The following are discussed in more detail in other sections of the labeling:
- Increased mortality in elderly patients with dementia-related psychosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
- Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS]
- Neuroleptic malignant syndrome [see WARNINGS AND PRECAUTIONS]
- QT prolongation [see WARNINGS AND PRECAUTIONS]
- Tardive dyskinesia [see WARNINGS AND PRECAUTIONS]
- Metabolic changes [see WARNINGS AND PRECAUTIONS]
- Hyperprolactinemia [see WARNINGS AND PRECAUTIONS]
- Orthostatic hypotension and syncope [see WARNINGS AND PRECAUTIONS]
- Leukopenia, neutropenia, and agranulocytosis [see WARNINGS AND PRECAUTIONS]
- Potential for cognitive and motor impairment [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNINGS AND PRECAUTIONS]
- Dysphagia [see WARNINGS AND PRECAUTIONS]
- Suicide [see WARNINGS AND PRECAUTIONS]
- Priapism [see WARNINGS AND PRECAUTIONS]
- Thrombotic Thrombocytopenic Purpura [see WARNINGS AND PRECAUTIONS]
- Disruption of body temperature regulation [see WARNINGS AND PRECAUTIONS]
- Avoidance of inadvertent injection into a blood vessel [see WARNINGS AND PRECAUTIONS]
- Antiemetic effect [see WARNINGS AND PRECAUTIONS]
- Increased sensitivity in patients with Parkinson's disease or those with dementia with Lewy bodies [see WARNINGS AND PRECAUTIONS]
- Diseases or conditions that could affect metabolism or hemodynamic responses [see WARNINGS AND PRECAUTIONS]
Throughout this section, a distinction is made between adverse events and adverse reactions. Adverse events are events reported by the clinician investigator and there is no attempt to assign causality to the study drug. Adverse reactions are adverse events that are considered to be reasonably associated with the use of INVEGA® SUSTENNA® (adverse drug reactions) based on a predetermined method of assessment, e.g., a comparison of adverse event rates for drug and placebo groups for the event of interest. It is not possible to reliably establish causality by considering individual adverse event reports for drug-treated patients. Thus, the section overall is labeled Adverse Reactions, however, individual subsections are labeled adverse reactions or adverse events, depending on what is included in the subsection.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The most common (at least 5% in any INVEGA® SUSTENNA® group) and likely drug-related (adverse events for which the drug rate is at least twice the placebo rate) adverse reactions from the double-blind, placebo-controlled trials were injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder.
The data described in this section are derived from a clinical trial database consisting of a total of 3817 subjects with schizophrenia who received at least one dose of INVEGA® SUSTENNA® in the recommended dose range of 39 mg to 234 mg and a total of 510 subjects with schizophrenia who received placebo. Among the 3817 INVEGA® SUSTENNA®-treated subjects, 1293 received INVEGA® SUSTENNA® in four fixed-dose, double-blind, placebo-controlled trials (one 9-week and three 13-week studies), 849 received INVEGA® SUSTENNA® in the maintenance trial (of whom 205 continued to receive INVEGA® SUSTENNA® during the double-blind placebo-controlled phase of this study), and 1675 received INVEGA® SUSTENNA® in five non-placebo controlled trials (three noninferiority active-comparator trials, one long-term open-label pharmacokinetic and safety study, and an injection site [deltoidgluteal] cross-over trial). One of the 13-week studies included a 234 mg INVEGA® SUSTENNA® initiation dose followed by treatment with either 39 mg, 156 mg, or 234 mg every 4 weeks.
Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.
The majority of all adverse reactions were mild to moderate in severity.
Commonly-Observed Adverse Events in Double-Blind, Placebo-Controlled Clinical Trials
Table 5 lists the adverse events reported in 2% or more of INVEGA® SUSTENNA®-treated subjects with schizophrenia in the four fixed-dose, double-blind, placebo-controlled trials.
