"Feb. 22, 2011 -- The FDA has issued a safety announcement notifying health care professionals that it has updated the pregnancy section of drug labels for the entire class of antipsychotic medications.
Antipsychotic drugs are used to "...
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 reactions, 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]
- Orthostatic hypotension and syncope [see WARNINGS AND PRECAUTIONS]
- Leukopenia, neutropenia, and agranulocytosis [see WARNINGS AND PRECAUTIONS]
- Hyperprolactinemia [See WARNINGS AND PRECAUTIONS]
- Potential for cognitive and motor impairment [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNINGS AND PRECAUTIONS]
- Dysphagia [see WARNINGS AND PRECAUTIONS]
- Priapism [see WARNINGS AND PRECAUTIONS]
- Disruption of body temperature regulation [see WARNINGS AND PRECAUTIONS]
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 in subjects with schizophrenia were injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder. No occurrences of adverse events reached this threshold in the long-term double-blind, placebo-controlled study in subjects with schizoaffective disorder.
The data described in this section are derived from a clinical trial database consisting of a total of 3817 subjects (approximately 1705 patient-years exposure) 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 (median exposure 229 days during the initial 33-week open-label phase of this study, of whom 205 continued to receive INVEGA SUSTENNA® during the double-blind placebo-controlled phase of this study [median exposure 171 days]), 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 [deltoid-gluteal] 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.
The safety of INVEGA SUSTENNA® was also evaluated in a long-term study in adult subjects with schizoaffective disorder. A total of 667 subjects received INVEGA SUSTENNA® during the initial 25-week open-label period of this study (median exposure 147 days); 164 subjects continued to receive INVEGA SUSTENNA® during the 15-month double-blind placebo-controlled period of this study (median exposure 446 days). Adverse reactions that occurred more frequently in the INVEGA SUSTENNA® than the placebo group (a 2% difference or more between groups) were weight increased, nasopharyngitis, headache, hyperprolactinemia, and pyrexia.
Clinical Trials Experience
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.
Commonly Reported Adverse Reactions In Double-Blind, Placebo-Controlled Clinical Trials
Table 10 lists the adverse reactions reported in 2% or more of INVEGA SUSTENNA®-treated subjects and at a greater proportion than in the placebo group with schizophrenia in the four fixed-dose, double-blind, placebo-controlled trials.
Table 10: Incidence of Adverse Reactions in ≥
2% of INVEGA SUSTENNA®-Treated Subjects (and greater than Placebo) with
Schizophrenia in Four Fixed-Dose, Double-Blind, Placebo-Controlled Trials
|System Organ Class Adverse Event||Placeboa
|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|
|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”.
Other Adverse Reactions Observed During The Clinical Trial Evaluation Of INVEGA SUSTENNA®
The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, or 4) which were not considered to have significant clinical implications.
Ear and labyrinth disorders: vertigo
Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurred
Gastrointestinal disorders: constipation, dyspepsia, flatulence, salivary hypersecretion
Immune system disorders: hypersensitivity
Metabolism and nutrition disorders: decreased appetite, hyperinsulinemia, increased appetite
Nervous system disorders: bradykinesia, cerebrovascular accident, convulsion, dizziness postural, drooling, dysarthria, dyskinesia, dystonia, hypertonia, lethargy, oromandibular dystonia, parkinsonism, psychomotor hyperactivity, syncope
Psychiatric disorders: insomnia, restlessness
Reproductive system and breast disorders: amenorrhea, breast discharge, erectile dysfunction, galactorrhea, gynecomastia, menstrual disorder, menstruation delayed, menstruation irregular, sexual dysfunction
Discontinuations Due To Adverse Events
The percentage of subjects who discontinued due to adverse events in the four fixed-dose, double-blind, placebo-controlled schizophrenia trials were similar for INVEGA SUSTENNA®-and placebo-treated subjects.
The percentage of subjects who discontinued due to adverse events in the open-label period of the long-term study in subjects with schizoaffective disorder was 7.5%. During the double-blind, placebo-controlled period of that study, the percentages of subjects who discontinued due to adverse events were 5.5% and 1.8% 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 in subjects with schizophrenia, 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 in adult subjects with schizophrenia provided information regarding 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 EPS, (4) the Abnormal Involuntary Movement Scale scores (mean change from baseline or scores at the end of trial) (Table 11), and (5) incidence of spontaneous reports of EPS (Table 12).
