors include the use of typical and atypical antipsychotic drugs, the elderly (especially post-menopausal women), previous brain injury or dementia, early extrapyramidal symptoms (EPS), and African American race.6 Therefore, in patients who require chronic treatment with an antipsychotic drug, the lowest dose necessary for response should be used. It may be helpful to periodically reassess the need for continued treatment.
  • If signs and symptoms of TD appear in a patient treated with INVEGA HAFYERA, drug discontinuation should be considered. The need for continued treatment should be reassessed periodically. Consideration should also be given to the long-acting nature of INVEGA HAFYERA.7

DOSAGE STRENGTH INFORMATION

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

  • INVEGA SUSTENNA doses expressed as 39, 78, 117, 156, and 234 mg of paliperidone palmitate are equal to 25, 50, 75, 100, and 150 mg eq. of paliperidone, respectively.
  • INVEGA TRINZA doses expressed as 273, 410, 546, and 819 mg of paliperidone palmitate are equal to 175, 263, 350, and 525 mg eq. of paliperidone, respectively.
  • INVEGA HAFYERA doses expressed as 1,092 or 1,560 mg of paliperidone palmitate are equal to 700 and 1,000 mg eq. of paliperidone, respectively.

CLINICAL Data

Noninferiority Trial1

  • A phase 3, randomized, DB, active-controlled, parallel-group, multicenter, non-inferiority trial was conducted to evaluate the efficacy and safety of INVEGA HAFYERA relative to INVEGA TRINZA on time to first relapse in adults with schizophrenia who were previously stabilized on corresponding doses of INVEGA SUSTENNA or INVEGA TRINZA. See Figure: Study Design1,2,8

Study Design1,2,8

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Abbreviations: CGI-S, Clinical Global Impression-Severity; D, deltoid; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, fifth edition; G, gluteal; NMS, neuroleptic malignant syndrome; PANSS, Positive and Negative Syndrome Scale; PP1M, paliperidone palmitate 1-month; PP3M, paliperidone palmitate 3-month; PP6M, paliperidone palmitate 6-month; PSP, Personal and Social Performance; R, randomization; TD, tardive dyskinesia.
aPatients had to be on the same dosage strength and frequency for 3 injection cycles before screening.
bPatients received doses of PP6M on day 1 in the left gluteal muscle and on day 183 in the right gluteal muscle, while receiving a placebo on day 92 in the right gluteal muscle and on day 274 in the left gluteal muscle.
cThe dose level and number of injections depend on the previous treatment and individual efficacy and tolerability results.
dOpen-label transition and maintenance, n=838.
eDose matched by straightforward progression or established conversion, per the dose received during screening or transition, as applicable.
fTotal PANSS score was required to be <70 to enter the double-blind treatment period. Randomization occurred on the day of first double-blind injection, 1 and 3 months after the maintenance injection of PP1M and PP3M, respectively.
gAfter randomization, for 2 consecutive assessments separated by 3-7 days.

Results

The mean duration of exposure during the DB phase was 329.8 days at a mean dose of 1,335 mg and 336.4 days at a mean dose of 690 mg for INVEGA HAFYERA and INVEGA TRINZA, respectively.1 The incidence of EPS-related treatment-emergent adverse events (TEAEs) was similar for patients treated with moderate or high doses of INVEGA HAFYERA (1,092 mg: 9.3% and 1,560 mg: 10.0%) as determined by dose level at the end of the maintenance phase.

During the DB phase the overall frequency of EPS-related TEAEs was similar for INVEGA HAFYERA and INVEGA TRINZA (9.6% and 8.5%, respectively) with the most common events in both treatment groups being categorized under parkinsonism (INVEGA HAFYERA: 5.0%; INVEGA TRINZA: 3.6%) and akathisia (INVEGA HAFYERA: 3.6%; INVEGA TRINZA: 3.6%).9 See Table: Movement-Related Treatment-Emergent Adverse Reactions

None of the EPS-related TEAEs were serious. During the DB phase, 1 case of treatment-emergent parkinsonism in the INVEGA HAFYERA group (0.2%) led to study drug discontinuation. One TEAE of tardive dyskinesia was reported in the INVEGA HAFYERA group (0.2%) in the DB phase; this event was not serious, nor did it lead to study drug discontinuation.9


