Paliperidone and paliperidone palmitate are atypical antipsychotic agents.1, 58, 59, 60, 61
Paliperidone extended release tablets (Invega®) are used for the treatment of schizophrenia in adults and adolescents 12-17 years of age and treatment of schizoaffective disorder as monotherapy or as an adjunct to mood stabilizers and/or antidepressants in adults.1
Paliperidone palmitate extended-release injectable IM suspension formulations (Invega Sustenna®; Erzofri®) are used for the treatment of schizophrenia in adults and for the treatment of schizoaffective disorder as monotherapy or as an adjunct to mood stabilizers or antidepressants in adults.58, 59
Paliperidone palmitate extended-release injectable IM suspension (Invega Trinza®) is used for the treatment of schizophrenia in patients following adequate initial treatment with Invega Sustenna® for at least 4 months.60
Paliperidone palmitate extended-release injectable IM suspension (Invega Hafyera®) is used for the treatment of schizophrenia in patients following adequate initial treatment with Invega Sustenna® for at least 4 months or Invega Trinza® for at least one 3-month cycle.61
Oral paliperidone and injectable paliperidone palmitate are used for the treatment of schizophrenia.1, 58, 59, 60, 61
The short-term efficacy of oral paliperidone extended-release tablets in the acute treatment of schizophrenia in adults was established in 3 placebo-controlled and active comparator (olanzapine)-controlled, fixed-dose clinical trials of 6 weeks' duration; these trials were conducted in 1665 adult patients with schizophrenia.1, 3, 6, 7, 8 In these 3 studies, patients receiving paliperidone (3-15 mg daily as extended-release tablets) demonstrated substantially greater improvement in the Positive and Negative Syndrome Scale (PANSS) than did patients receiving placebo.1, 3, 6, 7, 8 The mean effects at all dosages (3, 6, 9, 12, and 15 mg daily) were fairly similar, although higher dosages produced numerically superior results.1, 3, 6, 7, 8 Paliperidone also was found to be superior to placebo in improving scores on the Personal and Social Performance (PSP) scale in these trials.1, 3, 6, 7
In a longer-term study, adult outpatients with schizophrenia who had clinically responded to oral paliperidone and who had received a stable fixed dosage of paliperidone extended-release tablets for 2 weeks entered a 6-week, open-label, stabilization phase where they received a paliperidone dosage from 3-15 mg once daily as extended-release tablets.1, 4 After the stabilization phase, patients were randomized in a double-blind manner to either continue receiving paliperidone at their stable dosage or to receive placebo until they experienced a relapse of schizophrenia symptoms.1, 4 The median treatment exposure during this double-blind phase was 45 days for extended-release paliperidone and 29 days for placebo; the mean paliperidone dosage was approximately 11 mg daily throughout the phases of this trial.4 An interim analysis of the data showed a significantly longer time to relapse in the paliperidone-treated patients compared with those receiving placebo.1, 4 In addition, 25% of the paliperidone-treated patients experienced a relapse of schizophrenia symptoms compared with 53% of those receiving placebo.4 The study was stopped early because maintenance of efficacy was demonstrated.1, 4
The short-term efficacy of the once-monthly extended-release IM formulation of paliperidone palmitate (Invega Sustenna®) for the treatment of schizophrenia was established in 4 short-term (one 9-week and three 13-week) placebo-controlled, fixed-dose studies in acutely relapsed adult inpatients meeting Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for schizophrenia.58 Paliperidone palmitate extended-release injectable IM suspension was administered at fixed doses on days 1, 8, and 36 in the 9-week study, with an additional dose on day 64 in the 13-week studies.58, 62 The initial 2 doses were given one week apart, followed by maintenance dosing every 4 weeks.58 Efficacy was assessed using mean change in PANSS total score from baseline.58 Across the studies, paliperidone palmitate extended-release IM suspension demonstrated improved PANSS total scores compared to placebo.58 In Study 1 (PSY-3007), all 3 fixed doses (39 mg, 156 mg, and 234 mg every 4 weeks) were substantially more effective than placebo.58, 62 Similarly, in Study 3 (PSY-3004), all 3 doses (39 mg, 78 mg, and 156 mg every 4 weeks) showed superiority over placebo.58, 63 In Study 2 (PSY-3003), only the 156-mg dose demonstrated an improvement compared to placebo.58 In Study 4 (SCH-201), both tested doses (78 mg and 156 mg every 4 weeks) were superior to placebo in improving schizophrenia symptoms.58, 64
A longer-term maintenance study evaluated the once-monthly extended-release IM formulation of paliperidone palmitate (Invega Sustenna®) in adults meeting DSM-IV criteria for schizophrenia.58, 65 This trial included a minimum 12-week fixed-dose stabilization phase, followed by a 12-week randomized, placebo-controlled phase to assess relapse prevention.58, 65 A total of 410 stabilized patients were randomized to continue their stabilization dose of paliperidone palmitate extended-release IM injection (39 mg, 78 mg, or 156 mg every 4 weeks) or switch to placebo until relapse occurred.58, 65 Relapse was predefined based on criteria such as psychiatric hospitalization, a significant increase in PANSS total score, deliberate self-injury, violent behavior, suicidal/homicidal ideation, or worsening of specific PANSS items.58, 65 The primary efficacy endpoint was time-to-first relapse.58, 65 A pre-planned interim analysis showed a substantial delay in relapse for patients receiving paliperidone palmitate extended-release IM injection compared to placebo, leading to early termination of the study due to demonstrated maintenance of efficacy.58, 65
The long-term efficacy of the once-monthly extended-release IM formulation of paliperidone palmitate (Invega Sustenna®) in delaying treatment failure compared to commonly prescribed oral antipsychotics was evaluated in a 15-month, randomized, flexible-dose study involving adults with schizophrenia and a history of incarceration.58, 66 A total of 444 patients were randomized to either paliperidone palmitate extended-release IM suspension (recommended target dose of 156 mg) or 1 of 7 commonly used oral antipsychotic medications (aripiprazole, haloperidol, olanzapine, paliperidone, perphenazine, quetiapine, or risperidone) selected at the investigator's discretion.58, 66 The primary endpoint was time to first treatment failure, defined as events such as arrest/incarceration, psychiatric hospitalization, discontinuation due to safety or tolerability concerns, use of additional antipsychotic treatment due to inadequate efficacy, increased psychiatric services to prevent hospitalization, discontinuation due to inefficacy, or suicide.58, 66 Paliperidone palmitate extended-release IM suspension substantially prolonged the time to first treatment failure compared to oral antipsychotics, with a median time of 416 versus 226 days, respectively.58, 66
Efficacy of the once-monthly extended-release IM formulation of paliperidone palmitate (Erzofri®) for schizophrenia was established based on the results of the studies with the once-monthly IM formulation (Invega Sustenna®).59
Efficacy of the extended-release IM formulation of paliperidone palmitate administered once every 3 months (Invega Trinza®) was established in a placebo-controlled study involving adults stabilized on Invega Sustenna® for at least 4 months.60, 67 The study assessed time to relapse and included 3 treatment phases.60, 67 In the first phase, 506 patients entered a 17-week, open-label, stabilization period with flexible dosing of Invega Sustenna®, adjusted based on symptom response and tolerability.60, 67 To proceed to the next phase, patients had to achieve clinical stability, defined as a PANSS total score of less than 70.60, 67 In the second phase, 379 clinically stable patients received a single dose of Invega Trinza®, calculated as 3.5 times their last Invega Sustenna® dose.60, 67 Patients were monitored for an additional 12 weeks and had to remain clinically stable before entering the double-blind phase.60, 67 In the final phase, 305 stabilized patients were randomized to continue Invega Trinza® (273 mg, 410 mg, 546 mg, or 819 mg every 12 weeks) or switch to placebo.60, 67 The primary endpoint was time-to-first relapse, defined by psychiatric hospitalization, worsening PANSS scores, self-injury, violent behavior, or suicidal/homicidal ideation.60, 67 A pre-planned interim analysis demonstrated a substantial delay in relapse for patients treated with Invega Trinza® compared to placebo; overall, 7% of patients in the Invega Trinza® group experienced a relapse event compared to 23% in the placebo group.60, 67 These results led to early study termination.60, 67
Efficacy of the extended-release IM formulation of paliperidone palmitate administered once every 6 months (Invega Hafyera®) was established based on an active-controlled, non-inferiority study in adults meeting DSM-IV criteria for schizophrenia.61, 68 A total of 702 patients were randomized to receive Invega Hafyera® or Invega Trinza®.61, 68 The primary efficacy endpoint was time-to-first relapse, assessed by Kaplan-Meier 12-month estimates of relapse-free survival.61, 68 Relapse was defined as psychiatric hospitalization, a significant increase in PANSS score, self-injury, violent behavior, or suicidal/homicidal ideation.61, 68 Results showed relapse rates of 7.5% in the Invega Hafyera® group and 4.9% in the Invega Trinza® group; the upper bound of the confidence interval of the Kaplan-Meier estimate remained below the predefined non-inferiority margin of 10%, which confirmed Invega Hafyera®'s non-inferiority.61, 68