Table 5: Incidence of Treatment Emergent Adverse Events in
≥ 2% of INVEGA® SUSTENNA®-Treated Subjects with Schizophrenia in
Four Fixed-Dose, Double-Blind, Placebo-Controlled Trials
|System Organ Class Adverse Event||Placeboa (N=510)||39 mg (N=130)||78 mg (N=302)||156 mg (N=312)||234/39 mgb (N=160)||234/156 mgb (N=165)||234/234 mgb (N=163)|
|Total percentage of subjects with adverse event||70||75||68||69||63||60||63|
|Abdominal discomfort/abdominal pain upper||2||2||4||4||1||2||4|
|General disorders and administration site conditions|
|Injection site reactions||2||0||4||6||9||7||10|
|Infections and infestations|
|Upper respiratory tract infection||2||2||2||2||1||2||4|
|Urinary tract infection||1||0||1||< 1||1||1||2|
|Injury, poisoning and procedural complications|
|Skin laceration||< 1||2||< 1||0||1||0||0|
|Alanine aminotransferase increased||2||0||2||1||1||1||1|
|Musculoskeletal and connective tissue disorders|
|Musculoskeletal stiffness||1||1||< 1||< 1||1||1||2|
|Pain in extremity||1||0||2||2||2||3||0|
|Nervous system disorders|
|Respiratory, thoracic and mediastinal disorders|
|Percentages are rounded to whole numbers.
Table includes adverse events that were reported in 2% or more of subjects
in any of the INVEGA® SUSTENNA® dose groups and which occurred
at greater incidence than in the placebo group.
a Placebo group is pooled from all studies and included either deltoid or gluteal injection depending on study design.
b Initial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection. [See Clinical Studies]
Adverse events for which the INVEGA® SUSTENNA® incidence was equal to or less than placebo are not listed in the table, but included the following: dyspepsia, psychotic disorder, schizophrenia, and tremor. The following terms were combined: somnolence/sedation, breast tenderness/breast pain, abdominal discomfort/abdominal pain upper/stomach discomfort, and tachycardia/sinus tachycardia/heart rate increased. All injection site reaction-related adverse events were collapsed and are grouped under “Injection site reactions”.
Adverse Reactions Observed During the Clinical Trial Evaluation of INVEGA® SUSTENNA® and Not Listed in Table 2
The following additional adverse reactions occurred in INVEGA® SUSTENNA®-treated subjects in the above four fixed-dose, double-blind, placebo-controlled trials, in the double-blind phase of the maintenance trial, or in INVEGA® SUSTENNA®-treated subjects with schizophrenia who participated in other clinical trials, and were not reported in Table 2. They were determined to be adverse reactions based upon reasons to suspect causality such as timing of onset or termination with respect to drug use, plausibility in light of the drug's known pharmacology, occurrence at a frequency above that expected in the treated population or occurrence of an event typical of drug-induced adverse reactions.
Ear and labyrinth disorders: vertigo
Endocrine disorders: hyperprolactinemia
Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurred
Gastrointestinal disorders: salivary hypersecretion
Immune system disorders: hypersensitivity
Metabolism and nutrition disorders: decreased appetite, hyperglycemia, hyperinsulinemia, increased appetite
Nervous system disorders: bradykinesia, cerebrovascular accident, convulsion, dizziness postural, drooling, dysarthria, dyskinesia, dystonia, hypertonia, lethargy, neuroleptic malignant syndrome, oromandibular dystonia, parkinsonism, psychomotor hyperactivity, syncope, tardive dyskinesia
Psychiatric disorders: restlessness
Reproductive system and breast disorders: amenorrhea, breast discharge, erectile dysfunction, galactorrhea, gynecomastia, menstrual disorder, menstruation delayed, menstruation irregular, sexual dysfunction
Vascular disorders: orthostatic hypotension
Discontinuations Due to Adverse Events
The percentages of subjects who discontinued due to adverse events in the four fixed-dose, double-blind, placebo-controlled trials were 5.0% and 7.8% in INVEGA® SUSTENNA®- and placebo-treated subjects, respectively.
Dose-Related Adverse Reactions
Based on the pooled data from the four fixed-dose, double-blind, placebo-controlled trials, among the adverse reactions that occurred at ≥ 2% incidence in the subjects treated with INVEGA® SUSTENNA®, only akathisia increased with dose. Hyperprolactinemia also exhibited a dose relationship, but did not occur at ≥ 2% incidence in INVEGA® SUSTENNA®-treated subjects from the four fixed-dose studies.
An examination of population subgroups in the double-blind placebo-controlled trials did not reveal any evidence of differences in safety on the basis of age, gender, or race alone; however, there were few subjects ≥ 65 years of age.