Movement-Related Treatment-Emergent Adverse Reactions2
Open-Label
Double-Blind
INVEGA SUSTENNA
INVEGA TRINZA
(N=838)
n (%)
INVEGA TRINZA
(N=224)
n (%)
INVEGA HAFYERA
(N=478)
n (%)
Hyperkinesiaa
25 (3.0)
8 (3.6)
17 (3.6)
Dyskinesiab
11 (1.3)
2 (0.9)
8 (1.7
Dystoniac
3 (0.4)
2 (0.9)
5 (1.0)
Parkinsonismd
28 (3.3)
8 (3.6)
24 (5.0)
Tremor
2 (0.2)
0
1 (0.2)
aHyperkinesia includes akathisia, restless legs syndrome, and restlessness.
bDyskinesia includes muscle twitching and tardive dyskinesia.
cDystonia includes muscle spasms, oculogyric crisis, and blepharospasm.
dParkinsonism includes bradykinesia, drooling, hypokinesia, muscle rigidity, musculoskeletal stiffness, parkinsonism, parkinsonian rest tremor, and reduced facial expression.

EPS Based on Use of Anticholinergic Medication and Rating Scales

During the DB phase, both INVEGA TRINZA and INVEGA HAFYERA had similar rates of treatment-emergent EPS symptoms assessed by use of anticholinergic medication (INVEGA HAFYERA: 15.5%; INVEGA TRINZA: 12.9%) and rating scales.1 See Table: EPS Assessed by Use of Anticholinergic Medication and Rating Scale Incidence During the DB Phase


EPS Assessed by Use of Anticholinergic Medication and Rating Scale Incidence During the DB Phase2
 
INVEGA TRINZA (%)
N=224
INVEGA HAFYERA (%)
N=478
Use of Anticholinergic Medications
12.9
15.5
Parkinsonismb
6.3
6.5
Akathisiac
2.7
2.9
Dyskinesiad
1.3
1.0
aUse of Anti-EPS Medication During the Double-blind Phase.
bPercent of patients with Simpson-Angus Scale (SAS) Global Score >0.3 (Global Score defined as total sum of items score divided by the number of items).
cPercent of patients with Barnes Akathisia Rating Scale (BARS) Global Clinical Rating Score ≥2.
dPercent of patients with a score ≥3 on any of the first 7 items or a score ≥2 on 2 or more of any of the first 7 items of the Abnormal Involuntary Movement Scale (AIMS).

Regardless of treatment assignment, global clinical scores on the Barnes Akathisia Rating Scale (BARS), Simpson-Angus Scale (SAS), and total Abnormal Involuntary Movement Scale (AIMS) scores showed no clinically meaningful change from DB baseline to endpoint. Based on BARS global clinical rating scores, akathisia was rated as absent at DB endpoint in 95% and 96% of patients in the INVEGA HAFYERA and INVEGA TRINZA groups, respectively. No patient had marked or severe akathisia based on BARS scores during the DB phase.1 See Table: Changes in EPS Scales from DB Baseline to Endpoint, Safety Analysis Set


Changes in EPS Scales from DB Baseline to Endpoint, Safety Analysis Set1

N
INVEGA TRINZA
N
INVEGA HAFYERA
AIMS Total Score
   Median (Range) Change from Baseline
221
0.0 (-3;2)
477
0.0 (-7;14)
BARS Global Clinical Rating of Akathisia (DB Baseline), n (%)
   Absent
224
218 (97.3)
478
453 (94.8)
   Questionable
224
6 (2.7)
478
16 (3.3)
   Mild Akathisia
224
0 (0.0)
478
9 (1.9)
   Moderate Akathisia
224
0 (0.0)
478
0 (0.0)
   Marked Akathisia
224
0 (0.0)
478
0 (0.0)
   Severe Akathisia
224
0 0(.0)
478
0 (0.0)
BARS Global Clinical Rating of Akathisia (DB Endpoint), n (%)
   Absent
221
212 (95.9)
477
451 (94.5)
   Questionable
221
7 (3.2)
477
19 (4.0)
   Mild Akathisia
221
2 (0.9)
477
6 (1.3)
   Moderate Akathisia
221
0 (0.0)
477
1 (0.2)
   Marked Akathisia
221
0 (0.0)
477
0 (0.0)
   Severe Akathisia
221
0 (0.0)
477
0 (0.0)
SAS Global Score
   Mean (Range) Change from Baseline
220
0.0 (-1;2)
477
0.0 (-1;2)
Key: AIMS: Abnormal Involuntary Movement Scale; BARS: Barnes Akathisia Rating Scale; SAS: Simpson-Angus Scale.