Table 11: Extrapyramidal
Symptoms (EPS) Assessed by Incidence of Rating Scales and Use of
Anticholinergic Medication – Schizophrenia Studies in Adults
|Scale||Percentage of Subjects|
|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 EPS
Table 12: Extrapyramidal Symptoms (EPS)-Related Events
by MedDRA Preferred Term – Schizophrenia Studies in Adults
|EPS Group||Percentage of Subjects|
|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 in subjects with schizophrenia 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 in subjects with schizophrenia involving 234 mg initiation dosing, the incidence of any EPS 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%).
In the long-term study in subjects with schizoaffective disorder, the EPS during the 25-week open-label INVEGA SUSTENNA® treatment were hyperkinesia (12.3%), parkinsonism (8.7%), tremor (3.4%), dyskinesia (2.5%), and dystonia (2.1%). During the 15-month double-blind treatment, the incidence of any EPS was similar to that of the placebo group (8.5% and 7.1% respectively). The most commonly reported treatment-emergent EPS-related adverse events ( > 2%) in any treatment group in the double-blind phase of the study (INVEGA SUSTENNA® versus placebo) were hyperkinesia (3.7% vs. 2.9%), parkinsonism (3.0% vs. 1.8%), and tremor (1.2% vs. 2.4%).
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 in subjects with schizophrenia, 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, triglycerides, 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 in subjects with schizophrenia 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 in subjects with schizophrenia, 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 in subjects with schizophrenia, 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, 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
Reproductive system and breast disorders: breast engorgement, breast tenderness/breast pain, retrograde ejaculation
Skin and subcutaneous tissue disorders: rash papular
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 always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Reactions already listed in other parts of ADVERSE REACTIONS (6), or those considered in WARNINGS AND PRECAUTIONS (5) are not listed here.
Blood disorders: thrombotic thrombocytopenic purpura
Gastrointestinal disorders: ileus
Genitourinary disorders: urinary incontinence, urinary retention
Cases of anaphylactic reaction after injection with INVEGA SUSTENNA® have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral paliperidone.
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
Because 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
Paliperidone may antagonize the effect of levodopa and other dopamine agonists.
Because of its potential for inducing orthostatic hypotension, an additive effect may occur when INVEGA SUSTENNA® is administered with other therapeutic agents that have this potential [see WARNINGS AND PRECAUTIONS].
No dose adjustment is necessary for lithium when it is coadministered with INVEGA SUSTENNA®. Pharmacokinetic interaction between INVEGA SUSTENNA® and lithium is unlikely.
No dose adjustment is necessary for valproate when INVEGA SUSTENNA® is added to the therapy. Steady-state pharmacokinetics of valproate was not affected when patients were coadministered oral paliperidone extended-release tablets [see CLINICAL PHARMACOLOGY].
Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes [see CLINICAL PHARMACOLOGY].
Potential For Other Drugs To Affect INVEGA SUSTENNA®
On initiation of strong inducers of both CYP3A4 and P-gp (e.g., carbamazepine, rifampin, or St John's wort), it may be necessary to increase the dose of INVEGA SUSTENNA®. Conversely, on discontinuation of the strong inducer, it may be necessary to decrease the dose of INVEGA SUSTENNA® [see CLINICAL PHARMACOLOGY].
No dose adjustment is necessary for INVEGA SUSTENNA® when valproate is added to treatment [see CLINICAL PHARMACOLOGY].
No dose adjustment is necessary for INVEGA SUSTENNA® when it is coadministered with lithium. Pharmacokinetic interaction between INVEGA SUSTENNA® and lithium is unlikely.
In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism; however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone. Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or inducers of these isozymes 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.
Read the Invega Sustenna Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 4/13/2016
Additional Invega Sustenna Information
- Invega Sustenna Drug Interactions Center: paliperidone palmitate im
- Invega Sustenna Side Effects Center
- Invega Sustenna Overview including Precautions
- Invega Sustenna FDA Approved Prescribing Information including Dosage
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