Short-term efficacy and safety of paliperidone extended-release tablets in the acute treatment of schizophrenia in adolescents 12-17 years of age were established in a double-blind, placebo-controlled trial of 6 weeks' duration in 201 patients who met DSM-IV criteria for schizophrenia.1, 49 The trial used a fixed-dosage, weight-based treatment group design over a dosage range of 1.5-12 mg once daily given as extended-release tablets.1, 49 Patients were randomized to 1 of 4 treatment groups: a placebo group or a low-dosage (1.5 mg daily for all body weights), medium-dosage (3 or 6 mg daily depending on body weight), or high-dosage group (6 or 12 mg daily depending on body weight).1, 49 Efficacy was evaluated using the PANSS.1, 49 The study demonstrated the overall efficacy of paliperidone in adolescents with schizophrenia receiving dosages ranging from 3-12 mg once daily.1, 49 However, no clear improvement in efficacy was observed at the higher dosages studied (i.e., 6 mg daily for adolescents weighing less than 51 kg and 12 mg daily for adolescents weighing 51 kg or more).1, 49 Tolerability was adequate within the 3-12 mg daily dosage ran however, adverse effects were dose-related.1, 49
The American Psychiatric Association (APA) recommends that patients with schizophrenia be treated with an antipsychotic medication.107 The APA states that, with the possible exception of clozapine, there currently is no definitive evidence that one atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients.107 The choice of an antipsychotic agent should be individualized, considering patient preference, past response to therapy, concurrent medical conditions, and medication-specific factors (e.g., adverse effect profile, available formulations, potential drug interactions, receptor binding profiles, pharmacokinetic considerations).107 Patients whose symptoms improve on an antipsychotic medication should continue treatment long-term; in most patients, it is appropriate to continue the same antipsychotic medication rather than switch to another for maintenance therapy.107
Guidelines from the Department of Veterans Affairs and Department of Defense similarly recommend the use of antipsychotic medication for acute and maintenance treatment of schizophrenia.108 Choice of antipsychotic medication should be based on patient-specific factors and the side effect profiles of the different antipsychotic medications.108 Clozapine should generally be reserved for individuals with treatment-resistant schizophrenia.108
A practice parameter from the American Academy of Child and Adolescent Psychiatry (AACAP) recommend antipsychotic medication as a primary treatment for schizophrenia spectrum disorders in children and adolescents.234 The AACAP states that most atypical and typical antipsychotic medications, with the exception of clozapine, can be used as primary treatment in early-onset schizophrenia (i.e., onset of schizophrenia before 18 years of age).234 Depot antipsychotics (i.e., IM formulations) have not been studied in pediatric patients.234 Choice of antipsychotic medication in pediatric patients should be individualized based on FDA-labeling, side effect profiles, patient and family preferences, cost, and clinician familiarity.234
Oral paliperidone and injectable paliperidone palmitate are used for the treatment of schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers and/or antidepressant therapy in adults.1, 58, 59
The short-term efficacy of oral paliperidone extended-release tablets in the treatment of schizoaffective disorder was principally established in 2 international, double-blind, placebo-controlled trials of 6 weeks' duration in nonelderly adults.1, 54, 55, 56 Patients enrolled in these trials met DSM-IV criteria for schizoaffective disorder, a PANSS total score of at least 60, and prominent mood symptoms (confirmed by a score of at least 16 on the Young Mania Rating Scale [YMRS] and/or Hamilton Rating Scale for Depression [HRSD]).1, 54, 55, 56 The patients in these trials included individuals with schizoaffective disorder, bipolar and depressive types.1, 54, 55, 56 In the first trial, efficacy was assessed in 211 patients who received flexible dosages of paliperidone (3-12 mg once daily as extended-release tablets).1, 54, 56 In the second trial, efficacy was assessed in 203 patients who were assigned to one of two different dosages of paliperidone: 6 mg with the option to reduce to 3 mg once daily or 12 mg with the option to reduce to 9 mg once daily.1, 54, 55 In both studies, patients received paliperidone either as monotherapy (55%) or as an adjunct to mood stabilizers and/or antidepressants (45%).1, 54 The most commonly used mood stabilizers in the studies were valproic acid and lithium and the most commonly used antidepressants were selective serotonin-reuptake inhibitors and selective serotonin- and norepinephrine-reuptake inhibitors.1, 54 Efficacy was principally evaluated using the PANSS; as secondary outcomes, mood symptoms were evaluated using the Hamilton Depression Rating Scale (HAM-D-21) and YMRS.1, 54, 55, 56 The paliperidone-treated patients in the flexible-dose study (mean modal dosage of 8.6 mg daily) and the higher dosage group of paliperidone in the 2-dosage-level study were each found to be superior to placebo (as measured by the PANSS).1 The lower dosage group of paliperidone in the 2-dosage-level study (6 mg with option to reduce to 3 mg once daily) was not found to be substantially different from placebo (as measured by the PANSS).1 Improvements in mood symptoms (as measured by the HAM-D-21 and YMRS) also were observed in the studies.1
In an analysis of both placebo-controlled studies in schizoaffective disorder, oral paliperidone improved the symptoms of schizoaffective disorder at the study end points when administered either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants.1 An examination of population subgroups did not reveal evidence of differential responsiveness based on gender, age, or geographic region.1 There were insufficient data to explore differential effects based on race.1
The long-term efficacy of the once-monthly extended-release IM formulation of paliperidone palmitate (Invega Sustenna®) for maintaining symptom control in schizoaffective disorder was established in a placebo-controlled, flexible-dose study.58, 69 Patients who met DSM-IV criteria for schizoaffective disorder, including both bipolar and depressive types, and received IM paliperidone palmitate either as monotherapy or as adjunctive therapy with a stable antidepressant or mood stabilizer were included.58, 69 The study began with a 13-week, open-label, flexible-dose, lead-in phase (doses: 78 mg to 234 mg) enrolling 667 patients with acute psychotic and mood symptoms.58, 69 After achieving clinical stabilization, defined by PANSS total score of ≤70, YMRS of ≤12, and HAM-D-21 of ≤12, 432 patients entered a 12-week, fixed-dose, stabilization phase.58, 69 Of these, 334 patients who maintained stability for 12 consecutive weeks were randomized to continue IM paliperidone palmitate or switch to placebo for a 15-month, double-blind, maintenance phase.58, 69 The primary endpoint was time to relapse, defined by psychiatric hospitalization, worsening of psychotic symptoms, self-injury, or other clinical deterioration.58, 69 Results reported a substantial delay in time to relapse observed in the IM paliperidone palmitate group compared to placebo.58, 69 In the monotherapy group, relapse occurred in 32.9% of placebo-treated patients versus 11.5% of those receiving paliperidone; among patients receiving adjunctive therapy, relapse rates were 34.0% for placebo and 18.6% for IM paliperidone palmitate.58, 69
Efficacy of the once-monthly extended-release IM formulation of paliperidone palmitate (Erzofri®) for schizoaffective disorder was established based on the results of the studies with the once-monthly IM formulation (Invega Sustenna®).59
Schizoaffective disorder is a mental health condition that features a combination of schizophrenia symptoms (such as delusions and hallucinations) and mood disorder symptoms, including depression and mania.70 Due to overlapping features, individuals with schizoaffective disorder are frequently misdiagnosed initially with either schizophrenia or bipolar disorder.70 Since this condition has been less extensively researched compared to those disorders, its treatment strategies are often adapted from established approaches used for bipolar disorder and schizophrenia.70
Effective treatment of schizoaffective disorder focuses on managing both psychotic symptoms and mood disturbances, which may include depressive or bipolar features.70 According to the National Alliance on Mental Illness (NAMI), this dual-focus approach often involves a combination of antipsychotic medications, mood stabilizers, and antidepressants tailored to the individual's symptom profile.70 Oral paliperidone and IM paliperidone palmitate are the only FDA-approved treatments specifically indicated for schizoaffective disorder, either as monotherapy or as adjunctive therapy with mood stabilizers or antidepressants.1, 58, 59, 70
Paliperidone is administered orally.1 Paliperidone palmitate is administered only by IM injection.58, 59, 60, 61
