Summary

• 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 this class have been shown to produce some metabolic changes, each drug has its own specific risk profile.¹
• Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. Hyperglycemia or diabetes have been reported in trial subjects treated with INVEGA TRINZA.¹
• Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.¹
• In the double-blind (DB) phase of a long-term maintenance trial², the change in fasting serum glucose relative to DB baseline in patients receiving INVEGA TRINZA was 1.2 mg/dL compared to -1.6 mg/dL in patients receiving placebo (PBO).
• In a DB, noninferiority study, the change in fasting glucose was -0.004 mmol/L for INVEGA TRINZA and 0.086 mmol/L for INVEGA SUSTENNA from DB baseline to endpoint.³
• A phase 3, randomized, DB, active-controlled, parallel-group, multicenter, noninferiority trial evaluated the efficacy and safety of INVEGA HAFYERA relative to INVEGA TRINZA in adults with schizophrenia. During the DB phase, treatment-emergent adverse event (TEAE) of diabetes mellitus or hyperglycemia was reported by 15 (3.1%) patients in the INVEGA HAFYERA group and 6 (2.7%) patients in the INVEGA TRINZA group.⁴
• A real-world, retrospective study examining data from the EUDRAVigilance database reported hyperglycemia-related adverse drug reactions (ADRs) in patients treated with INVEGA TRINZA. The number of cases of hyperglycemia/new onset diabetes mellitus was reported for the combined INVEGA SUSTENNA and INVEGA TRINZA group (n=115/8,056 of Individual Case Safety Reports [ICSRs]).⁵

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate can be expressed in milligram equivalents (mg eq) 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 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 and 1,560 mg of paliperidone palmitate are equal to 700 and 1,000 mg eq of paliperidone, respectively.

PRODUCT LABELING

Please refer to the following sections of the Full Prescribing Information,¹ which are relevant to your inquiry: WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

BACKGROUND

The use of second-generation antipsychotics has been associated with weight gain and metabolic abnormalities, including diabetes and reports of acute metabolic decompensation (e.g., diabetic ketoacidosis).⁶ Metabolic abnormalities such as diabetes observed in these patients may result in increased cardiovascular risk. Because there are limited data in drug-naïve patients, it is unclear whether these metabolic abnormalities are due to the drug treatment or to the psychiatric disease itself. The prevalence of diabetes in patients with schizophrenia has been estimated to be approximately 1.5- to 2-fold higher than the prevalence in the general population; however, lifestyle changes such as sedentary behavior may contribute to the higher prevalence of metabolic abnormalities. Changes in body composition and weight gain may be contributing factors to metabolic abnormalities such as insulin resistance, prediabetes, and diabetes. Another possible mechanism for drug-associated hyperglycemia may be associated with direct effects on insulin-sensitive tissue targets. Treatment selection must be individualized on the basis of specific patient risk factors to ensure the benefits outweigh the risks. Consensus panel guidelines recommend that fasting plasma glucose be monitored at baseline, 3 months posttreatment, and every year thereafter (if glucose levels are normal) or more often if clinically indicated (high risk for diabetes or rapid weight gain).^6,7 Hemoglobin A_1C may be an acceptable alternative if fasting blood glucose is not attainable.⁷ Glucose values indicative of diabetes are ≥126 mg/dL (fasting blood glucose), >200 mg/dL (random blood glucose), or hemoglobin A_1C >6.1%; any of these values should prompt follow-up with a primary health care provider or internist. Immediate care is recommended for patients with symptomatic or severe hyperglycemia (glucose level ≥300 mg/dL) or symptomatic hypoglycemia or for patients with glucose readings ≤60 mg/dL, regardless of symptom status.⁶

SCHIZOPHRENIA CLINICAL STUDIES

Pivotal Trial

Berwaerts et al (2015)^1,2 conducted a DB, PBO-controlled, relapse-prevention study to evaluate the efficacy and safety of INVEGA TRINZA in delaying time to relapse of schizophrenia symptoms in patients previously treated with INVEGA SUSTENNA for at least 4 months.

Study Design/Methods

The study included 4 phases: a screening and oral tolerability testing phase of up to 3 weeks, a 17-week open-label (OL) transition phase, a 12-week OL maintenance phase, and a DB phase of variable length. During the transition phase, all patients except those who were receiving other long-acting injectable antipsychotics or those who were receiving INVEGA SUSTENNA before entering the study received 4 months of INVEGA SUSTENNA treatment. Dosing included the following: day 1: INVEGA SUSTENNA 234 mg (deltoid intramuscular [IM] administration); day 8: INVEGA SUSTENNA 156 mg (deltoid IM administration); days 36 and 64: INVEGA SUSTENNA 78, 117, 156, or 234 mg flexible doses (deltoid IM or gluteal IM administration); and day 92: the same dose of INVEGA SUSTENNA as was administered on day 64. During the maintenance phase, patients received a single dose of INVEGA TRINZA (273, 410, 546, or 819 mg; a 3.5-fold multiple of the final INVEGA SUSTENNA dose administered on day 92) in either the deltoid or gluteal muscle. During the DB phase, stabilized patients were randomized 1:1 to receive a fixed dose of INVEGA TRINZA (the same dose as during the maintenance phase) or PBO. In addition to efficacy, safety and laboratory parameters were measured.