Extrapyramidal Symptoms (EPS)
Pooled data from the two double-blind, placebo-controlled, 13-week, fixed-dose trials provided information regarding treatment-emergent EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score (mean change from baseline or score at the end of trial) which broadly evaluates Parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score (mean change from baseline or score at the end of trial) which evaluates akathisia, (3) use of anticholinergic medications to treat emergent EPS, (4) the Abnormal Involuntary Movement Scale scores (mean change from baseline or scores at the end of trial) (Table 6), and (5) incidence of spontaneous reports of EPS (Table 7).
Table 6:Treatment-Emergent Extrapyramidal Symptoms (EPS)
Assessed by Incidence of Rating Scales and Use of Anticholinergic Medication
|Scale||Percentage of Subjects|
|Placebo (N=262)||INVEGA® SUSTENNA®|
|39 mg (N=130)||78 mg (N=223)||156 mg (N=228)|
|Use of Anticholinergic Medicationsd||12||10||12||11|
|a For Parkinsonism, percent of
subjects with Simpson-Angus Total score > 0.3 at endpoint (Total score
defined as total sum of items score divided by the number of items)
b For Akathisia, percent of subjects with Barnes Akathisia Rating Scale global score ≥ 2 at endpoint
c For Dyskinesia, percent of subjects with a score ≥ 3 on any of the first 7 items or a score ≥ 2 on two or more of any of the first 7 items of the Abnormal Involuntary Movement Scale at endpoint
d Percent of subjects who received anticholinergic medications to treat emergent EPS
Table 7: Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related
Adverse Events by MedDRA Preferred Term
|EPS Group||Percentage of Subjects|
|Placebo (N=262)||INVEGA® SUSTENNA®|
|39 mg (N=130)||78 mg (N=223)||156 mg (N=228)|
|Overall percentage of subjects with EPS-related adverse events||10||12||11||11|
|Parkinsonism group includes: Extrapyramidal
disorder, hypertonia, musculoskeletal stiffness, parkinsonism, drooling,
masked facies, muscle tightness, hypokinesia
Hyperkinesia group includes: Akathisia, restless legs syndrome, restlessness
Dyskinesia group includes: Dyskinesia, choreoathetosis, muscle twitching, myoclonus, tardive dyskinesia
Dystonia group includes: Dystonia, muscle spasms
The results across all phases of the maintenance trial exhibited comparable findings. In the 9-week, fixed-dose, double-blind, placebo-controlled trial, the proportions of Parkinsonism and akathisia assessed by incidence of rating scales were higher in the INVEGA® SUSTENNA® 156 mg group (18% and 11%, respectively) than in the INVEGA® SUSTENNA® 78 mg group (9% and 5%, respectively) and placebo group (7% and 4%, respectively).
In the 13-week study involving 234 mg initiation dosing, the incidence of any treatment-emergent EPS-related adverse events was similar to that of the placebo group (8%), but exhibited a dose-related pattern with 6%, 10%, and 11% in the INVEGA® SUSTENNA® 234/39 mg, 234/156 mg, and 234/234 mg groups, respectively. Hyperkinesia was the most frequent category of EPS-related adverse events in this study, and was reported at a similar rate between the placebo (4.9%) and INVEGA® SUSTENNA® 234/156 mg (4.8%) and 234/234 mg (5.5%) groups, but at a lower rate in the 234/39 mg group (1.3%).
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
Laboratory Test Abnormalities
In the pooled data from the two double-blind, placebo-controlled, 13-week, fixed-dose trials, a between-group comparison revealed no medically important differences between INVEGA® SUSTENNA® and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no differences between INVEGA® SUSTENNA® and placebo in the incidence of discontinuations due to changes in hematology, urinalysis, or serum chemistry, including mean changes from baseline in fasting glucose, insulin, c-peptide, triglyceride, HDL, LDL, and total cholesterol measurements. However, INVEGA® SUSTENNA® was associated with increases in serum prolactin [see WARNINGS AND PRECAUTIONS]. The results from the 13-week study involving 234 mg initiation dosing, the 9-week, fixed-dose, double-blind, placebo-controlled trial, and the double-blind phase of the maintenance trial exhibited comparable findings.