Paliperidone extended-release tablets are administered orally once daily, usually in the morning, with or without food.1 Tablets are available in 3 mg, 6 mg, and 9 mg doses.1
Paliperidone extended-release tablets should be swallowed whole with fluids and should not be chewed, divided, or crushed.1 Patients should be advised not to become concerned if they notice a tablet-like substance in their stools; this is normal since the tablet is designed to remain intact and slowly release the drug from a nonabsorbable shell during passage through the GI tract.1
Store tablets at temperatures up to 25°C.1 Short-term exposure between 15-30°C is acceptable.1 Keep protected from moisture.1
Clinicians should be aware that there are several different extended-release IM formulations of paliperidone palmitate with different indications, dosages, and dosing frequencies.58, 59, 60, 61
Paliperidone palmitate extended-release IM suspension (Invega Sustenna®) is given once monthly and is available in 39 mg, 78 mg, 117 mg, 156 mg, and 234 mg single-dose prefilled syringes.58 The injection must be administered only by a healthcare professional.58 Administer the dose in a single injection; it should not be administered in divided injections.58 Paliperidone palmitate should only be administered using the needles provided in the kit.58 The kit contains a prefilled syringe and 2 safety needles (a 1 ½-inch 22 gauge needle and a 1-inch 23 gauge needle) for IM injection.58 Shake the syringe vigorously for a minimum of 10 seconds to ensure a homogeneous suspension.58 For deltoid injections, a 1-inch, 23-gauge needle is recommended for patients weighing less than 90 kg, while a 1½-inch, 22-gauge needle is recommended for those weighing 90 kg or more.58 Deltoid injections should be alternated between the 2 deltoid muscles.58 For gluteal injections, regardless of patient weight, a 1½-inch, 22-gauge needle should be used, with administration into the upper-outer quadrant of the gluteal muscle.58 Gluteal injections should also be alternated between both gluteal muscles.58 Store at room temperature (25°C); brief exposure to temperatures between 15-30°C is allowed.58 For a missed second injection or maintenance dose, follow the instructions outlined by the manufacturer in the prescribing information.58
Paliperidone palmitate extended-release injectable IM suspension (Erzofri®) is given once monthly and is available as 39 mg, 78 mg, 117 mg, 156 mg, 234 mg and 351 mg single-dose prefilled syringes.59 The injection must be administered only by a healthcare professional.59 Administer only as an IM injection into the deltoid or gluteal muscle.59 Shake the syringe vigorously for a minimum of 10 seconds to ensure a homogeneous suspension prior to administration.59 The first dose should be given in the deltoid muscle, while monthly maintenance doses can be given in either the deltoid or gluteal muscles.59 The kit contains a prefilled syringe and 2 safety needles (a 1 ½-inch 22 gauge needle and a 1-inch 23 gauge needle).59 For deltoid injections, a 1-inch, 23-gauge needle is recommended for patients weighing less than 90 kg, while a 1½-inch, 22-gauge needle is recommended for those weighing 90 kg or more.59 For gluteal injections, regardless of patient weight, a 1½-inch, 22-gauge needle should be used, with administration into the upper-outer quadrant of the gluteal muscle.59 Store at 20-25°C; brief exposure to temperatures between 15-30°C is allowed.59 For a missed maintenance dose, follow the instructions outlined by the manufacturer in the prescribing information.59
Paliperidone palmitate extended-release IM suspension (Invega Trinza®) is given once every 3 months and is available as 273 mg, 410 mg, 546 mg, and 819 mg single-dose prefilled syringes.60 The injection must be administered only by a healthcare professional.60 The full dose should be given as a single injection; do not divide it into multiple injections.60 Inject slowly and deeply into either the deltoid or gluteal muscle.60 Only the thin wall needles included in the kit should be used for administration.60 The kit contains a prefilled syringe and 2 safety needles (a 22 gauge, 1-inch safety needle and a 22 gauge, 1½-inch safety needle).60 Do not use needles from the 1-month paliperidone palmitate pack or other commercially available needles, as this increases the risk of blockage.60 Shake the prefilled syringe vigorously for at least 15 seconds within 5 minutes before administering the dose.60 For deltoid injections, the recommended needle size depends on the patient's weight.60 Patients weighing less than 90 kg should receive the injection with a 1-inch, 22-gauge thin wall needle, while those weighing 90 kg or more should be given the injection using a 1½-inch, 22-gauge thin wall needle.60 Injections should be administered into the center of the deltoid muscle and alternated between both deltoid sites.60 For gluteal injections, regardless of weight, a 1½-inch, 22-gauge thin wall needle is recommended.60 The injection should be given into the upper-outer quadrant of the gluteal muscle, alternating between the left and right sides.60 Store at 20-25°C; brief exposure to temperatures between 15-30°C is allowed.60 For a missed maintenance dose, follow the instructions outlined by the manufacturer in the prescribing information.60
Paliperidone palmitate extended-release IM suspension (Invega Hafyera®) is given once every 6 months and is available as 1,092 mg and 1,560 mg single-dose prefilled syringes.61 The injection must be administered only by a healthcare professional.61 It must be administered as a gluteal IM injection; do not administer by any other route.61 The kit contains a single-dose prefilled syringe and a 20 gauge, 1½-inch safety needle.61 Do not use needles from the 1- or 3-month paliperidone palmitate packs or other commercially available needles, as this increases the risk of blockage.61 Shake syringe with syringe tip cap pointing up very fast for 15 seconds, rest briefly, then shake again for 15 seconds.61 The full dose should be given as a single injection; do not divide it into multiple injections.61 Inject slowly and deeply into the upper-outer quadrant of the gluteal muscle.61 Future injections should be alternated between the 2 gluteal muscles.61 Store at 20-25°C; brief exposure to temperatures between 15-30°C is allowed.61 For a missed maintenance dose, follow the instructions outlined by the manufacturer in the prescribing information.61
For patients naïve to oral paliperidone or oral or injectable risperidone, tolerability with oral paliperidone or oral risperidone should be established prior to initiating treatment with paliperidone palmitate extended-release IM suspension formulations (Invega Sustenna®; Erzofri®).58, 59
Paliperidone palmitate extended-release IM suspension (Invega Trinza®) should be initiated only after a patient has been stabilized on the once-monthly paliperidone palmitate extended-release injectable suspension for a minimum of 4 months.60
Paliperidone palmitate extended-release IM suspension (Invega Hafyera®) should be initiated in patients who have been appropriately stabilized with either: a once-monthly paliperidone palmitate extended-release injection (for a minimum of 4 months), or an every-3-month paliperidone palmitate extended-release injection (for at least one 3-month dosing cycle).61
For the management of schizophrenia in adults , the usual recommended initial dosage of oral paliperidone is 6 mg orally once daily in the morning; initial dosage titration is not required.1 Although it remains to be systematically evaluated whether dosages exceeding 6 mg once daily provide additional clinical benefit, a general trend for greater clinical effects with higher dosages has been observed.1 However, the potential for increased clinical efficacy at higher dosages must be weighed against the potential for a dose-related increase in adverse effects.1 Some patients may benefit from higher dosages of up to 12 mg once daily, while a lower dosage of 3 mg once daily may be sufficient for other patients.1 The manufacturer states that increases beyond a dosage level of 6 mg once daily should be made only after clinical reassessment and generally should be made at intervals of more than 5 days.1 When dosage increases are necessary, increments of 3 mg daily are recommended.1 The maximum recommended dosage in adults is 12 mg once daily.1
Paliperidone palmitate extended-release IM suspension formulations (Invega Sustenna®; Erzofri®) are indicated for the treatment of schizophrenia in adults.58, 59 Dosage recommendations for both agents are summarized in Table 1. Before starting Invega Sustenna® or Erzofri®, patients who have not previously used oral paliperidone or oral/injectable risperidone should first have their tolerability confirmed with one of these oral medications.58, 59 For patients who are already stable on another long-acting injectable antipsychotic, Invega Sustenna® or Erzofri® should be initiated at the time of their next scheduled dose and then maintained with monthly injections.58, 59 Follow the instructions outlined by the manufacturer in the prescribing information for more detailed information regarding switching from other oral or long-acting injectable antipsychotics.58, 59
Agent | Initiation Dosing (Deltoid) | Monthly Maintenance Dose (Deltoid or Gluteal)a | Maximum Monthly Dose |
|---|---|---|---|
Invega Sustenna® | Day 1: 234 mg Day 8: 156 mg | 39-234 mgb | 234 mg |
Erzofri® | Day 1: 351 mg Day 8: NA | 39-234 mgc | 234 mg |
aRecommended maintenance dose for treatment of schizophrenia is 117 mg. Some patients may benefit from lower or higher maintenance doses.