Post Hoc Subgroup Analyses of the DB Phase of the Noninferiority Study

Giron-Hernandez et al (2023)3 reported the results of a post hoc subgroup analysis of the noninferiority study that evaluated 384 patients with schizophrenia who were enrolled in European investigational sites and received INVEGA TRINZA (n=124) or INVEGA HAFYERA (n=260). In the DB phase, akathisia, parkinsonism, and dyskinesia were reported in 3 (2.4%), 1 (0.8%), and zero patients, respectively, in the INVEGA TRINZA group, and 8 (3.1%), 4 (1.5%), and 4 (1.5%) patients, respectively, in the INVEGA HAFYERA group.

Richarz et al (2023)4 reported the results of a post hoc analysis of the Asian subgroup enrolled in the noninferiority study. Ninety patients were evaluated in this subgroup (INVEGA TRINZA, n=28; INVEGA HAFYERA, n=62). In the DB phase, parkinsonism and akathisia were reported in 1 (3.6%) and 3 (10.7%) patients in the INVEGA TRINZA group, respectively, and 6 (9.7%) and 2 (3.2%) patients in the INVEGA HAFYERA group, respectively.

OLE Phase of the Noninferiority Study

Najarian et al (2023)5 conducted a 2-year, single-arm, OLE study to evaluate the long-term safety, efficacy, and tolerability of INVEGA HAFYERA in 178 patients who remained relapse-free in the DB study and elected to continue treatment with INVEGA HAFYERA in the OLE phase. Data was reported separately for patients who were treated with either INVEGA TRINZA (n=57) or INVEGA HAFYERA (n=121) in the DB phase before transitioning to INVEGA HAFYERA in the OLE phase. Tremor was reported in 1.7% (3/178) of the patients on INVEGA HAFYERA during the OLE phase.

LITERATURE SEARCH

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 25 April 2024.

References

1 Najarian D, Sanga P, Wang S, et al. A randomized, double-blind, multicenter, noninferiority study comparing paliperidone palmitate 6-month versus the 3-month long-acting injectable in patients with schizophrenia. Int J Neuropsychopharmacol. 2022;25(3):238-251.  
2 Data on File. A double-blind, randomized, active-controlled, parallel-group study of paliperidone palmitate 6-month formulation, Version 003. Janssen Research & Development, LLC; Paliperidone Palmitate CSR; EDMS-ERI-204509811; 2020.  
3 Giron‐Hernandez C, Han JH, Alberio R, et al. Efficacy and safety of paliperidone palmitate 6-month versus paliperidone palmitate 3-month long-acting injectable in European patients with schizophrenia: a post hoc analysis of a global phase-3 double-blind randomized non-inferiority study. Neuropsychiatr Dis Treat. 2023;19:895-906.  
4 Richarz U, Han J, Bai YM, et al. Efficacy and safety of paliperidone palmitate 6-monthly long-acting injectable in reduction of relapses in patients with schizophrenia: an Asian subgroup analysis of phase 3, randomized study. Medicine. 2023;102(34):e34623.  
5 Najarian D, Turkoz I, Knight R, et al. Long-term efficacy and safety of paliperidone 6-month formulation: an open-label 2-year extension of a 1-year double-blind study in adult participants with schizophrenia. Int J Neuropsychopharmacol. 2023;26:(8):537-544.  
6 Cornett E, Novitch M, Kaye A, et al. Medication-induced tardive dyskinesia: a review and update. Ochsner J. 2017;17(2):162-174.  
7 Data on File. Company Core Data Sheet - Paliperidone palmitate 6-month injection. Version 003. Janssen Research & Development, LLC. EDMS-RIM-137311; 2022.  
8 Data on File. Protocol R092670PSY3015. Version 005. Janssen Research & Development, LLC. EDMS-ERI-130495167; 2019.  
9 Data on File. Clinical Overview, Paliperidone Palmitate 6-month injection. Janssen Research & Development, LLC; EDMS-RIM-54909; 2020.