Results

During the OL maintenance phase, 1 (0.3%) patient experienced a hyperglycemia-related TEAE of type 2 diabetes mellitus. During the DB phase, a higher percentage of PBO-treated patients (8 of 145 [6%]) vs INVEGA TRINZA-treated patients (4 of 160 [3%]) experienced glucose-related TEAEs. These included increase in blood glucose (2% [3/145] vs 2% [3/160]) and hyperglycemia (3% [4/145] vs 0% [0/160]), respectively.²

Noninferiority Trial

Savitz et al (2016)³ conducted a randomized, DB, parallel-group, multicenter, noninferiority study of INVEGA TRINZA and INVEGA SUSTENNA. The primary endpoint was the percentage of patients who remained relapse-free at the end of the 48-week DB phase.

Study Design/Methods

The study consisted of 4 phases: a 3-week screening phase, a 17-week, OL stabilization phase, a 48-week DB phase, and a follow-up phase.

The study included patients between the ages of 18-70 years with a Positive and Negative Syndrome Scale (PANSS) score between 70-120 who had worsening schizophrenia symptoms and discontinued other antipsychotics due to insufficient efficacy, safety or tolerability issues with current treatment, or those with a preference for injectable medications.

During the OL phase, 1,429 patients received INVEGA SUSTENNA in the following doses:

• Day 1: 234 mg (deltoid administration)
• Day 8: 156 mg (deltoid administration)
• Weeks 5 and 9: flexible dosing between 78-234 mg (deltoid or gluteal administration). The week 13 dose was the same as week 9

Based on predefined criteria, patients who were clinically stable after completing the OL phase were randomized (1:1) into the DB phase. Patients in the DB phase received fixed doses of INVEGA SUSTENNA (78, 117, 156, or 234 mg; n=512) or INVEGA TRINZA (273, 410, 546, or 819 mg; n=504) in the deltoid or gluteal muscle. In the INVEGA SUSTENNA group, injections occurred every 4 weeks, and in the INVEGA TRINZA group, active drug was administered every 3 months along with PBO injections given monthly when active therapy was not administered.

Results

The mean duration of exposure was 295.1 days for INVEGA TRINZA at a mean dose of 647.01 mg and 286.7 days for INVEGA SUSTENNA at a mean dose of 185.8 mg. A lower frequency of diabetes mellitus and hyperglycemia-related TEAEs was reported in the INVEGA TRINZA group (2.6%) vs INVEGA SUSTENNA group (4.9%). From DB baseline to endpoint, the change in insulin and fasting glucose was 1.1 pmol/L and -0.004 mmol/L, respectively, for INVEGA TRINZA and 6.9 pmol/L and 0.086 mmol/L, respectively, for INVEGA SUSTENNA.

Najarian et al (2022)⁴ conducted a phase 3, randomized, DB, active-controlled, parallelgroup, multicenter, noninferiority trial 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.

Study Design/Methods

The study consisted of 3 phases as follows: a 28-day screening phase, a 1- to 3-month OL maintenance phase (depending upon treatment received, INVEGA SUSTENNA or INVEGA TRINZA), and a 12-month DB phase.

The study included patients aged 18-70 years with a Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) diagnosis of schizophrenia for ≥6 months before screening, and PANSS total score of <70 points at the time of screening.

Patients received 1 dose of either INVEGA SUSTENNA or INVEGA TRINZA during the OL maintenance phase. During the DB phase, patients were randomized (2:1) to receive equivalent doses of INVEGA HAFYERA or INVEGA TRINZA.

• Patients who received INVEGA SUSTENNA 156 or 234 mg during the OL phase were assigned to receive INVEGA TRINZA 546 or 819 mg during the DB phase, respectively, and those who received INVEGA TRINZA 546 or 819 mg during the OL phase continued at same doses during the DB phase.
• Patients who received INVEGA SUSTENNA 156 mg or INVEGA TRINZA 546 mg during the OL phase were assigned to receive INVEGA HAFYERA 1,092 mg during the DB phase, and those who received INVEGA SUSTENNA 234 mg or INVEGA TRINZA 819 mg during the OL phase were assigned to receive INVEGA HAFYERA 1,560 mg during the DB phase.

Results

Overall, 838 patients were enrolled in the study, and 702 patients who completed the OL phase were further randomized to the DB phase (INVEGA HAFYERA, n=478; INVEGA TRINZA, n=224). In the DB phase, TEAE of diabetes mellitus or hyperglycemia was reported by 15 (3.1%) patients in the INVEGA HAFYERA group and 6 (2.7%) patients in the INVEGA TRINZA group.

Real-world Study

Cicala et al (2023)⁵ conducted a real-world, retrospective study by analyzing ICSR data reported in the EUDRAVigilance database between 2011 and 2022 for the use of INVEGA SUSTENNA and INVEGA TRINZA.

A total of 8,152 ICSRs for INVEGA SUSTENNA and INVEGA TRINZA were reported out of 20,226 second generation antipsychotic long-acting injectable cases examined. There were 115 (out of 8,056) cases of hyperglycemia/new onset diabetes mellitus (95% CI: 0.340.51; reporting odds ratio, 0.42).

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 23 October 2024.