Paliperidone palmitate extended-release IM suspension (Invega Trinza®) is indicated for the treatment of schizophrenia in patients following an adequate initial treatment with Invega Sustenna® for at least 4 months.60 Initial dosage recommendations are summarized in Table 2. After the initial dose of Invega Trinza®, the medication should be given once every 3 months.60 If necessary, the dosage can be adjusted at 3-month intervals, within a range of 273 mg to 819 mg, depending on how well the patient tolerates the treatment and how effective it is.60 Because Invega Trinza® is a long-acting medication, it may take several months to observe the effects of any dose changes.60 Follow the instructions outlined by the manufacturer in the prescribing information for more detailed information regarding switching to/from other oral or long-acting injectable antipsychotics.60
If the Last Dose of Invega Sustenna® is: | Initiate Invega Trinza® at the Following Dose: |
|---|---|
78 mg | 273 mg |
117 mg | 410 mg |
156 mg | 546 mg |
234 mg | 819 mg |
Paliperidone palmitate extended-release IM suspension (Invega Hafyera®) is indicated for the treatment of schizophrenia in patients following adequate initial treatment with Invega Sustenna® for at least 4 months or Invega Trinza® for at least one 3-month cycle.61 Dosage recommendations are summarized in Table 3. Invega Hafyera® can be given up to one week before or after the patient's next scheduled paliperidone palmitate 1-month (PP1M) injection.61 When transitioning from once-a-month paliperidone palmitate extended-release injectable suspension to Invega Hafyera®, it is important that the last 2 once-a-month doses prior to the switch are of the same strength before initiating Invega Hafyera®.61 When transitioning from every-three-month paliperidone palmitate extended-release injectable suspension to Invega Hafyera®, begin Invega Hafyera® at the time the next paliperidone palmitate 3-month (PP3M) dose is due.61 It can be administered as early as 2 weeks before or as late as 2 weeks after the scheduled PP3M injection.61 Because Invega Hafyera® is a long-acting medication, it may take several months to observe the effects of any dose changes.61 Follow the instructions outlined by the manufacturer in the prescribing information for more detailed information regarding switching to/from other oral or long-acting injectable antipsychotics.61
Adults adequately treated with once-a-month paliperidone palmitate extended-release injectable suspension (PP1M) (Invega Sustenna®; Erzofri®) | |
If the last dose of PP1M is: | Initiate Invega Hafyera® at the following dose once every 6 months: |
156 mg | 1092 mg |
234 mg | 1560 mg |
Adults adequately treated with every-3-month paliperidone palmitate injectable suspension (PP3M) (Invega Trinza®) | |
If the last dose of PP3M is: | Initiate Invega Hafyera® at the following dose once every 6 months: |
546 mg | 1092 mg |
819 mg | 1560 mg |
The recommended initial and target dosage of oral paliperidone for the treatment of schizoaffective disorder in adults is 6 mg orally once daily.1 Initial dosage titration is not required.1 However, some patients may benefit from lower or higher dosages within the recommended dosage range of 3-12 mg once daily.1 Although a general trend for greater clinical effects with higher dosages has been observed, the potential for increased clinical efficacy must be weighed against the potential for a dose-related increase in adverse effects.1 Dosage adjustment, if necessary, should occur only after clinical reassessment and generally should be made at intervals of more than 4 days.1 When dosage increases are necessary, increments of 3 mg daily are recommended.1 The maximum recommended adult dosage is 12 mg once daily.1
Paliperidone palmitate extended-release IM suspension formulations (Invega Sustenna®; Erzofri®) are indicated for the treatment of schizoaffective disorder as monotherapy or as an adjunct to mood stabilizers or antidepressants in adults.58, 59 Dosage recommendations for both agents are summarized in Table 4.
Agent | Initiation Dosing (Deltoid) | Monthly Maintenance Dose (Deltoid or Gluteal)a | Maximum Monthly Dose |
|---|---|---|---|
Invega Sustenna® | Day 1: 234 mg Day 8: 156 mg | 78-234 mga | 234 mg |
Erzofri® | Day 1: 351 mg Day 8: NA | 78-234 mg b | 234 mg |
For the management of schizophrenia in adolescents 12-17 years of age, the usual recommended initial dosage of oral paliperidone is 3 mg (regardless of body weight) orally once daily in the morning; initial dosage titration is not required.1 The manufacturer states that dosage increases, if considered necessary, should be made only after clinical reassessment and should made in increments of 3 mg daily at intervals of more than 5 days.1 The recommended adolescent dosage range for patients weighing less than 51 kg is 3-6 mg once daily and for those weighing 51 kg or more is 3-12 mg once daily.1 However, clinicians should consider that, in the adolescent schizophrenia study, there was no clear improvement in efficacy at the higher paliperidone dosage studied (i.e., 6 mg once daily for adolescents weighing less than 51 kg and 12 mg once daily for adolescents weighing 51 kg or more) while adverse effects were found to be dose-related.1
Oral dosage adjustment is not necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A and B).1 Paliperidone has not been studied in patients with severe hepatic impairment.1
Paliperidone palmitate IM formulations (Invega Sustenna®; Erzofri®; Invega Trinza®; Invega Hafyera®) have not been studied in patients with hepatic impairment.58, 59, 60, 61 Based on a study with oral paliperidone, no dosage adjustment is required in patients with mild or moderate hepatic impairment.58, 59, 60, 61
The manufacturer states that the dosage of oral paliperidone must be individualized according to the patient's renal function status.1 In patients with mild renal impairment (creatinine clearance of 50-79 mL/minute), the recommended initial oral dosage of paliperidone is 3 mg once daily.1 The dosage may then be increased up to a maximum of 6 mg once daily based on clinical response and tolerability.1 In patients with moderate to severe renal impairment (creatinine clearance of 10-49 mL/minute), the recommended initial oral dosage of paliperidone is 3 mg every other day, which may be increased to a maximum of 3 mg once daily after clinical reassessment.1 Use in patients with a creatinine clearance below 10 mL/minute is not recommended since paliperidone has not been studied in such patients.1
For patients with mild renal impairment (creatinine clearance 50-79 mL/min), Invega Sustenna® should be started with 156 mg on day 1 and 117 mg on day 8, both administered in the deltoid.58 Monthly maintenance should continue with 78 mg, given in the deltoid or gluteal muscle, and adjusted as needed within the range of 39-156 mg based on tolerability and effectiveness.58 The maximum monthly dose for this group is 156 mg.58 Use of Invega Sustenna® is not recommended for patients with moderate to severe renal impairment (creatinine clearance below 50 mL/min).58
For patients with mild renal impairment (creatinine clearance 50-79 mL/min), Erzofri® should be initiated with a 234 mg dose in the deltoid on day 1, followed by a monthly maintenance dose of 78 mg in either the deltoid or gluteal muscle.59 Dosage may be adjusted based on response and tolerability within the 39-156 mg range, with 156 mg as the maximum monthly dose.59 Erzofri® is not recommended for patients with moderate to severe renal impairment (creatinine clearance below 50 mL/min).59
For those with mild renal impairment (creatinine clearance 50-79 mL/min), the Invega Trinza® dosage should first be adjusted and stabilized using the 1-month paliperidone palmitate injection before transitioning to Invega Trinza®.60 Refer to the prescribing information for appropriate dosing.60 Invega Trinza® is not recommended for patients with moderate to severe renal impairment (creatinine clearance below 50 mL/min).60
For those with mild renal impairment (creatinine clearance 50-79 mL/min), the Invega Hafyera® dosage should first be adjusted and stabilized using a 1-month paliperidone palmitate injection, or a 1-month paliperidone palmitate injection followed by an every 3-month paliperidone palmitate injection, before transitioning to Invega Hafyera®.61 Refer to the respective prescribing information packets for appropriate dosing.61 Invega Hafyera® is not recommended for patients with moderate to severe renal impairment (creatinine clearance below 50 mL/min).61