Pain Assessment and Local Injection Site Reactions
In the pooled data from the two 13-week, fixed-dose, double-blind, placebo-controlled trials, the mean intensity of injection pain reported by subjects using a visual analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from the first to the last injection (placebo: 10.9 to 9.8; 39 mg: 10.3 to 7.7; 78 mg: 10.0 to 9.2; 156 mg: 11.1 to 8.8). The results from both the 9-week, fixed-dose, double-blind, placebo-controlled trial and the double-blind phase of the maintenance trial exhibited comparable findings.
In the 13-week study involving 234 mg initiation dosing, occurrences of induration, redness, or swelling, as assessed by blinded study personnel, were infrequent, generally mild, decreased over time, and similar in incidence between the INVEGA® SUSTENNA® and placebo groups. Investigator ratings of injection pain were similar for the placebo and INVEGA® SUSTENNA® groups. Investigator evaluations of the injection site after the first injection for redness, swelling, induration, and pain were rated as absent for 69-100% of subjects in both the INVEGA® SUSTENNA® and placebo groups. At Day 92, investigators rated absence of redness, swelling, induration, and pain in 95-100% of subjects in both the INVEGA® SUSTENNA® and placebo groups.
Adverse Reactions Reported in Clinical Trials with Oral Paliperidone
The following is a list of additional adverse reactions that have been reported in clinical trials with oral paliperidone:
Cardiac disorders: bundle branch block left, sinus arrhythmia
Gastrointestinal disorders: abdominal pain, flatulence, small intestinal obstruction
General disorders and administration site conditions: edema, edema peripheral Immune system disorders: anaphylactic reaction
Infections and infestations: rhinitis
Psychiatric disorders: sleep disorder
Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, pneumonia aspiration
Skin and subcutaneous tissue disorders: rash papular
Vascular disorders: hypotension, ischemia
The following adverse reactions have been identified during postapproval use of paliperidone; because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: angioedema, priapism, swollen tongue, urinary incontinence, urinary retention.
Adverse Reactions Reported With Risperidone
Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with oral risperidone and risperidone long-acting injection can be found in the ADVERSE REACTIONS sections of the package inserts for those products.
Read the Invega Sustenna (paliperidone palmitate extended-release injectable suspension) Side Effects Center for a complete guide to possible side effects »
Since paliperidone palmitate is hydrolyzed to paliperidone [see CLINICAL PHARMACOLOGY], results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential.
Potential for INVEGA® SUSTENNA® to Affect Other Drugs
Given the primary CNS effects of paliperidone [see ADVERSE REACTIONS], INVEGA® SUSTENNA® should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists.
Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when INVEGA® SUSTENNA® is administered with other therapeutic agents that have this potential [see WARNINGS AND PRECAUTIONS].
Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.
Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivo data are available and the clinical relevance is unknown.
Pharmacokinetic interaction between INVEGA® SUSTENNA® and lithium is unlikely.
In a drug interaction study, co-administration of oral paliperidone extended-release tablets (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC24h and Cmax,ss) of valproate in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when oral paliperidone extended-release tablets 3-15 mg/day was added to their existing valproate treatment.
Potential for Other Drugs to Affect INVEGA® SUSTENNA®
Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. In vitro studies have shown that paliperidone is a P-gp substrate.
Co-administration of oral paliperidone extended release once daily with carbamazepine 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. A minor decrease in the amount of drug excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. On initiation of carbamazepine, the dose of INVEGA® SUSTENNA® should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of INVEGA® SUSTENNA® should be re-evaluated and decreased if necessary.
Paliperidone is metabolized to a limited extent by CYP2D6 [see CLINICAL PHARMACOLOGY]. In an interaction study in healthy subjects in which a single 3 mg dose of oral paliperidone extended release was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers. Higher doses of paroxetine have not been studied. The clinical relevance is unknown.
Co-administration of a single dose of an oral paliperidone extended-release 12 mg tablet with divalproex sodium extended-release tablets (two 500 mg tablets once daily at steady-state) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Although this interaction has not been studied with INVEGA® SUSTENNA®, a clinically significant interaction would not be expected between divalproex sodium and INVEGA® SUSTENNA® intramuscular injection.
Pharmacokinetic interaction between lithium and INVEGA® SUSTENNA® is unlikely.
Drug Abuse And Dependence
INVEGA® SUSTENNA® (paliperidone) is not a controlled substance.
Paliperidone has not been systematically studied in animals or humans for its potential for abuse.
Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.
Last reviewed on RxList: 10/6/2011
This monograph has been modified to include the generic and brand name in many instances.
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