The manufacturers of paliperidone and paliperidone palmitate make no specific dosage recommendations for geriatric patients.1, 58, 59, 60, 61
Because geriatric patients may have reduced renal function, dosage adjustment for oral paliperidone may be required based on renal function status.1 Geriatric patients with normal renal function generally may receive the same dosage recommended for younger adults with normal renal function.1 In geriatric patients with moderate or severe renal impairment, (creatinine clearance 10-49 mL/min), the maximum recommended paliperidone dosage is 3 mg once daily.1
Lower doses for paliperidone palmitate IM formulations (Invega Sustenna®; Erzofri®; Invega Trinza®) are recommended in patients with impaired renal function; since older adults are more likely to have reduced kidney function, dosing should be adjusted accordingly based on renal status.58, 59, 60 Invega Hafyera® is not recommended to be used in elderly patients with mild, moderate or severe renal impairment.61
Increased Mortality in Geriatric Patients with Dementia-related Psychosis
A boxed warning is included in the prescribing information regarding the increased risk of death when geriatric patients with dementia-related psychosis are treated with antipsychotic drugs.1, 58, 59, 60, 61 Analysis of 17 placebo-controlled trials (modal duration of 10 weeks) revealed an approximate 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (i.e., aripiprazole, olanzapine, quetiapine, risperidone) compared with that observed in patients receiving placebo.1, 58, 59, 60, 61 Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group.1, 58, 59, 60, 61 Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.1, 58, 59, 60, 61 Observational studies suggest that, similar to atypical antipsychotics, treatment with conventional (first-generation) antipsychotics may increase mortality; the extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients remains unclear.1, 58, 59, 60, 61 The manufacturer states that paliperidone is not approved for the treatment of patients with dementia-related psychosis.1, 58, 59, 60, 61
Adverse Cerebrovascular Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis
An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies.1, 58, 59, 60, 61 The manufacturers state that paliperidone and paliperidone palmitate are not approved for the treatment of patients with dementia-related psychosis.1, 58, 59, 60, 61
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including paliperidone formulations.1, 58, 59, 60, 61 Neuroleptic malignant syndrome typically presents with high fever, muscle stiffness, changes in mental status such as delirium, and signs of autonomic instability like irregular heart rate or blood pressure, rapid heartbeat, excessive sweating, and abnormal heart rhythms.1, 58, 59, 60, 61 Other possible symptoms include elevated creatine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure.1, 58, 59, 60, 61 If NMS is suspected, discontinue paliperidone and/or paliperidone palmitate formulations and provide symptomatic treatment and monitoring.1, 58, 59, 60, 61
Paliperidone causes a modest increase in the corrected QT (QTc) interval.1, 58, 59, 60, 61 The risk of torsades de pointes in association with drugs that prolong the QTc interval may be increased in patients with bradycardia, hypokalemia, or hypomagnesemia; patients receiving other drugs that prolong the QTc interval; and in those with congenital prolongation of the QT interval.1, 58, 59, 60, 61 Therefore, the manufacturer states that paliperidone should be avoided in patients concurrently receiving other drugs known to prolong the QTc interval, patients with congenital long QT syndrome, and those with a history of cardiac arrhythmias.1, 58, 59, 60, 61
Because use of antipsychotic agents may be associated with tardive dyskinesia (a syndrome of potentially irreversible, involuntary, dyskinetic movements), paliperidone formulations should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome.1, 58, 59, 60, 61 Chronic antipsychotic treatment generally should be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.1, 58, 59, 60, 61 In patients who require chronic treatment, the lowest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically.1, 58, 59, 60, 61
If signs and symptoms of tardive dyskinesia appear in a paliperidone-treated patient, paliperidone discontinuance should be considered; however, some patients may require continued treatment with the drug despite the presence of the syndrome.1, 58, 59, 60, 61
Atypical antipsychotic agents have been associated with metabolic changes that may increase cardiovascular and cerebrovascular risk, including hyperglycemia, dyslipidemia, and body weight gain.1, 58, 59, 60, 61 While all of these drugs produce some metabolic changes, each drug has its own specific risk profile.1, 58, 59, 60, 61
Hyperglycemia and Diabetes Mellitus
Hyperglycemia and diabetes mellitus, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, have been reported in patients treated with all atypical antipsychotic agents.1, 58, 59, 60, 61 These cases were mainly seen in postmarketing clinical use and epidemiologic studies, not in clinical trials, and there have been few reports of hyperglycemia or diabetes mellitus in paliperidone-treated patients to date.1, 58, 59, 60, 61 While confounding factors such as an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population make it difficult to establish with certainty the relationship between use of agents in this drug class and glucose abnormalities, epidemiologic studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with atypical antipsychotic agents.1, 58, 59, 60, 61
Patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be closely monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes) should undergo fasting blood glucose testing upon therapy initiation and periodically throughout treatment.1, 58, 59, 60, 61 Any patient who develops manifestations of hyperglycemia (including polydipsia, polyuria, polyphagia, and weakness) during treatment with an atypical antipsychotic should undergo fasting blood glucose testing.1, 58, 59, 60, 61 In some cases, patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other cases, hyperglycemia resolved with discontinuance of the antipsychotic.1, 58, 59, 60, 61
Undesirable changes in lipid parameters have been observed in patients treated with some atypical antipsychotics.1, 58, 59, 60, 61 Data from short- and longer-term clinical studies suggest that the risk of developing clinically important dyslipidemia during paliperidone therapy is minimal.1, 58, 59, 60, 61
Weight gain has been observed with atypical antipsychotic therapy.1, 58, 59, 60, 61 Monitoring of weight is recommended in patients receiving paliperidone and other atypical antipsychotic agents.1, 58, 59, 60, 61
Similar to other antipsychotic agents and drugs with dopamine D2 antagonistic activity, paliperidone can elevate serum prolactin concentrations.1, 58, 59, 60, 61 Paliperidone's prolactin-elevating effect is similar to that seen with risperidone, which appears to be associated with a higher level of prolactin elevation than other currently available antipsychotic agents.1, 58, 59, 60, 61 Clinical disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been associated with prolactin-elevating drugs.1, 58, 59, 60, 61 In addition, chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both female and male patients.1, 58, 59, 60, 61
If paliperidone therapy is considered in a patient with previously detected breast cancer, clinicians should consider that approximately one-third of human breast cancers are prolactin-dependent in vitro.1, 58, 59, 60, 61
As with other nondeformable material, oral extended-release paliperidone tablets do not appreciably change in shape in the GI tract.1 Therefore, extended-release tablets of the drug generally should not be administered to patients with severe, preexisting GI narrowing (either pathologic or iatrogenic).1 Rare cases of obstructive symptoms in patients with known strictures have been reported in association with the ingestion of drugs in nondeformable, controlled-release formulations.1 Because of the extended-release design of paliperidone tablets, the drug should only be used in patients who are able to swallow the tablet whole.1
Decreased bioavailability of paliperidone extended-release tablets would be expected in patients with a decreased GI transit time (e.g., those with diarrhea) while an increased bioavailability would be expected in patients with an increased GI transit time (e.g., those with GI neuropathy, diabetic gastroparesis, or due to other causes).1 Such changes in bioavailability are more likely when changes in transit time occur in the upper GI tract.1
Orthostatic Hypotension and Syncope
Orthostatic hypotension and syncope may occur during paliperidone therapy in some patients, particularly early in treatment, perhaps because of the drug's α1-adrenergic blocking activity.1, 58, 59, 60, 61 Syncope occurred in <1% of patients receiving paliperidone or paliperidone palmitate in controlled clinical trials.1, 58, 59, 60, 61
Paliperidone should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction, ischemic heart disease, conduction abnormalities), cerebrovascular disease, or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy) and in antipsychotic-naïve patients.1, 58, 59, 60, 61 Consideration should be given to monitoring orthostatic vital signs in paliperidone-treated patients who are susceptible to hypotension (e.g., geriatric patients).1, 58, 59, 60, 61
Use of antipsychotics, including paliperidone formulations, has been associated with drowsiness, low blood pressure upon standing, and impaired motor or sensory function, all of which can increase the risk of falls and potentially lead to fractures or other fall-related injuries.1, 58, 59, 60, 61 This risk is especially important to consider in elderly patients or those with medical conditions or medications that may worsen these effects.1, 58, 59, 60, 61 Fall risk should be evaluated when starting antipsychotic treatment and reassessed regularly during long-term use.1, 58, 59, 60, 61
Leukopenia, Neutropenia, and Agranulocytosis
In clinical trial and/or postmarketing experience, leukopenia and neutropenia have been temporally related to antipsychotic agents, including paliperidone formulations.1, 58, 59, 60, 61 Agranulocytosis also has been reported with antipsychotic agents.1, 58, 59, 60, 61
Possible risk factors for leukopenia and neutropenia include a preexisting low leukocyte count and a history of drug-induced leukopenia and neutropenia.1, 58, 59, 60, 61 Patients with a preexisting low leukocyte count or a history of drug-induced leukopenia or neutropenia should have their complete blood count monitored frequently during the first few months of therapy.1, 58, 59, 60, 61 Paliperidone should be discontinued at the first sign of a decline in leukocyte count in the absence of other causative factors.1, 58, 59, 60, 61
Patients with clinically important neutropenia should be carefully monitored for fever or other signs or symptoms of infection and promptly treated if such signs and symptoms occur.1, 58, 59, 60, 61 In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm3), paliperidone formulations should be discontinued and the leukocyte count monitored until recovery occurs.1, 58, 59, 60, 61
Cognitive and Motor Impairment
Like other antipsychotic agents, paliperidone potentially may impair judgment, thinking, or motor skills.1, 58, 59, 60, 61 Drowsiness, sedation, and dizziness have been reported as side effects in individuals receiving paliperidone formulations.1, 58, 59, 60, 61 Patients should be advised to avoid activities that require full mental alertness (such as driving or operating heavy machinery) until they are confident that the medication does not impair their ability to do so safely.1, 58, 59, 60, 61
Seizures have occurred in approximately <1% of patients with schizophrenia receiving paliperidone or paliperidone palmitate formulations in premarketing clinical studies.1, 58, 59, 60, 61 As with other antipsychotic agents, paliperidone should be used with caution in patients with a history of seizures or with other conditions that may lower the seizure threshold (e.g., dementia of the Alzheimer's type); conditions that lower the seizure threshold may be more prevalent in patients 65 years of age or older.1, 58, 59, 60, 61
Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents.1, 58, 59, 60, 61 Paliperidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.1, 58, 59, 60, 61
Drugs possessing α-adrenergic blocking activity have been reported to cause priapism.1, 58, 59, 60, 61 Priapism has been reported in oral paliperidone-treated patients during postmarketing surveillance and with Invega Hafyera® during clinical trials.1, 58, 59, 60, 61 Severe priapism may require surgical intervention.1, 58, 59, 60, 61
Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents.1, 58, 59, 60, 61 The manufacturer recommends appropriate caution when paliperidone is used in patients who will be experiencing conditions that may contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, concomitant use of agents with anticholinergic activity, dehydration).1, 58, 59, 60, 61
A pregnancy exposure registry is available to track outcomes in women who are exposed to atypical antipsychotics, such as paliperidone, during pregnancy.1, 58, 59, 60, 61 Healthcare providers are encouraged to enroll patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388 or online at [Web].1, 58, 59, 60, 61
Overall, data from published epidemiological studies involving pregnant women exposed to paliperidone have not shown a clear link between the drug and an increased risk of major birth defects, miscarriage, or negative outcomes for the mother or fetus.1, 58, 59, 60, 61 However, both untreated schizophrenia and the use of antipsychotics like paliperidone during pregnancy carry potential risks for the mother.1, 58, 59, 60, 61
Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.1, 58, 59, 60, 61 Symptoms reported to date have included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder.1, 58, 59, 60, 61 Neonates exhibiting such symptoms should be monitored.1, 58, 59, 60, 61 The complications have varied in severity; some neonates recovered within hours to days without specific treatment while others have required intensive care unit support and prolonged hospitalization.1, 58, 59, 60, 61
Limited published data indicate that paliperidone can pass into human breast milk, though its effects on nursing infants and milk production are unknown.1, 58, 59, 60, 61 However, exposure to risperidone (paliperidone's parent compound) has been linked to sedation, poor weight gain, jitteriness, and movement disorders in breast-fed infants.1, 58, 59, 60, 61 Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for paliperidone and any potential adverse effects on the breast-fed child from paliperidone or the mother's underlying condition.1, 58, 59, 60, 61 Infants exposed to paliperidone through breastmilk should be monitored for sedation, failure to thrive, jitteriness, and abnormal movements.1, 58, 59, 60, 61
Females and Males of Reproductive Potential
Due to paliperidone's pharmacologic effect as a D2 receptor antagonist, treatment may elevate serum prolactin levels, potentially causing a reversible decrease in fertility in females of reproductive potential.1, 58, 59, 60, 61 Advise females of reproductive potential that treatment with paliperidone or paliperidone palmitate formulations may impair fertility due to an increase in serum prolactin levels.1, 58, 59, 60, 61 The effects on fertility are reversible.1, 58, 59, 60, 61
Safety and efficacy of oral paliperidone in the treatment of schizophrenia in adolescents 12-17 years of age have been established in a double-blind, placebo-controlled study of 6 weeks' duration.1
Safety and efficacy of oral paliperidone in the treatment of schizophrenia have not been established in pediatric patients younger than 12 years of age.1
Safety and efficacy of oral paliperidone in the treatment of schizoaffective disorder have not been established in pediatric patients younger than 18 years of age.1
The safety and efficacy of IM formulations of paliperidone palmitate have not been established in pediatric patients <18 years of age.58, 59, 60, 61
The manufacturer states that the long-term effects of paliperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.1, 58, 59, 60
In clinical studies of oral paliperidone, approximately 7% of nearly 1800 patients were 65 years of age or older.1 In addition, the short-term efficacy and safety of paliperidone have been demonstrated in a placebo-controlled trial of 6 weeks' duration in 114 geriatric patients with schizophrenia.1 While no substantial differences in efficacy or safety relative to younger adults were observed in these studies or in other clinical experience with the drug, increased sensitivity cannot be ruled out.1
Clinical trials for paliperidone palmitate IM formulations (Invega Sustenna®; Erzofri®; Invega Trinza®; Invega Hafyera®) included too few participants aged 65 and older to assess whether their response differs from that of younger individuals.58, 59, 60, 61
Because geriatric patients may have reduced renal function, oral paliperidone dosage adjustment may be required based on renal function status; consider monitoring renal function.1 Lower doses for paliperidone palmitate IM formulations (Invega Sustenna®; Erzofri®; Invega Trinza®) in patients with impaired renal function are recommended; since older adults are more likely to have reduced kidney function, dosing should be adjusted accordingly based on renal status.58, 59, 60 Invega Hafyera® use is not recommended to be used in elderly patients with mild, moderate, or severe renal impairment.61
Patients with Parkinson's Disease or Lewy Body Dementia
Patients with Parkinson's disease or dementia with Lewy bodies may be more sensitive to oral paliperidone and paliperidone palmitate IM formulations (Invega Sustenna®; Erzofri®; Invega Trinza®; Invega Hafyera®).1, 58, 59, 60, 61 Patients may experience symptoms such as confusion, reduced alertness, balance issues leading to frequent falls, movement disorders, and signs resembling neuroleptic malignant syndrome.1, 58, 59, 60, 61
After oral administration of paliperidone, patients with moderate hepatic impairment (Child-Pugh class B) exhibited similar plasma concentrations of free paliperidone as healthy individuals, although total paliperidone exposure decreased because of decreased protein binding.1 Dosage adjustment for oral paliperidone is not necessary in patients with mild to moderate hepatic impairment).1 The effect of severe hepatic impairment on paliperidone pharmacokinetics is not known.1
IM formulations of paliperidone palmitate have not been studied in patients with mild or moderate hepatic impairment.58, 59, 60, 61 Based on a study with oral paliperidone, no dosage adjustment is required in patients with mild or moderate hepatic impairment.58, 59, 60, 61 IM formulations of paliperidone palmitate have not been studied in patients with severe hepatic impairment.58, 59, 60, 61
After administration of a single dose paliperidone 3 mg extended-release tablet, clearance decreased by an average of 32, 64, and 71% in patients with mild, moderate, and severe renal impairment, respectively.1 Oral paliperidone dosage adjustment is recommended in patients with renal impairment.1, 58, 59, 60, 61 See manufacturer prescribing information for specific dosing guidance.1, 58, 59, 60, 61
Adverse effects reported in 5% or more of adults receiving oral paliperidone for schizophrenia and at a frequency at least twice that reported with placebo include extrapyramidal symptoms, tachycardia, and akathisia.1
Adverse effects reported in 5% or more of adolescents receiving oral paliperidone for schizophrenia and at a frequency at least twice that reported with placebo include somnolence, extrapyramidal symptoms (e.g., akathisia, tremor, dystonia, cogwheel rigidity), anxiety, increased weight, and tachycardia.1
Adverse effects reported in 5% or more of adults receiving oral paliperidone for schizoaffective disorder and at a frequency at least twice that reported with placebo include extrapyramidal symptoms, somnolence, dyspepsia, constipation, increased weight, and nasopharyngitis.1
Adverse effects reported in 5% or more of adults receiving a monthly IM formulation of paliperidone palmitate (Invega Sustenna®; Erzofri®) at a frequency at least twice that reported with placebo include injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder.58, 59
Adverse effects reported in 5% or more of adults receiving IM paliperidone palmitate dosed every 3 months (Invega Trinza®) at a frequency at least twice that reported with placebo include injection site reaction, increased weight, headache, upper respiratory tract infection, akathisia, and parkinsonism.60
The most common adverse effects reported in adults receiving IM paliperidone palmitate dosed every 6 months (Invega Hafyera®) include upper respiratory tract infection, injection site reaction, increased weight, headache, and parkinsonism.61
Since paliperidone palmitate is hydrolyzed to paliperidone, results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential.58, 59, 60, 61
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors or inducers of cytochrome P-450 (CYP) isoenzymes 2D6, 1A2, 2A6, 2C9, and 2C19: pharmacokinetic interaction unlikely.1 Concomitant use of paliperidone and strong inducers of CYP3A4 (e.g., carbamazepine, rifampin, or St. John's Wort) may decrease the exposure of paliperidone.58, 59, 60, 61 If administering a strong CYP3A4 inducer is necessary when using IM formulations of paliperidone palmitate, consider managing the patient using paliperidone extended-release tablets.58, 59, 60, 61
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, or CYP3A5: pharmacokinetic interaction unlikely.1, 58, 59, 60, 61
Drugs Inhibiting P-glycoprotein Transport System
Concomitant use of paliperidone and strong inducers of P-glycoprotein may decrease the exposure of paliperidone.58, 59, 60, 61 If administering a strong inducer of P-glycoprotein is necessary when using IM formulations of paliperidone palmitate, consider managing the patient using paliperidone extended-release tablets.58, 59, 60, 61
Drugs that Prolong QT Interval
Potential pharmacologic interaction (additive effect on QT-interval prolongation); avoid concomitant use of other drugs known to prolong the QT interval (e.g., amiodarone, quinidine, procainamide, sotalol, other Class Ia and III antiarrhythmics, chlorpromazine, thioridazine, gatifloxacin, moxifloxacin).1
Potential pharmacologic interaction (additive CNS effects).1, 58, 59, 60, 61 Avoid alcoholic beverages during paliperidone therapy.1, 58, 59, 60, 61
Potential pharmacologic interaction (additive CNS effects).1, 58, 59, 60, 61 Use with caution.1, 58, 59, 60, 61
Potential pharmacologic interaction (possible disruption of body temperature regulation); use paliperidone with caution in patients concurrently receiving drugs with anticholinergic activity.1
Concurrent administration of carbamazepine and paliperidone decreased mean steady-state peak plasma concentrations and area under the concentration-time curves (AUCs) of paliperidone by approximately 37%.1 The manufacturer recommends reevaluating the dosage of paliperidone upon initiation of carbamazepine and increasing it, if necessary, based on clinical assessment.1 Upon discontinuance of carbamazepine, the dosage of paliperidone should also be reevaluated and decreased, if necessary.1
Because of its α1-adrenergic blocking activity and potential to cause hypotension, the manufacturer recommends that paliperidone be used with caution in patients receiving antihypertensive agents; monitoring of orthostatic vital signs should be considered in such patients.1, 58, 59, 60, 61
Levodopa and Dopamine Agonists
Paliperidone may antagonize the effect of levodopa and other dopamine agonists.1, 58, 59, 60, 61
Concomitant administration of paroxetine (20 mg daily) and a single dose of paliperidone (3 mg as extended-release tablets) caused a small, clinically insignificant increase in paliperidone AUCs compared with paliperidone administration alone.1 Clinical relevance is unknown.1, 58, 59, 60, 61
Because paliperidone is the principal active metabolite of risperidone, consideration should be given to additive paliperidone exposure if risperidone and paliperidone are concomitantly administered.1, 58, 59, 60
Concurrent administration of a single dose of oral paliperidone (12 mg) and divalproex sodium extended-release tablets (two 500-mg tablets once daily) resulted in an approximate 50% increase in peak plasma concentrations and AUCs of paliperidone.1 The manufacturer states that oral paliperidone dosage reduction should be considered when valproate is concomitantly administered with paliperidone.1 No dosage adjustment is required when valproate is concomitantly administered with IM formulations of paliperidone palmitate.58, 59, 60, 61
Pharmacokinetic interaction unlikely.1 Dosage adjustment in patients who smoke is not necessary.1
Paliperidone is a benzisoxazole-derivative antipsychotic agent that differs chemically from other currently available first-generation (typical) antipsychotic agents (e.g., butyrophenones, phenothiazines) and has been referred to as an atypical or second-generation antipsychotic agent.1, 3, 4, 5, 6, 7, 8 Paliperidone is the major active metabolite of risperidone, another atypical antipsychotic agent.1 Paliperidone palmitate is a prodrug of paliperidone and is hydrolyzed to its active ingredient, paliperidone, following administration.58, 59, 60, 61
The exact mechanism of paliperidone's antipsychotic action, like that of other antipsychotic agents, has not been fully elucidated, but may involve antagonism of central dopamine type 2 (D2) and serotonin type 2 (5-hydroxytryptamine [5-HT2A]) receptors.1, 58, 59, 60, 61 Antagonism at α1- and α2-adrenergic and histamine (H1) receptors may contribute to other therapeutic and adverse effects observed with the drug.1, 58, 59, 60, 61 Paliperidone possesses no affinity for cholinergic muscarinic and β1- and β2-adrenergic receptors.1, 58, 59, 60, 61
After oral administration of a single-dose, administered as extended-release tablets, paliperidone levels in plasma peak around 24 hours.1 Its pharmacokinetics are dose-proportional across the approved range, with a terminal half-life of about 23 hours.1 Steady-state levels are typically achieved within 4-5 days, with a peak-to-trough ratio of 1.7 (range, 1.2-3.1) for a 9 mg dose.1 Paliperidone's oral bioavailability is 28%.1 A high-fat meal increases Cmax and AUC by 60% and 54%, respectively, compared to fasting.1 The drug is 74% protein-bound.1
Approximately 80% and 11% of a single 1-mg oral dose of radiolabeled, immediate-release paliperidone is recovered in urine and feces, respectively, within 1 week.1 About 59% of the administered dose is recovered as unchanged drug in urine and 32% is recovered as metabolites.1
For one-month paliperidone palmitate extended-release IM suspension formulations (Invega Sustenna®) after a single injection, plasma levels rise gradually, peaking around day 13, with drug release beginning on day 1 and continuing up to 126 days.58 Injecting into the deltoid muscle yields about 28% higher peak concentrations than the gluteal site.58 Initial loading doses (234 mg on day 1 and 156 mg on day 8, both deltoid) rapidly achieve therapeutic levels.58 The drug shows sustained exposure, with AUC values proportional to dose (39-234 mg), though peak concentrations increase less than proportionally above 78 mg.58 Steady-state peak-to-trough ratios are 1.8 for gluteal and 2.2 for deltoid administration at 156 mg.58 The plasma protein binding of racemic paliperidone is 74%.58 The median apparent half-life of paliperidone after a single Invega Sustenna® dose (39-234 mg) ranges from 25-49 days.58 Overall, initial plasma concentrations achieved with Invega Sustenna® fall within the exposure range of 6-12 mg oral extended-release paliperidone.58
For one-month paliperidone palmitate extended-release IM suspension formulations (Erzofri®), after a single injection, paliperidone levels peak between 16 and 28 days, with drug release beginning on day 1 and lasting up to 176 days.59 For Erzofri®, steady-state plasma levels are achieved within 7 days of the initial injection.59 In patients receiving multiple injections (351 mg on day 1, followed by 156 mg every 28 days for five more doses), average plasma concentrations were around 30.3 ng/mL during initiation, stabilizing at 42.6 ng/mL (Cmax), 28.3 ng/mL (Ctrough), and 909 ng*hr/mL (AUC) at steady state.59 Deltoid injections produced higher peak concentrations than gluteal injections (43% higher for 156 mg and 21% higher for 351 mg).59 Despite these differences, overall drug exposure (AUC) between injection sites was similar across the 39-234 mg dose range.59 The plasma protein binding of racemic paliperidone is 74%.59 The median apparent half-life following Erzofri® single-dose administration at 156 mg is approximately 27 days.59
For every-3-month paliperidone palmitate extended-release IM suspension (Invega Trinza®), after a single IM dose, peak plasma concentrations are reached between days 30 and 33.60 Invega Trinza® begins releasing paliperidone as early as day 1 and continues for up to 18 months.60 Deltoid injections produce 11-12% higher peak levels compared to gluteal injections.60 The formulation maintains therapeutic drug levels over a 3-month period, with dose-proportional total and peak exposure across the 273-819 mg range.60 At steady state, the peak-to-trough ratio averages 1.6 for gluteal and 1.7 for deltoid administration.60 The plasma protein binding of racemic paliperidone is 74%.60 The median half-life ranges from 84-95 days (deltoid) to 118-139 days (gluteal).60 Residual drug levels at 18 months post-dose are estimated at 3% (deltoid) and 7% (gluteal) of steady-state levels.60 Doses of Invega Trinza® that are 3.5 times higher than monthly paliperidone doses yield paliperidone exposures that are comparable to once-monthly formulations and extended-release oral tablets.60
The pharmacokinetics for every-6-month paliperidone palmitate extended-release IM suspension (Invega Hafyera®) that are described are based on gluteal administration only.61 Invega Hafyera® begins releasing the drug on day 1 and sustains exposure for over 18 months.61 Administered in doses of 1,092 mg or 1,560 mg via gluteal injection, peak plasma levels are reached between days 29 and 32.61 These doses provide total drug exposure within the range of equivalent once monthly or every-3-month doses of paliperidone palmitate, or daily extended-release oral paliperidone.61 However, trough levels are 20-25% lower, while peak concentrations are 1.4-1.5 times higher compared to every-3-month formulations.61 The median half-life is 148 days for 1,092 mg and 159 days for 1,560 mg.61 At 18 months post-dose, about 18% of steady-state paliperidone remains in circulation.61 The plasma protein binding of racemic paliperidone is 74%.61 Exposure is consistent across the 2 dose levels, with a steady-state peak-to-trough ratio of around 3.0-3.1, indicating sustained plasma concentrations over the 6-month dosing interval.61
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, extended-release | 1.5 mg* | Paliperidone extended-release tablets | |
3 mg* | ||||
Paliperidone extended-release tablets | ||||
6 mg* | Invega® | Janssen | ||
Paliperidone extended-release tablets | ||||
9 mg* | Invega® | Janssen | ||
Paliperidone extended-release tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injectable suspension, extended-release, for IM use | 39 mg/0.25 mL* | Invega Sustenna® (available as a kit containing a prefilled syringe and 2 safety needles) | Janssen |
Paliperidone palmitate extended-release injectable suspension, for IM use | ||||
78 mg/0.5 mL* | Invega Sustenna® (available as a kit containing a prefilled syringe and 2 safety needles) | Janssen | ||
Paliperidone palmitate extended-release injectable suspension, for IM use | ||||
117 mg/0.75 mL* | Invega Sustenna® (available as a kit containing a prefilled syringe and 2 safety needles) | Janssen | ||
Paliperidone palmitate extended-release injectable suspension, for IM use | ||||
156 mg/mL* | Invega Sustenna® (available as a kit containing a prefilled syringe and 2 safety needles) | Janssen | ||
Paliperidone palmitate extended-release injectable suspension, for IM use | ||||
234 mg/1.5 mL* | Invega Sustenna® (available as a kit containing a prefilled syringe and 2 safety needles) | Janssen | ||
Paliperidone palmitate extended-release injectable suspension, for IM use | ||||
39 mg/0.25 mL | Erzofri® (available as a kit containing a prefilled syringe and 2 safety needles) | Shandong Luye Pharmaceutical Co. | ||
78 mg/0.5 mL | Erzofri® (available as a kit containing a prefilled syringe and 2 safety needles) | Shandong Luye Pharmaceutical Co. | ||
117 mg/0.75 mL | Erzofri® (available as a kit containing a prefilled syringe and 2 safety needles) | Shandong Luye Pharmaceutical Co. | ||
156 mg/mL | Erzofri® (available as a kit containing a prefilled syringe and 2 safety needles) | Shandong Luye Pharmaceutical Co. | ||
234 mg/1.5 mL | Erzofri® (available as a kit containing a prefilled syringe and 2 safety needles) | Shandong Luye Pharmaceutical Co. | ||
351 mg/2.25 mL | Erzofri® (available as a kit containing a prefilled syringe and 2 safety needles) | Shandong Luye Pharmaceutical Co. | ||
273 mg/0.88 mL | Invega Trinza® (available as a kit containing a prefilled syringe and 2 safety needles) | Janssen | ||
410 mg/1.32 mL | Invega Trinza® (available as a kit containing a prefilled syringe and 2 safety needles) | Janssen | ||
546 mg/1.75 mL | Invega Trinza® (available as a kit containing a prefilled syringe and 2 safety needles) | Janssen | ||
819 mg/2.63 mL | Invega Trinza® (available as a kit containing a prefilled syringe and 2 safety needles) | Janssen | ||
1.092 mg/3.5 mL | Invega Hafyera® (available as a kit containing a prefilled syringe and safety needle) | Janssen | ||
1.560 mg/5 mL | Invega Hafyera® (available as a kit containing a prefilled syringe and safety needle) | Janssen |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions October 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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